Treatment Protocol Copyright © 2018 Kostoff Et Al

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PREVENTION AND REVERSAL OF ALZHEIMER'S DISEASE: TREATMENT PROTOCOL

Ronald N. Kostoffa, Alan L. Porterb, Henry. A. Buchtelc

(a) Research Affiliate, School of Public Policy, Georgia Institute of Technology, USA

(b) Professor Emeritus, School of Public Policy, Georgia Institute of Technology, USA

KEYWORDS

Alzheimer's Disease; Dementia; Text Mining; Literature-Based Discovery; Information Technology; Treatments

CITATION TO MONOGRAPH

Kostoff RN, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's disease: treatment protocol. Georgia Institute of Technology. 2018. PDF. https://smartech.gatech.edu/handle/1853/59311

Printed in the United States of America; First Printing, 2018

CREATIVE COMMONS LICENSE

This work can be copied and redistributed in any medium or format provided that credit is given to the original author. For more details on the CC BY license, see: http://creativecommons.org/licenses/by/4.0/

This work is licensed under a Creative Commons Attribution 4.0 International License.

DISCLAIMERS

The views in this monograph are solely those of the authors, and do not represent the views of the Georgia Institute of Technology or the University of Michigan.

This monograph is not intended as a substitute for the medical advice of physicians. The reader should regularly consult a physician in matters relating to his/her health and particularly with respect to any symptoms that may require diagnosis or medical attention. Any information in the monograph that the reader chooses to implement should be done under the strict guidance and supervision of a licensed health care practitioner.

ABSTRACT

This monograph presents a five-step treatment protocol to prevent and reverse Alzheimer's Disease (AD), based on the following systemic medical principle: at the present time, removal of cause is a necessary, but not necessarily sufficient, condition for restorative treatment to be effective. Implementation of the five-step AD treatment protocol is as follows:

FIVE-STEP TREATMENT PROTOCOL TO PREVENT AND REVERSE AD

Step 1: Obtain a detailed medical and habit/exposure history from the patient. Step 2: Administer written and clinical performance and behavioral tests to assess the severity of the higher-level symptoms and degradation of executive functions Step 3: Administer laboratory tests (blood, urine, imaging, etc) Step 4: Eliminate ongoing AD contributing factors Step 5: Implement AD treatments

This individually-tailored AD treatment protocol can be implemented with the data available in the biomedical literature presently. Additionally, while the methodology developed for this study was applied to comprehensive identification of diagnostics, contributing factors, and treatments for AD, it is general and applicable to any chronic disease that, like AD, has an associated substantial research literature. Thus, the protocol and methodology we have developed to prevent or reverse AD can be used to prevent or reverse any chronic disease (with the possible exceptions of individuals with strong genetic predispositions to the disease in question or who have suffered irreversible damage from the disease).

PREFACE Why did we write this monograph, what are its contents, what is new, who is the intended audience, and how will readers benefit from it?

Motivation

Non-communicable diseases have overtaken communicable diseases as the leading cause of global mortality. The impacts of non-communicable disease expansion on healthcare and associated costs have been dramatic. In the USA, these costs, and how to deal with them, have become a central political issue.

The mainstream medical approach emphasizes treatments over prevention for non-communicable diseases. Given the expansion of non-communicable diseases, the present treatment-dominant approach is insufficient. More balance between treatment and prevention is required. Eliminating the actionable foundational causes of these diseases is at least as important as applying new treatments, if there is to be any hope for full or partial reversal of non-communicable diseases.

Toward that end, the first author developed a systemic medical principle that would form the bedrock of a healing protocol for diseases: At the present time, removal of cause is a necessary, but not necessarily sufficient, condition for restorative treatment to be effective (where "removal" encompasses "neutralization" in those cases where actual "removal" is not possible, and "restoration" encompasses restoration of health to the organ/tissue as well as restoration of function). To prevent disease, the actionable foundational causes that underlie the disease symptoms need to be identified and removed as comprehensively, thoroughly, and rapidly as possible. To reverse disease (if irreversible damage has not been done and genetic predisposition to the disease in question is not a dominant factor), the preventive steps above need to be implemented as well. If the preventive protocols alone are inadequate for reversing disease progression, they need to be augmented by treatments. The first step in either disease prevention or reversal is to identify the full spectrum of potential foundational causes/contributing factors for the disease(s) of interest.

In April 2017, we published a monograph entitled Prevention and Reversal of Alzheimer's Disease, which focused on identifying and eliminating the foundational causes of AD. The approach and findings of the April 2017 monograph were based on two observations:

1) much of the information required to identify and eliminate these foundational causes of disease is in the biomedical literature already, but is not being extracted and exploited adequately;

2) the biomedical literatures for diseases such as Alzheimer's Disease (AD) are large, and extracting these AD foundational causes comprehensively from the literatures is a complex text mining problem.

A number of readers of the April 2017 monograph suggested that a similar analysis focused on identifying AD treatments would be valuable. Since the two observations on AD foundational causes in the previous paragraph are equally applicable to AD treatments, we decided to extend our approach to the identification of AD treatments. The present monograph identifies a wide spectrum of AD treatments and Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

the AD characteristics they impact, and integrates the identified AD treatments, characteristics, and causes to generate an individually-tailored treatment protocol.

Contents

The overall theme of the April 2017 monograph and the present monograph is preventing and reversing AD based on the systemic medical principle described above. The specific focus of the present monograph is identifying, categorizing, and analyzing the existing and potential AD treatments. This would complement the elimination of the foundational causes of AD on the path to AD reversal. Identification of these AD treatments is based on analysis of many thousands of biomedical journal articles from the premier biomedical literature.

Moreover, identifying both AD causes and treatments, in concert with identifying their impacts on specific AD 'characteristics' (measurable quantities such as biomarkers, behaviors, performance, etc), allows AD treatment protocols to be tailored to each person's unique condition. This monograph presents the comprehensive AD treatment protocol we have developed, and provides illustrative examples of how the AD treatment protocol would be implemented.

There is a lengthy section in the present monograph describing the text mining/information technology advances that allowed the existing and potential AD treatments to be extracted efficiently from the large numbers of journal articles retrieved from the premier biomedical literature, and the impacts of these treatments and causes to be extracted from the literature. Major advances were made in the text mining approach for extracting both existing and potential treatments from the biomedical literature (and their impacts), and these advances could be applied to identifying existing and potential foundational causes for any disease from the literature as well.

Novelty

While the individual existing and potential AD treatments identified in this monograph are "known", in the sense that they exist scattered throughout the published literature (although the potential AD treatments have not been previously associated with AD in the literature), they have not been integrated to the extent they are integrated in this monograph. The new "insights" in this monograph are:

1) the sheer number of existing and potential AD treatments;

2) the sheer number of potential combinations of AD treatments that have to be identified and researched (many of whose individual components have not yet been identified);

3) the sheer number of AD characteristics that can be used as diagnostics to identify causes and treatments for individual patients;

4) the approach for discovering treatments from the non-AD literature, which allows both the repurposing of drugs that have been used for treating other diseases and identification of non-drug substances that will correct the abnormal AD biomarker values;

Audience

There are three communities to whom this monograph is targeted. First is the "AD prevention and reversal" community. This encompasses the public health community, the AD research community, medical practitioners involved clinically with AD prevention and reversal, caretakers for AD patients, and individuals interested in what the present approach has to offer (they should heed the warnings in the Disclaimer). The AD treatment taxonomies and discussions in Chapter 2, and the treatment protocol in Chapter 3, should be of particular interest to this community.

Second is the text mining and information technology community. This would cover the full spectrum of researchers interested in extraction of useful information from any type of text, since the techniques developed in this monograph can be readily adapted to extracting useful information from myriad types of biomedical and non-biomedical text. The concepts, algorithms, and discussions in Chapter 6 should be of special interest to this community.

Third is the broader medical and health policy community. While the findings in the present monograph relate specifically to AD prevention and reversal, the methodology is applicable to prevention and reversal of any disease that has an associated substantial research literature.

Benefits

The interested reader of this monograph will gain a deeper understanding of the main treatments available for AD. The reader will also gain an understanding of the broad spectrum of rigorous actions required to prevent and/or reverse AD, when reading the present monograph in concert with the April 2017 monograph. Finally, and most importantly, the motivated reader will see that much of what is required to prevent and reverse AD may be available in the here and now (for those who have not suffered irreversible damage or have an overwhelming genetic predisposition for AD)!

Ronald N. Kostoff, 26 January 2018, Gainesville, VA

TABLE OF CONTENTS

TITLE

CITATION TO MONOGRAPH

CREATIVE COMMONS LICENSE

DISCLAIMERS

ABSTRACT

PREFACE

EXECUTIVE SUMMARY

ES-1. Overview

ES-2. Results

ES-3. AD Treatment Protocol

ES-4. Health Policy

ES-5. Near-Term Implementation of Findings

References - Executive Summary

Chapter 1 - INTRODUCTION

1A. Overview

1B. Present and Projected AD Incidence and Prevalence

1C. Mainstream Medical Approach

1D. Our Proposed Approach

1E. Remaining Structure of Monograph

References - Chapter 1

Chapter 2 - RESULTS AND DISCUSSION

2A. Overview

2B. AD Characteristics

2D. AD Causes

2E. Matrices of AD Treatments and AD Characteristics Impacted by Treatments

2F. Matrix of AD Causes vs AD Characteristics Impacted

2G. Under-representation of AD Causes, Treatments, and Characteristics

References - Chapter 2

Chapter 3 - TREATMENT PROTOCOL

3A. Overview

3B. AD Treatment Protocol in Chronological Order

References - Chapter 3

Chapter 4 - SUGGESTED FURTHER RESEARCH

4A. Identifying Additional AD Treatments

4B. Institute Clinical Trials Combining Removal of Potential AD Contributing Factors with Implementation of AD Treatments

4C. Identifying Additional AD Characteristics

4D. Develop Measurement Devices for Potential AD Contributing Factor Exposures

References - Chapter 4

Chapter 5 - BACKGROUND

5A. Overview

5B. AD Causes and Treatments Studies

5C. Text Mining to Identify Causes and Treatments for Disease

5D. Definitions

5D1. Foundational Cause Definition

5D2. Treatment Definition

5D3. Characteristics Definition

5D4. Linking Term Definition

5D6. AD Hypothesis Definition

References - Chapter 5

Chapter 6 - METHODOLOGY

6A. Overview and Strategy

6B. Methodology for Identifying Existing AD Treatments

6C. Identify Potential AD Treatments (Discovery)

6D. Identify Existing AD Characteristics

6E. Identify Potential AD Characteristics (Discovery)

6F. Identify Existing and Potential AD Contributing Factors

References - Chapter 6

Appendices - Chapter 6

Appendix 6-1 - AD Treatment Discovery Query

Chapter 7 - TABLES AND CONCORDANCE SOFTWARE

7A. Tables

7B. Use of Concordance Software for Identifying Existing AD Characteristics and Treatments

References - Chapter 7

Chapter 8 - CONCLUSIONS FROM APRIL 2017 MONOGRAPH

8A. Contributing Factors Identified

8B. Synergies/Combination Effects/Additional Contributing Factors

8C. Health Policy

References - Chapter 8

Chapter 9 - METHODOLOGY FROM APRIL 2017 MONOGRAPH

9A. Methodology for Identifying AD Foundational Causes

References - Chapter 9

Appendices - Chapter 9

Appendix 9A-2 - Unambiguous MeSH Terms - Streamlined Approach

Chapter 10 - REFERENCES

10A. Overview

10B. Executive Summary and Chapter References

--10B0. Executive Summary References

--10B1. Chapter 1 References

--10B2. Chapter 2 References

--10B3. Chapter 3 References

--10B4. Chapter 4 References

--10B5. Chapter 5 References

--10B6. Chapter 6 References

--10B7. Chapter 7 References

--10B8. Chapter 8 References

--10B9. Chapter 9 References

10C. AD Treatment Bibliography

ACKNOWLEDGEMENTS

ABOUT THE AUTHORS

EXECUTIVE SUMMARY

ES-1. Overview

Recent clinical results have shown that reversal of cognitive decline in patients with early Alzheimer's Disease (AD) or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), is obtainable today [1, 2, 3, 4]. These results were generated by: eliminating a modest number of actionable foundational causes (e.g., poor diet, lack of exercise, use of recreational drugs, etc.) in selected patients; increasing health-promoting practices (e.g., adequate sleep, adequate exercise, stress-reduction practices, etc.); and, in some cases, providing myriad supplements to bring selected metabolic parameters into targeted ranges [1, 2, 3].

These approaches are founded on the assumptions that AD/dementia symptoms are driven mainly by external factors, and can be prevented/reversed by elimination of these external factors (excluding those cases where genetic predispositions are overwhelming or irreversible damage has been done), possibly supplemented by other therapies. The effectiveness of these approaches will be limited by the comprehensiveness of external factors that have been identified, addressed, and eliminated, and the breadth of treatments (in the broader sense) that can be applied effectively in parallel with the elimination of the adverse external factors.

The goal of the present monograph is to overcome these limitations by identifying as many of these adverse external factors and supportive treatments as possible. Towards that end, we have developed a novel information technology approach that selects those biomedical literature articles identifying existing and potential AD/dementia foundational contributing factors, existing and potential AD treatments, and existing AD characteristics impacted by both the AD foundational causes and AD treatments. These findings are then integrated operationally based on the following systemic medical principle: At the present time, removal of cause is a necessary, but not necessarily sufficient, condition for restorative treatment to be effective.

To prevent AD (or any chronic disease), the foundational causes that underlie the AD symptoms need to be identified and removed as comprehensively, thoroughly, and rapidly as possible. To reverse AD (if irreversible damage has not been done and strong genetic predisposition to AD is not a dominant factor), the preventive steps above need to be implemented, and treatments to reverse AD progression need to be applied.

We have identified a wide spectrum of AD foundational contributing factors in an April 2017 monograph [5]. Combining the results from reference [5] with the wide spectrum of AD treatments identified in the present study and the AD 'characteristics' impacted by the AD causes and AD treatments also identified in the present study allows development of an AD treatment protocol that can be tailored to individual patients. This AD treatment protocol (based on the systemic medical principal described above) is available with the information at our disposal today! Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

ES-2. Results

ACCESSING FIGURES/SUPPLEMENTARY DATA REFERENCED IN THIS MONOGRAPH

This short note describes how to access those figures that are large Excel spreadsheets (and could not be contained within the monograph proper), and supplementary material too large for the monograph (detailed queries referenced in Chapter 9, and bibliography referenced in Chapter 10).

The present monograph is contained in a file located on a Web page with URL https://smartech.gatech.edu/handle/1853/59311. There are four files in the left column of this Web page listed under the heading View/Open. MONOGRAPH_FINAL.pdf contains the monograph narrative; FIGURES_FINAL.xlsx contains the figures from the monograph in Excel spreadsheet format; SUPPLEMENTARY_FINAL.pdf contains supplementary bibliography and queries; and README.pdf is the ReadMe file. The two data files are referenced in the monograph as either "(see file FIGURES_FINAL.xlsx)" or "(see file SUPPLEMENTARY_FINAL.pdf)", as appropriate.

Note: Most of the figures in this monograph are based on Excel spreadsheets. A truncated version of each of the Excel spreadsheet-based figures is contained within the present monograph, while the full Excel spreadsheet is accessible through the attached Excel file FIGURES_FINAL.xlsx. The figure numbers are on the tabs of the Excel spreadsheets in the Excel workbook.

ES-2A. AD Treatments

ES-2A1. Listing of AD treatments

We have applied our novel methodology to the Medline database, and identified ~600-700 AD treatments (the exact number depending on how these treatments are aggregated). These AD treatments are listed in Table 2-6.

Structure of Table 2-6

There are two columns in Table 2-6. The righthand column contains the name of the treatment, and the lefthand column contains the number of records in which the treatment name is found. The treatments listed are a combination of treatment categories (e.g., cholinesterase inhibitor) and specific treatments (e.g., Memantine). As the record frequency decreases, the concentration of specific treatment names increases.

The number of AD treatments identified represents an order of magnitude more AD treatments than we have seen in any AD/dementia article in the published literature. As emphasized in the text, far more AD treatments could be identified in an expanded study.

ES-2A2. Categorization of AD treatments

We have categorized the ~600-700 AD treatments using two different approaches: text clustering and factor analysis. Each approach provides insight and perspective to the types and categories of AD treatments identified.

ES-2A2a. Text clustering categorization of AD treatments

The high-level AD treatment categories from the text clustering approach are presented in Figure 2-3.

Structure of Figure 2-3

There are three columns in Figure 2-3. The lefthand column contains two category headings/themes, and reflects the top-level categorization of the treatment taxonomy. The center column contains four category headings/themes, and reflects the first-level categorization. The righthand column contains eight category headings/themes, and reflects the second-level categorization. The righthand column also contains the number of records resulting from the text clustering, in parentheses.

At the highest level of AD treatment categorization, two main themes emerge:

 Laboratory and Clinical Research, and  Patient Management.

 Patient Management can be sub-divided further into o patient dementia prevention and treatment, and o patient caretaking drug and non-drug therapies.

ES-2A2b. Factor analysis categorization of AD treatments

The AD treatment categories from the factor analysis approach are presented in Figure 2-2 of the attached Excel workbook (see file FIGURES_FINAL.xlsx).

Structure of Figure 2-2

The lefthand column contains each factor theme and the significant phrases under each theme. The theme of each factor is shown in red, and is followed by the members of that factor. The theme of each factor is assigned by the analyst, and may or may not be an actual phrase in the database.

Thus, cell A7, the theme of Factor 1, is Anti-Psychotic Agents. The members of Factor 1 are a mix of general anti-psychotic agents (e.g., antipsychotic agents [which coincides with the theme of Factor 1, and is an actual phrase in the database], anticholinergic medications) and specific antipsychotic agents (e.g., olanzapine, risperidone, quetiapine).

The numbers highlighted in green in row 6 are the 35 factor numbers (#16, 17, 22 each had two distinct themes, and each theme was considered as a separate factor). The numbers in the cells for each factor are the factor loadings, which represent the influence of each member on determining the factor theme. The code for the shading of these numerical cells is shown at the top of the matrix.

These AD treatment category headings from Figure 2-2 are summarized as follows:

AD TREATMENT CATEGORIES - FACTOR ANALYSIS Factor 1. Anti-Psychotic Agents Factor 17b. Plant-Based Supplements Factor 2. Acetylcholinesterase Inhibitors - NMDA Factor 18. 5-HT5a Receptor Antagonists Receptor Antagonists (Main Theme: FDA- Approved Drugs for AD) Factor 3. Statins - HMG-CoA Reductase Inhibitors Factor 19. Flavonoids Factor 4. Nutrient Supplementation Factor 20. Immunotherapy Factor 5. Plant Components in Chinese Medicine Factor 21. Uncaria Rhynchophylla Alkaloids Factor 6. M1-Selective Muscarinic Agonists Factor 22a. Anti-Hypertension Drugs Factor 7. Spices Emphasizing Curcumin Factor 22b. Garlic Components Factor 8. Caloric Restriction Factor 23. Xanthoceras Sorbifolio Extracts Factor 9. Polyphenols Factor 24. Anti-Depression Treatments Factor 10. Multi-Target Therapies Emphazing Factor 25. Medicinal Plants Sensory Stimulation Factor 11. Retinoic Acid Receptor Agonists Factor 26. Stem Cell Transplantation Factor 12. Antiepileptics/Anticonvulsants Factor 27. Monoamine Oxidase B Inhibitors Factor 13. Retinoid X Receptor Agonists Factor 28. Plant-Based Anti-Oxidants Factor 14. Anti-Diabetic Therapies Factor 29. Aged Garlic Constituents Factor 15. Gamma-Secretase Modulators Factor 30. Nootropic Agents Factor 16a. Omega-3 Fatty Acid Supplementation Factor 31. Neurosteroids Factor 16b. Multi-Nutrient Diets Factor 32. Anti-Abeta Antibodies Factor 17a. Allium-Based Supplements

The number of AD treatment categories identified was limited by the number of factors selected, representing a balance between comprehensiveness and excessive detail. The treatment categories shown above range from high-technology to low-technology. The high technology surgeries and drugs tend to have adverse side effects, and therefore higher risk. The low technology dietary and sensory stimulation approaches tend to have far fewer adverse side effects, and therefore lower risk.

Many of the identified AD treatments are not shown in Figure 2-2. Either they were not related strongly to other AD treatments in the same category, or they were in a completely different category with very few or zero other members.

ES-2b. AD Characteristics

Using our novel methodology, we have identified ~250 AD characteristics (the exact number depending on how these AD characteristics are aggregated), and they are listed in Table 2-1.

Structure of Table 2-1

Table 2-1 is a list of the AD characteristics, arranged in decreasing order of the number of records in which they appeared. On average, those AD characteristics at the beginning of the list (appearance in large numbers of records) are more general, and those AD characteristics near the end of the list (appearance in small numbers of records) are much more specific.

The number of AD characteristics identified in Table 2-1 represents an order of magnitude more AD characteristics than we have seen in any AD/dementia article in the published literature. As emphasized in the text, far more AD characteristics could be identified in an expanded study.

We have categorized the ~250 AD characteristics using two different approaches: manual taxonomy construction and factor analysis. The higher-level AD characteristics categories from the manual taxonomy are shown in Table 2-3.

Structure of Table 2-3

This table lists the myriad types of potential AD treatment benefits/AD characteristics. They range from broad benefits (e.g., reverse dementia, reverse AD) to behavior benefits (e.g., reduce depression, reduce anxiety) to specific benefits measurable by laboratory tests (e.g., inhibit Tau phosphorylation, improve metal homeostasis). The higher level categories of potential AD treatment benefits are summarized after the next paragraph.

More detailed AD characteristics categories from the manual taxonomy are shown in Table 2-4.

Structure of Table 2-4

This table is an expansion of Table 2-3, and presents a more detailed description of the potential benefits from AD treatments. For example, while category number 1.15 has the general theme of 'improve synapse plasticity', the sub-categories listed under category number 1.15 offer more insight as to what is meant operationally by 'improve synapse plasticity' (e.g., 1.1502 - reduce SREBP2, 1.1506 - increase CMRglc, 1.1507 - increase MAP1B). Many of the specific benefits identified were derived with search terms that used the treatment-related verbs (linking terms) shown in the table (increase, restore, improve, regenerate, rescue, ameliorate, etc.) to identify AD treatments and their associated benefits.

The highest level AD characteristics categories in the manual taxonomy (from the perspective of AD treatment benefits) can be summarized as follows:

AD CHARACTERISTICS CATEGORIES - MANUAL TAXONOMY 1. Neurotransmission modulation --9.3 Growth factor restoration 2. Tau modulation --9.4 Metal homeostasis improvement 3. Abeta modulation --9.5 Epigenetic modification 4. Insulin and energy metabolism improvement --9.6 Caspase inhibition 5. Oxidative stress reduction --9.7 Nitric oxide synthase modulation 6. Mitochondrial function improvement --9.8 Combinatorial improvements 7. Modulation of cellular calcium homeostasis 10. Cognition/Memory/Learning improvement 8. Inflammation alleviation 11. Behavior improvement 9. Others 12. Prevent and reverse neuropathology --9.1 Hormone dyshomeostasis improvement 13. Prevent and reverse AD/dementia --9.2 Lipid dyshomeostasis improvement

The AD characteristics categories from the factor analysis approach are presented in Figure 2-1 of the attached Excel spreadsheet (see file FIGURES_FINAL.xlsx).

Structure of Figure 2-1

Thus, cell B24, the theme of Factor 2, is Epigenetic Modification. The members of Factor 2 are specific AD characteristic changes that contribute to epigenetic modification (HDAC inhibition, histone acetylation increase, DNA methylation increase, tubulin restoration, SIRT1 increase, histamine increase).

The numbers highlighted in green in row 6 are the 23 factor numbers (20 factors, with three of the factors [#1, 6, 20] having two distinct themes). The numbers in the cells for each factor are the factor loadings, which represent the influence of each member on determining the factor theme. The code for the shading of these numerical cells is shown at the top of the matrix.

These AD characteristics category headings are summarized as follows:

AD CHARACTERISTICS CATEGORIES - FACTOR ANALYSIS Factor 1a. Mood/Behavior Improvement Factor 11. Insulin Signaling Restoration Factor 1b. AD Prevention through Immunotherapy Factor 12. Neuroinflammation Reduction and Memory Enhancement Factor 2. Epigenetic Modification Factor 13. Hormone Restoration Factor 3. Neuroinflammation Reduction Factor 14. Oxidative Stress Reduction Factor 4. Tau Pathology Reduction Factor 15. Nonamyloidogenic Enhancement Factor 5. Apoptosis Inhibition Factor 16. Neurogenesis Stimulation Factor 6a. Cognitive Performance Improvement Factor 17. Abeta Enzymatic Degradation Factor 6b. Abeta Reduction through Factor 18. Neurogenesis Increase Immunotherapy Factor 7. Enhance Amyloid Clearance Factor 19. Reduce Synaptic Deficits Factor 8. Nutrient Deficiency Amelioration Factor 20a. Plasticity Improvement Factor 9. Metabolic Homeostasis Regulation Factor 20b. Blood-Brain Barrier Enhancement through Adipokines Factor 10. Excitotoxicity Reduction

While there is some overlap between the two taxonomies, there are a number of differences due to the perspectives of the different approaches. The number of AD treatment categories identified using the factor analysis approach was limited by the number of factors selected. The number of factors presented here represents a balance between comprehensiveness and excessive detail.

ES-2c. AD Contributing Factors

We have applied our methodology to the Medline AD database, and identified ~400-600 foundational AD contributing factors (the exact number depending on how these AD contributing factors are aggregated) [5]. These AD contributing factors are listed in Table 2-7C.

Structure of Table 2-7C

There are three columns in Table 2-7C. The lefthand column alphanumeric reflects the category to which the cause/contributing factor has been assigned. The middle column is the name of the cause/contributing factor. The righthand column reflects the impact(s) of the cause/contributing factor. These impacts are an earlier and much truncated version of the expansive AD characteristics developed for the present study.

The number of AD contributing factors identified represents an order of magnitude more AD contributing factors than we have seen in any AD/dementia article in the published literature. As emphasized in the text, far more AD contributing factors could be identified in an expanded study. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

We have categorized the ~400-600 AD contributing factors using two different manual assignment approaches. The first approach produced a detailed taxonomy based on type of AD contributing factor, and is shown in Table 2-7A.

Structure of Table 2-7A

There are two columns in Table 2-7A. The lefthand column alphanumeric reflects the cause/contributing factor category theme. The righthand column is the name of the cause/contributing factor category. Table 2-7A is the framework for the more detailed Table 2-7C.

It has five top-level categories:

 Lifestyle  Iatrogenic  Biotoxic Agents  Occupational/Environmental Exposures  Psychosocial/Socioeconomic

A sixth top-level category, Genetics, is also shown in Table 2-7A. However, no specific category members (AD contributing factors) were included. The thrust of the study [5] was to identify AD foundational causes (tangible causes which are actionable), and we concluded that the genetic problems were not actionable with present-day technology.

The second manual assignment approach identified the latent categories underlying the detailed categories of the first approach. The top-level latent categories are:

 Direct Technology  Indirect Technology  Inadequate Regulation  Individual Choice  Poverty

A discussion of these categories is contained in section 8A1, Latent Variables. The Direct Technology and Inadequate Regulation categories are summarized here because of their importance.

DIRECT TECHNOLOGY

Direct Technology (the degree of direct impact of technology on foundational causes) plays a strong role in Lifestyle, Iatrogenic, and Occupational/ Environmental foundational causes. In addition, through its impact on the immune and other critical systems, modern technology may play a role in whether exposure to bacteria and viruses results in symptoms and diseases. Modern technology impacts the growing, processing, and preparation of foods, and many of the adverse effects identified in reference [6] can be traced back to the use (mis-use) of technology in the food cycle. The Iatrogenic adverse effects of modern technology result mainly from the high-technology-based drugs, surgery, diagnostics, and therapy that characterize much of modern medicine today. The Occupational/Environmental adverse effects result mainly from the employment of modern technology in commerce, the environment, and the workplace.

INADEQUATE REGULATION

Inadequate Regulation is coupled strongly to the introduction of high technology in all aspects of life. Many of the problems with foods derive from relatively unregulated chemicals, materials, and other contaminants entering the food supply during agriculture and animal husbandry. Many of the Occupational/Environmental exposures arise from relatively unregulated harmful substances entering the workplace and the environment. This is especially true in less developed countries, but occurs in more developed countries as well. Many of the Iatrogenic problems could be traced to drugs, diagnostics, therapies, and other procedures entering practice with insufficient front-end long-term testing (especially testing on humans), and inadequate evaluation of side-effects.

Two major aspects of Inadequate Regulation revolve around insufficient safety: inadequate safety data gathering, and inadequate safety testing. Much of the adverse impact data gathering tends to be from passive surveillance systems, where response rates can be an order of magnitude (or more) less than real- world incidence rates. Pre-market testing, in many cases, suffers from inadequate sample sizes, unrepresentative samples, insufficient long-term testing, and insufficient combination testing to identify potential synergistic effects. Insufficient long-term testing on humans is particularly troubling, since many serious diseases such as AD may have decadal latency periods from specific toxic stimuli. Transgenerational effects could not be excluded without appropriate long-term testing [7].

Additionally, results from animal testing (which could be long-term from the perspective of many short- lived animals used in testing) do not necessarily translate to human outcomes. First, there is a species difference, and impacts on one species do not necessarily carry over to the same types of impacts on another species. Second, laboratory animals are raised in relatively pristine environments, and subjected to a very few toxic substances during studies on disease contributing factors. Conversely, humans experience many of the contributing factors identified in reference [6], and the synergy from these combinations would not have been replicated in the laboratory animal testing.

ES-3. AD Treatment Protocol

We have integrated the AD contributing factors, treatments, and characteristics to produce a comprehensive five-step AD treatment protocol. A complete description of the AD treatment protocol is contained in Chapter 3, and a summary of the AD treatment protocol is contained in section 3B6. It is structured to adhere closely to our underlying systemic medical principle: at the present time, removal of cause is a necessary, but not necessarily sufficient, condition for restorative treatment to be effective.

FIVE-STEP TREATMENT PROTOCOL TO PREVENT AND REVERSE AD

Step 1: Obtain a detailed medical and habit/exposure history from the patient. Step 2: Administer written and clinical performance and behavioral tests to assess the severity of the higher-level symptoms and degradation of executive functions Step 3: Administer laboratory tests (blood, urine, imaging, etc.) Step 4: Eliminate ongoing AD contributing factors Step 5: Implement AD treatments

The five step treatment protocol to prevent and reverse AD will now be described in more detail.

Step 1. The first step in the protocol is to obtain a detailed medical and habit/exposure history from the AD patient. The patient would be provided a detailed questionnaire focusing mainly on practices and exposures that are potential AD contributing factors. The contributing factor component of the questionnaire would be based on Table 2-7C, or, preferably, on a similar, but even more extensive, table derived from an expanded study.

Step 2. The second step in the protocol is to administer written and clinical performance and behavioral tests to assess the severity of the higher-level symptoms and degradation of executive functions. This would include tests for memory, learning, cognition, etc., and for apathy, depression, anxiety, aggression, agitation, etc. The latter group of mood-related tests would have some overlap with the medical history on the initial questionnaire.

Step 3. The third step in the protocol is to administer laboratory tests (blood, urine, imaging, etc.). Any abnormalities shown by these tests would help prioritize the AD contributing factors to be eliminated and AD treatments to be implemented. Table 3-1 contains the approximately seventy AD characteristics selected for initial laboratory tests in the streamlined AD protocol.

Structure of Table 3-1

The AD characteristics are listed in alphabetical order.

These ~seventy AD characteristics were culled from the ~250 AD characteristics identified in the course of the study, in order to reduce the number of diagnostics to a level acceptable to both the health practitioner and the patient. These ~seventy AD characteristics reflect the ~twenty AD pathological themes (Table 3-2) derived from the myriad AD Hypotheses and the major themes from the AD characteristics factor matrix (Figure 2-1 in attached Excel workbook).

Structure of Table 3-2

These AD pathological themes are listed in alphabetical order.

Based on the laboratory test results, the health practitioner could require further tests to gain detailed information on problematic areas.

Step 4. The fourth step in the protocol is to eliminate ongoing AD contributing factors. For reasons explained in section 2D, a strongly reduced version of the Table 2-7C contributing factors/causes is used in the present study for matrixing purposes. We extracted a few of the causes for each of the five major categories defined in Table 2-7C, and aggregated very detailed members of a class into a broader category, in some cases (e.g., pesticides). Figure 3-1 is a matrix of these fifty AD contributing factors/causes vs the AD characteristics impacted by these AD contributing factors/causes.

Structure of Figure 3-1

Figure 3-1 contains two matrices of AD causes/contributing factors vs their impacts on the AD characteristics. The upper matrix contains the raw data and the lower matrix contains data normalized by the inclusion index.

Column A in both matrices contains the number of records in which the AD cause/contributing factor is found. Row 8 reflects the impact of the AD cause/contributing factor on the AD characteristic in the upper matrix, and row 68 reflects the same quantity for the lower matrix. Cell J8, for example, signifies an increase in ROS (reactive oxygen species).

The numerical entry in cell i,j of the upper matrix reflects the number of records containing both the AD cause/contributing factor i and the AD characteristic impact j. As an example, the number 42 in cell J15 means there were 42 records that linked a high AGEs (advanced glycation end products) diet with an increase in ROS. The parallel cell in the normalized matrix, cell J75, contains the number 0.105793. This means that ~10% of the time that 'high AGEs diet' appeared in the database, it was associated with an increase in ROS.

The color coding used to delineate the significance of each numerical cell entry is defined at the top of each matrix.

As Figure 3-1 shows, each AD contributing factor typically impacts many AD characteristics, and each AD characteristic is typically impacted by many AD contributing factors. Thus, in the general case, AD characteristic values abnormalities in the lab tests will not be uniquely related to specific AD contributing factors. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

To circumvent this problem, we propose a combined 'direct-identification' and 'reverse- engineering' approach that has the virtue of simplicity. The 'direct-identification' component consists of eliminating the AD contributing factors listed on the initial medical/exposure questionnaire. The 'reverse- engineering' component

1) identifies all the AD characteristics with abnormal laboratory test values,

2) identifies the number of these abnormal AD characteristics impacted by each AD contributing factor, then

3) prioritizes the AD contributing factors for elimination according to the number of AD characteristics impacted by each AD contributing factor.

See Table 3-1A and the surrounding narrative for an illustrative example of how this prioritization, and further sub-prioritizations, would operate.

Structure of Table 3-1A

The lefthand column in Table 3-1A contains the truncated list of fifty AD contributing factors, and the righthand column contains the number of AD characteristics (from a total of the five following AD characteristics assumed to have abnormal measured values and arbitrarily selected for illustrative purposes: high AGEs, low ATP, low BDNF, high Homocysteine, high IL-6) impacted by each of the fifty AD contributing factors listed. Thus, a 'high AGEs diet' would increase the abnormal values of all five of these AD characteristics selected, while 'recreational drugs' would increase the abnormal values of only one of these five AD characteristics selected.

Two points of note in this example. First, AGEs is both an AD contributing factor and an AD characteristic. Some foods are high in AGEs, and AGEs can be increased further in the diet through high-temperature cooking. AGEs are also amenable to measurement, and can be used for diagnostic purposes.

Second, the numbers of AD characteristics impacted by the AD contributing factors are based on what is reported in the literature. Absence of evidence (of an impact of an AD contributing factor on an AD characteristic) is not evidence of absence. The contributing factor-characteristic link may not have been the subject of research, or it may have been suppressed for publication through myriad pathways.

The recommended prioritization above is based on numbers of AD characteristics impacted by each AD contributing factor. However, it does not distinguish between one record describing the impact (for a particular AD contributing factor) or ten records describing the impact; distinguish among the strengths of impact described in different records; or, weight the AD characteristics by relative importance. This additional information could be used by the healthcare practitioner to modify the prioritization illustrated above.

In addition, there are some cases where 'reverse-engineering' may be more straightforward. For example, high serum or urine readings of heavy metals (such as cadmium or mercury) would identify specific targets for elimination. These would be the exception rather than the rule, in terms of specificity.

The above prioritization approach would serve as a proxy for the more comprehensive elimination of all 'low-hanging fruit' recommended in reference [5]. To the degree possible, the patient should strive to eliminate as many of these 'low-hanging fruit' AD contributing factors as possible. The combination of lack of knowledge about harmful exposures (limiting what can be answered on the initial medical/exposure questionnaire) and incompleteness of AD characteristics measured will result in AD contributing factors not being identified through the complete testing/evaluation process. Eliminating as many of the 'low-hanging fruit' AD contributing factors as possible will compensate partially for this lack of knowledge. Many of these items are under the patient's/caretaker's control, and can be readily eliminated. This 'low-hanging fruit' recommendation is repeated here, because of its importance and centrality to the effectiveness of the overall protocol.

LOW-HANGING FRUIT RECOMMENDATIONS

1) curb the dietary excesses identified and remove the dietary deficiencies identified in Table 2-7C, the medical questionnaire, and the lab tests; 2) eliminate food additives to the extent knowable and possible, including those dietary excesses that derive from food additives (excessive fat, sugar, salt); 3) reverse the sedentary behavior patterns identified; 4) remove the foundational impediments to better sleep; 5) eliminate the use of 'recreational' drugs, including smoking and excessive alcohol; 6) eliminate the use of medicinal drugs shown to be potential AD contributing factors from Table 2-7C, unless these drugs are absolutely necessary; 7) eliminate any elective (not absolutely necessary) diagnostic or surgical procedures that involve inhalational anesthetics or high doses of ionizing radiation in head region (e.g., CT scans); 8) minimize exposures to some hydrocarbons, such as diesel exhaust, kerosene, polycyclic aromatic hydrocarbons (including those found in smoke), etc; 9) minimize exposures to some solvents, especially petroleum-based solvents, chlorinated solvents, and organic solvents; 10) minimize inhalation and ingestion exposures to pesticides, herbicides, insecticides, and fungicides; 11) minimize exposures to heavy metals in food, in water, and in the air; 12) minimize exposure to particulates, especially air pollution; 13) minimize exposures to ionizing radiation, non-ionizing non-visible radiation (such as cell phones, cell towers, WiFi, smart meters, etc.), non-ionizing visible radiation (such as excessive UV radiation), sound radiation (high noise levels), temperature fields (such as cold water hypothermia/stress, heat shock/hyperthermia), and force fields (high impacts, especially to head region); 14) minimize chronic stress (mental/emotional/psychological), increasing mental activities; 15) minimize social isolation.

There is an implicit assumption (in some/many of these AD contributing factor elimination recommendations) of a treatment implementation. For example, elimination of a high-fat diet (AD contributing factor) implies adoption of a low-fat diet (AD treatment). Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Step 5. The fifth step in the protocol is to implement AD treatments. Because of risk associated with implementation of many AD treatments in parallel, and the lack of knowledge of how overall risk increases because of treatment combination synergies, it is highly recommended that the lowest-risk treatments be implemented initially. Higher-risk treatments can always be implemented at a later date, if the combination of AD contributing factor elimination and initial low-risk AD treatments is not achieving the desired results.

Even among low-risk AD treatments, some prioritization may be possible. The approach recommended parallels that for eliminating AD contributing factors in Step 4. The approach is a hybrid of 'direct-identification' and 'reverse-engineering'. The 'direct-identification' component consists of identifying AD contributing factors from the medical/exposure questionnaire. Where applicable, treatments that are positive behaviors/habits would be substituted for the negative AD contributing factors under the patient's control. Thus, if the patient is eating a high AGEs diet, the 'treatment' would consist of substituting a low AGEs diet. If the patient is participating in minimal intellectually challenging activities, he/she would be encouraged to participate in more intellectually challenging activities.

The 'reverse-engineering' component' would be based on the laboratory tests. In parallel with the approach in Step 4, AD treatments would be prioritized based on the number of abnormal AD characteristics they would impact. The caveats of Step 4 about relying on numbers of characteristics impacted would apply here as well.

The categories of AD treatments identified in the present monograph include the following:

CATEGORIES OF AD TREATMENTS  drugs  talk/behavior therapies  exercise  touch therapies  diet (including herbs/spices/plant extracts)  social interaction enhancement therapies  vitamins/supplements  enhanced leisure/educational activities  sleep  electromagnetic therapies  stress reduction therapies  memory/cognitive training/environmental enrichment

Most of the AD treatment research reported in the biomedical literature is in the drugs category (e.g., cholinesterase inhibitors, donepezil, antioxidants, immunotherapy, antiinflammatory agents, NMDA receptor antagonists, memantine, antipsychotic agents, rivastigmine, galantamine, anti-Abeta therapy, antidepressant, tacrine, secretase inhibitors, psychotropic agents, NSAIDs, statin therapy, etc.). Since the drugs tend to be in the higher-risk treatment category, they are not included in our recommendations for initial low-risk AD treatments. They can be implemented at a later date, if the initial lower-risk AD treatments do not produce the results desired.

The specific AD treatments employed would be selected based on the medical questionnaire results, the neuropsychology evaluation, and the lab tests results.

Some of the following AD treatments would (in practice) be substitutions for the AD contributing factors eliminated; others would be new activities implemented.

RECOMMENDED INITIAL LOW-RISK TREATMENTS (partial list)

 Exercise (such as aerobic exercise, walking, resistance training, treadmill, calisthenics, stretching, balancing)  Sleep Improvement (such as quiet environment, minimal light, minimal food before bedtime, maintain regular sleep schedule)  Stress Reduction (such as tai chi, yoga, massage, aromatherapy, art therapy, music therapy, doll therapy, accupuncture, accupressure, sensory stimulation, physiotherapy, animal-assisted therapy, horticultural therapy, meditation)  Talk/Behavior Therapies (such as psychotherapy, occupational therapy, reminiscence therapy, milieu therapy, validation therapy)  Social Interaction Therapies (group therapy, dance therapy, reality orientation  Enhanced Leisure/Educational Activities/ Memory Training/Cognitive Training/Environmental Enrichment (take college classes, mentor young students, learn new skills [art, music], play complex games)  Diet: choose foods high in o polyphenols (such as cloves, star anise, capers, curry powder, ginger, cinnamon, peppermint, oregano, sage, rosemary, thyme, basil, cocoa, tea, red wine, chokeberries, elderberries, blueberries, plums, cherries, black currants, blackberries, strawberries, raspberries, grapes, flaxseeds, celery seeds, chestnuts, hazelnuts, pecans, almonds, walnuts, olives, artichokes, chicory, red onion, spinach, broccoli, apples, pomegranates, peaches, apricots, olive oil, canola oil), especially . flavonoids (such as apples, blueberries, strawberries, red grapes, cabbage, broccoli, onions, capers, dark chocolate, cocoa, tea, red wine), isoflavones/genistein (such as soybeans, natto, tempeh, tofu, miso), and . anthocyanins (such as blackberries, black currants, blueberries, strawberries, cranberries, eggplant, cherries, prunes, raisins, and the darker versions of raspberries, cabbage, plums, radish, grapes, plums, apples, beans, beets, cabbage, onions, pears, wines) o DHA/omega-3 fatty acid (such as salmon, herring, mackerel, anchovy, sardine, trout, shark, swordfish, mussel, sea bass, pollock, whiting, flounder, sole, lobster, halibut, carp, oyster, crab, mullet, tuna, perch, snapper, shrimp, octopus) o Vitamins B12/B6/Folate (such as meat [beef liver, lamb, beef], fish [sardines, mackerel, salmon], dairy [feta cheese, cottage cheese], eggs, legumes [chickpeas, fermented soy, pinto beans, lentils], fruit [banana, avocado], vegetables [spinach, parsley, broccoli, beets, turnip, asparagus,]) o Vitamin C (such as fruits [guavas, acerola cherry, kiwifruit, rose hips, strawberries, oranges, papayas], vegetables [bell peppers, broccoli, tomatoes, snow peas, kale]) o Vitamin D (such as fish [sardines, salmon, mackerel, tuna], liver [beef, calf, cod liver oil], dairy [milk, yogurt]; most importantly, sunlight on exposed skin) o Vitamin E (such as seeds [sunflower seeds, pumpkin seeds], nuts [almonds, hazelnuts, pine nuts], fish [abalone, salmon, trout], fruit [avocado, mango, kiwifruit], vegetables [red peppers, turnip greens, spinach, chard, squash, broccoli]) o lycopene (such as tomatoes, guavas, watermelon, papaya, grapefruit), o oleic acid (such as nuts [almonds, peanuts, pecans, cashews, pistachios, hazelnuts] seeds Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

[sesame, sunflower], avocados, olives, and vegetable oils [safflower, almond, olive, sesame, sunflower]), o luteolin (such as dried oregano, celery seed, hot peppers, peppermint, sage, rosemary, juniper berries, thyme, radicchio, chinese celery), o quercetin (such as capers, lovage leaves, elderberry juice, dock leaves, radish leaves, arugula, dill weed, coriander, and fennel, cilantro, banana peppers, juniper berries, oregano, onions, carob flour, radicchio, red leaf lettuce, onions, watercress, raw, asparagus, kale, okra, cocoa powder, chia seeds) o sulforaphane (such as broccoli sprouts, broccoli, cauliflower, kale, brussels sprouts, cabbage, collards, arugula, turnips) o resveratrol (such as red wine, red grapes, peanut butter, pistachios, cocoa powder, dark chocolate, strawberries, blueberries, bilberries, cranberries) o epigallocatechin-3-gallate (such as green tea, black tea, carob powder, apples, blackberries).

Additional important foods from Table 2-6 include curcumin, garlic, and ginseng.

There are a number of dietary caveats, and they are listed at the end of section 3B6, here.

ES-4. Health Policy

The protocol contains implicit assumptions that patients will be able to

1) pay for any expensive drugs (if necessary),

2) afford pesticide-free, and other harmful-chemical-free, foods,

3) leave jobs where the working environment is toxic,

4) move from residences where the environment is toxic, etc.

This flexibility might not be available to many patients with limited income and/or limited assets.

There is also the implicit assumption that, if one has sufficient assets and flexibility, toxin-free environments can be found and toxin-free lifestyles can be achieved. This assumption is open to question, as shown by the following example.

Probably the key exogenous contributing factor to the development of AD (and many other chronic diseases) is the incorporation of technology in all aspects of modern life without adequate regulation and safety testing [6, 7]. To compound the problem, some/many of these new technologies are effectively mandated by government, and impossible to avoid, even if the AD patient is wealthy. One example follows, but it is reflective of myriad other technologies contributing in part to AD.

Wireless radiation technology has become ubiquitous in modern life (cell phones, WiFi, smart meters, etc.). Research has shown that wireless radiation in the cell phone radiofrequency part of the spectrum contributes to oxidative stress and inflammation of the brain [8, 9, 10], among many other adverse effects. As our AD study results show, oxidative stress and inflammation are key AD characteristics. Chronic exposure to wireless radiation would be a factor contributing to increase the incidence of AD (and many other chronic diseases in which these two characteristics are important).

Wireless radiation technology requires an infrastructure. For cell phones, the major infrastructure is cell towers. The Telecommunications Act of 1996 effectively mandates the construction of cell towers with no opposition allowed based on health considerations. As of this writing, the FCC is attempting to implement similar effective mandates for the next generation of mobile wireless technology, known as 5G. A million or more 'short' cell towers (in the USA alone) would be required for 5G implementation, since the propagation of radiation energy at the high frequencies characteristic of 5G is poor, and the distances between 'short' cell towers is relatively small by necessity.

This means that populated areas will be blanketed (around the clock) with 3GHz-30GHz (or higher) radiofrequency radiation. This is a range of the frequency spectrum essentially untested for adverse health effects, especially over the long-term in humans, and especially in combination with other toxic stimuli [8]. It is no different in principle from a contractor proposing to spray the populated areas of the USA with Agent Orange around the clock, and the relevant government regulatory agency stating that no opposition to the spraying is allowed based on health considerations. In effect, the USA Federal government is mandating an increase in rates of AD, with the potential of this increase being very large.

Thus, we have a dichotomy in the relevant USA Federal policy. On the one hand, the Federal government is investing heavily in biomedical research to treat and reverse AD. On the other hand, the Federal government is allowing essentially unrestricted and inadequately regulated expansion of technologies that are important contributing factors to AD. Metaphorically, the Federal government is drilling holes in the floor of the boat at the same time they are pumping water out of the boat! These policies are diametrically opposed, and will limit the effectiveness of any AD treatment protocol, no matter how strictly followed.

ES-5. Near-Term Implementation of Findings

To gain operational experience with exploiting the findings in this monograph, clinical trials should be started in the near future. Given the limitations in knowing exposures to many potential AD contributing factors outlined above, these trials could start with incorporating the "low-hanging fruit" contributing factors that have been identified previously. These are potential AD contributing factors that could be estimated or measured relatively easily. If elimination of these AD contributing factors does not yield the results desired, then low-risk treatments could be instituted.

References - Executive Summary

Chapter 1

INTRODUCTION

1A. Overview

Chapter 1 describes

1) the present and projected incidence and prevalence of AD in our society,

2) the mainstream medical approach to treating this disease, and

3) the relationship of our proposed approach to some segments of the mainstream medical approach.

This chapter ends with an outline of the monograph's structure and contents.

1B. Present and Projected AD Incidence and Prevalence

Alzheimer's Disease (AD) is a brain disease, and the most common form of dementia. Currently, it affects those 65 years old and above overwhelmingly; incidence increases with age. The prevalence of AD in the USA was approximately 4.7 million people in 2010, and is projected to increase to 5.8 million in 2020, 8.4 million in 2030, and 11.6 million in 2040 [1].

These projections may be strong under-estimates. AD has an environmental component. There have been many potentially harmful [2] and effectively un-regulated high-technology additions to the environment in the past few decades (e.g., wireless radiation, vaccine combinations, agricultural chemicals, etc., have expanded greatly). Because of latency delays, inadequate time has elapsed to show linkages between these potentially harmful environmental additions and changes in the incidence of AD in human populations. As was shown in our April 2017 monograph on AD foundational causes [2], the adverse impact of (for example) recent potentially harmful environmental and dietary additions on AD characteristics measures ominously portends increased incidence and prevalence of AD in the future.

Many of the toxic stimuli that are contributing factors to AD also contribute to many other serious diseases [3]. Many of these diseases can be fatal, and may not have the multi-decadal latencies associated with AD. Thus, these lethal diseases serve to cull out people who would have been high-risk candidates for AD had they lived. This culling out of high-risk individuals artificially depresses and masks the real incidence of AD had these high-risk people survived.

1C. Mainstream Medical Approach

The mainstream medical approach is rooted in myriad hypotheses about AD pathology, such as the Amyloid-beta Hypothesis, the Tau Hypothesis, etc. The pathology related to each hypothesis can be broad or narrow. There are AD characteristics whose measurements reflect the extent of the pathology. Selection of a specific AD hypothesis by a specific researcher typically results in the selection of AD characteristics the researcher will use for diagnostic purposes and AD treatment research and application. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

A summary of these AD hypotheses is shown in the following list:

COMPREHENSIVE SUMMARY OF AD HYPOTHESES

The most widely used AD hypotheses are shown in a 2016 review [4]:  the amyloid cascade hypothesis (accumulation of Abeta as plaques in the brain is the main pathogenic event),  the tau hypothesis (hyperphosphorylation of tau as the primary event);  the cholinergic hypothesis (reduction in the activity of choline acetyltransferase and acetylcholine levels in areas such as the cerebral cortex),  the mitochondrial cascade hypothesis (impairment of brain mitochondria as the first pathogenic event leading to neurodegeneration),  the metabolic hypothesis (the disease is caused by changes in metabolic processes such as obesity, diabetes, and hypercholesterolemia), and  the vascular hypothesis (reduction of cerebral blood flow as the main characteristic).

Other AD hypotheses have been proposed as well, including, but not limited to:  the calcium hypothesis (disruption of calcium signaling as the underlying cause of neuronal dysfunction) [5,6],  the inflammatory hypothesis (inflammatory mechanisms play an important role in the pathogenesis of AD) [7],  the oxidative stress hypothesis (oxidative stress associated with the onset and progression of AD) [8],  the aluminum hypothesis (human exposure to aluminum linked to AD) [9],  the metal hypothesis (neuropathogenic effects of Abeta in AD are promoted by, and possibly even dependent on, Abeta-metal interactions) [10]  the cognitive reserve hypothesis (persons with greater education begin to experience acceleration in cognitive decline closer to the time of diagnosis than persons with lower reserve, but that their rate of decline is more rapid after the time of acceleration due to increased disease burden) [11],  the cell cycle/mitosis failure hypothesis (cell cycle reentry is an early event in AD and produces apoptosis) [12],  the deleterious network hypothesis (close interactions among abnormal amyloid precursor protein metabolism, oxidative damage, compromised energy metabolism and impaired calcium homeostasis is the common pathway of AD) [13],  the aminopeptidase hypothesis (aminopeptidase-catalyzed proteolysis of Abeta may limit the rate of Abeta catabolism whose reduction would lead to Abeta dyscatabolism and thus to deposition [14],  the ammonia hypothesis (ammonia is a factor able to produce symptoms of AD) [15],  the attrition hypothesis (activation of the effector caspase-6 in AD due to one or a variety of insults is responsible for the breakdown of the cytoskeletal structure of neurites and damages proper trafficking of proteins and organelles thus resulting in the observed clinical and pathological features of AD) [16], and  the protein cancer hypothesis (abnormal or malignant proteins--such as prion proteins--generated in a cell grow and propagate from cell to cell by converting normal proteins, and this propagation causes disease progression) [17].

All the above hypotheses are centered around AD pathology, specifically, symptoms associated with AD. The typically high-technology treatments that accompany these hypotheses focus on removing/suppressing these pathological symptoms, rather than removing the causes of these symptoms. These treatments (in the absence of comprehensive cause removal) don't work because they violate the systemic medical principle that forms the basis of our methodology.

Interestingly, there are no foundational causes-based hypotheses of AD, e.g., the Deficient-Diet Hypothesis, the Iatrogenic Hypothesis, the Sedentary Lifestyle Hypothesis, the Radiation Exposure Hypothesis, the Toxic Chemical Exposure Hypothesis, etc. There are many articles in the literature 1) questioning the validity of each of the above-listed pathology-based AD hypotheses and 2) showing the deficiencies in their associated treatments on reversing AD.

The strategy of identifying symptoms as pathological mechanisms that must be suppressed or removed for healing is a mainstay of Western Medicine. However, another perspective is to view these symptoms in a positive light, as having two basic functions: serve as a warning signal that dysfunction exists and actions need to be taken to remove the cause of this dysfunction, and serve as a protective mechanism.

There are many examples in the biomedical literature supporting the concept of disease symptoms as warning signals and protective mechanisms, as shown by the following:

EXAMPLES OF DISEASE SYMPTOMS AS PROTECTIVE MECHANISMS

 "the down-regulation of energy metabolism in AD is a protective response of the neurons to the reduced level of nutrient and oxygen supply in the microenvironment" [18];  "Neurofibrillary tangle formation as a protective response to oxidative stress in Alzheimer’s Disease" [19];  "Autophagy is a protective response to the oxidative damage to endplate chondrocytes in intervertebral disc" [20];  "loss of appetite in the acute phase of illness is indeed an adaptive, protective response that improves cell recycling (autophagy) and detoxification" [21];  "Cataract is a self-defence reaction to protect the retina from oxidative damage" [22].

Additionally, in his 2017 book [23], Bredesen states: "Alzheimer's disease is actually a protective response to, specifically, three different processes: inflammation, suboptimal levels of nutrients and other synapse-supporting molecules, and toxic exposures." Other AD researchers have drawn similar conclusions. If Bredesen's view that the AD symptoms serve as a protective response against more serious damage is correct, then the mainline drug-based AD treatment approach of removing these pathologies/symptoms without removing their foundational causes comprehensively in parallel

1) effectively removes the protective shield reflected by these pathologies/symptoms and

2) exacerbates the progression of AD!

How effective has the mainstream drug-based approach to treating AD been? Bredesen states: "In the case of Alzheimer’s disease, there is not a single therapeutic that exerts anything beyond a marginal, un-sustained symptomatic effect, with little or no effect on disease progression. Furthermore, in the past decade alone, hundreds of clinical trials have been conducted for AD, at an aggregate cost of billions of dollars, without success. This has led some to question whether the approach taken to drug development for AD is an optimal one [23]." Sherzai and Sherzai [24] summarize their views about mainstream AD research as follows: "When it comes to slowing or stopping Alzheimer's disease, the current success rate is 0 percent"! Comments similar to Bredesen's and the Sherzais' have been expressed in a significant number of the journal paper abstracts that were reviewed for the present monograph in the process of identifying existing and potential AD treatments.

Bredesen is an AD researcher/clinician who has shown that "reversal of cognitive decline in patients with early Alzheimer's disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment)" is obtainable today [25]. Basing his approach on optimizing metabolic parameters, Bredesen used a combination of eliminating some potential AD contributing factors, substituting positive health practices, and adding dietary supplements to achieve his AD/MCI/SCI reversal results.

Sherzai and Sherzai are AD researchers/clinicians who claim to have had very positive results with patients based on: "lifestyle intervention as the cure for cognitive decline" [24]. Their lifestyle modification approach (based on addressing their assumed four main pathways to AD: inflammation, oxidation, glucose dysregulation, lipid dysregulation) has five main components: nutrition, exercise, stress management, adequate sleep, and mental challenges.

1D. Our Proposed Approach

Bredesen's and the Sherzais' approach can be viewed as one "footprint" of a more general systemic medical principle for preventing or reversing disease developed by the first author over the time period 2012-2017: At the present time, removal of cause is a necessary, but not necessarily sufficient, condition for restorative treatment of disease to be effective. To prevent AD, or any disease, the foundational causes that underlie the disease symptoms need to be identified and removed as comprehensively, thoroughly, and rapidly as possible. To reverse AD (if irreversible damage has not been done and strong genetic predisposition to AD is not a dominant factor), the preventive steps above need to be implemented, and treatments to reverse progression (if necessary) need to be applied.

Thus, our approach is not constrained by hypotheses based primarily on symptoms/pathological mechanisms. We use symptoms, pathological mechanisms, and other abnormal AD characteristics as a guidepost to identify causes to be eliminated and treatments to be implemented for individual patients. Our approach is based on cause and effect as evidenced in the premier biomedical literature. We identify as many AD characteristics as exist in the literature, and then relate adverse changes in the values of these AD characteristics to potential underlying foundational causes. Preferably, the research findings will identify the biological mechanisms that link a foundational cause to its impact(s) on AD characteristics. However, even in the absence of such mechanisms, the linkage is retained. We also relate beneficial changes in the values of these AD characteristics to potential treatments, again, whether or not the biological mechanisms that link treatments to positive impacts have been identified. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

In the present monograph, the treatments identified cover research over the past ~thirty years. We do not exclude treatments that have 'failed' in human clinical trials, for the following reasons. Our reading of thousands of abstracts on laboratory experiments and clinical trials of potential AD treatments has shown

1) in vitro experiments typically performed on neural cells tend to have reasonably positive outcomes, at least for those papers that surface in the peer-reviewed published literature;

2) in vivo experiments typically performed on rodents (but other small animals as well) tend to also have reasonably positive outcomes, albeit somewhat less than in vitro experiments;

3) when these potential treatments reach the human clinical trial stage, especially the later phases, the success rates plummet!

The explanation for this discrepancy given most often is the species difference. Humans are different from rodents et al, and their physiological responses to stimuli are different as well. However, the toxic experiential and exposure background differences between humans who live in the sea of toxic exposures in the real world and animals who live in the very controlled environment of the laboratory are rarely, if ever, discussed.

As our previous AD foundational causes monograph [2] has shown, there are many hundreds of potential causes for AD (ranging from Lifestyle to Occupational/Environmental exposures). For a given individual, some causes have happened in the past, and are no longer happening, but their damage trail remains. Other causes are ongoing, have caused damage, and continue to cause damage.

Why would anyone expect a human being with such a toxic history to respond to a potential treatment the same way that a laboratory animal raised in a controlled environment would respond to that treatment? Furthermore, why would anyone expect a human being with such a toxic history to respond to a potential treatment the same way that another human being without such a toxic burden would respond to that treatment?

In references [26, 27], the first author gives the example of Dr. Terri Wahls, an M.D. who was able to reverse her own case of Multiple Sclerosis (MS). She used two main types of treatments: lifestyle changes (mainly dietary) to reverse the MS and neuromuscular electrical stimulation (NMES) to reverse the damage resulting from MS. It was only when her diet achieved near-pristine status that the NMES produced positive effects.

While Dr. Wahls' experience represents only one data point, it is a very powerful data point. Consider its implications. Suppose a clinical trial were conducted to evaluate the potential for NMES to reverse the damage from MS. Suppose further that Dr. Wahls' dietary-dominant contributing factor to MS and her reaction to NMES were typical of the participants in such a clinical trial. If the participants did not address their diet during the clinical trial, they would not respond positively to the NMES (as was the case for Dr. Wahls initially). The trial would be interpreted as a failure of NMES. However, in this hypothetical example, the NMES is not the reason for the clinical trial's lack of success. Failure to remove the cause of the disease and subsequent damage is the problem! Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

We cannot rule out failure to remove cause as a reason for the massive failure of myriad AD treatments in the clinical trials of the past three decades. That is why we have retained even so-called 'failed' treatments in the present full-spectrum study of existing AD treatments. We don't know which treatments failed because 1) they were intrinsically ineffective or 2) their beneficial effects were overwhelmed by the strong negative effects of the ongoing causes remaining operable. In fact, we don't know whether comprehensive, timely, and thorough removal of the relevant AD causes by themselves would have obviated the need for many of these AD treatments!

For our comprehensive treatment process, the first step in both AD prevention and reversal protocols is to identify the full spectrum of potential AD foundational causes/contributing factors. The second step (in parallel with the elimination of the actionable causes identified in the first step) is to identify AD treatments that can be implemented to accelerate AD reversal. The first step was taken with our previous monograph [2]. The remainder of the present monograph takes the second step, and identifies a wide spectrum of existing and potential AD treatments. In addition, by identifying a wide spectrum of AD 'characteristics' impacted by both AD causes and treatments, the present monograph is able to integrate these AD causes, treatments, and characteristics, and present a treatment protocol for preventing and reversing AD tailored to the individual.

1E. Structure of Remaining Monograph Chapters

*Chapter 2 presents Results and Discussion from our AD study.

*Chapter 3 integrates the findings from our previous monograph [2] and the present study to outline an individualized Treatment Protocol for preventing and reversing AD, in selected cases.

*Chapter 4 contains Suggested Further Research, based on both the deficiencies and opportunities identified by this study.

*Chapter 5 contains the Background for the present study, including definitions of key terms.

*Chapter 6 presents the detailed Methodology used to identify existing and potential AD treatments and existing AD characteristics.

*Chapter 7 contains Tables and Concordance Software illustrations.

*Chapter 8 contains important summary material from the April 2017 monograph [2], in order to make the present monograph as self-contained as possible.

*Chapter 9 contains the detailed Methodology used to identify the AD foundational causes for the April 2017 monograph, again to make the present monograph as self-contained as possible.

*Chapter 10 contains the References for each chapter, and a comprehensive bibliography of treatment references.

Chapter 2

RESULTS AND DISCUSSION

2A. Overview

The existing and potential AD treatments identified in our study (using the methodology described in Chapter 6) are presented in this chapter. Different methods of categorizing these AD treatments are discussed. Additionally, two top-level AD treatment categorizations are presented: an eight category taxonomy derived from a text clustering analysis of the AD treatment records using the CLUTO software [1], and an approximately thirty category taxonomy derived from a factor analysis of the AD treatment phrases using the Vantage Point (VP) software [2].

Existing AD characteristics identified in our study (using the Chapter 6 methodology) are presented. Additionally, two AD characteristics categorizations are presented: an approximately forty category taxonomy based on pathological mechanisms and abnormal behaviors constructed manually, and an approximately twenty+ category taxonomy derived from a VP factor analysis of the AD characteristics phrases.

Because the treatment protocol presented in Chapter 3 requires integration of AD characteristics, treatments, and causes, the present chapter will also present a list of selected AD causes/contributing factors for illustrative purposes. These causes were identified initially in our April 2017 monograph [3], and have been streamlined substantially and modified to allow integration into the present format. A more comprehensive perspective on the full spectrum of AD causes identified in reference [3] was presented in the Conclusions section of reference [3]. It is reproduced almost verbatim in Chapter 8, in order to keep the present monograph as self-contained as possible

2B. AD Characteristics

2B1. Existing AD Characteristics

Existing AD characteristics are those characteristics that occur in the AD literature, and their measured values change direction as AD improves or worsens. There could be other AD characteristics of interest (potential AD characteristics) that have not yet been identified as such in the AD literature.

The existing AD characteristics are listed in Table 2-1 in summary form. These AD characteristics are essentially the myriad diagnostics gathered from lab and clinical tests and questionnaires for the purpose of identifying corrective measures for preventing or reversing AD.

Over 250 existing AD characteristics were identified in the present study. However, this number (while extremely large compared to any other published list of existing AD characteristics/diagnostics) is a gross under-estimate of what could be extracted from the published biomedical literature in an expanded study.

What leads us to this conclusion? Linking terms were used to help extract these existing AD characteristics from text, in addition to visual examination of the high frequency abstract phrases. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

However,

1) not all linking terms identified were used,

2) not all existing AD characteristics appeared in text in proximity to the identified linking terms, and

3) software limitations on extracted phrase length excluded those existing AD characteristics not in very close proximity to the identified linking terms.

An expanded study could easily overcome these limitations, and probably double (or more) the number of existing AD characteristics identified. For purposes of the present proof-of-principle demonstration, the ~250 major and semi-major existing AD characteristics are more than adequate.

The existing AD characteristics in Table 2-1 encompass myriad categories at different hierarchical levels. These categories include:

 behaviors (e.g., aggression, agitation, delerium, etc.);  performance (e.g., cognition, memory, learning, etc.);  psychological states (e.g., apathy, anxiety, etc.);  biomarker/metabolic function (e.g., oxidative stress, neuroinflammation, Abeta, tau phosphorylation, mitochondrial function, synaptic plasticity, etc.); and  biomarker/metabolic metrics (e.g., acetylcholine, ABCA1, BCL-2, BDNF, ADAM10, GSK- 3, homocysteine, BACE1, etc.).

The AD characteristics at the high frequency (appear in large numbers of records) end of the list tend to be in the higher level categories above (behaviors, performance, psychological states), and those at the low frequency end of the list tend to be at the level where they can be measured by accepted laboratory tests. In practice, evaluations of the higher level characteristics would be more subjective, and those of the lower level characteristics would be more objective. Evaluation of AD characteristics at all levels shown is important for a comprehensive picture of the patient's AD status.

2B1a. Existing AD characteristics impacted by existing AD causes

Table 2-2 shows how existing AD characteristics are impacted by AD causes. Each entry includes the AD characteristic and the direction in which it is driven by the cause. Thus, an AD cause will typically increase Abeta, degrade memory, increase tau pathology, decrease Bcl-2, increase cortisol, etc. This table of existing AD characteristics impacts was derived from the list of existing AD characteristics impacted by existing AD treatments (Table 2-3), and was streamlined slightly.

2B1b. Existing AD characteristics impacted by existing AD treatments

Since the present monograph focuses on AD treatments, most of the existing AD characteristics development centered on existing AD treatment benefits. Table 2-3 contains a taxonomy of AD treatment impacts/benefits on AD characteristics (AD treatment benefits), categorized by types of improvement/benefit. Table 2-4 contains a more detailed picture of the contents of this taxonomy. Reversing the directions of these AD treatment impacts on the AD characteristics would translate into a categorization of the impact of AD causes.

Table 2-4 was developed by extracting thousands of phrases with linking terms reflecting existing AD treatment benefits, and then manually assigning these extracted phrases to appropriate categories. The five-digit numbering scheme shown reflects the level of detail required to develop the final AD treatments taxonomy. References [3] and [4] were helpful in initiating the AD treatment categorization process, but extensive modifications and category additions were made to arrive at the final comprehensive AD treatments categorization.

Another perspective on categorizing AD treatment benefits was obtained using a factor analysis of the existing AD treatment benefits list. Figure 2-1 is a factor matrix of the AD treatment benefits. The x axis contains the factor numbers, the y axis contains the AD treatment benefits phrases, and each matrix cell x,y contains the factor loadings (a measure of the influence of treatment benefit y on the theme of factor x). A truncated version of Figure 2-1 is presented below, to illustrate the figure's structure. The complete Excel spreadsheet containing Figure 2-1 is presented in the attached Excel workbook (see file FIGURES_FINAL.xlsx); click on the Excel workbook tab containing Figure 2-1.

Figure 2-1 (truncated)

Figure 2-1 (truncated) FACTOR MATRIX OF POTENTIAL AD TREATMENT BENEFITS (COLORED RECTANGLES CONTAIN FACTOR LOADINGS, ORDERED BY DECREASING ABSOLUTE VALUE) (BOTH TAILS OF FACTOR LOADINGS SHOWN FOR FACTORS 1, 6, 20) FACTOR 1A 1B 2 FACTOR 1A - MOOD/BEHAVIOR IMPROVEMENT AGITATION reduc -0.6 0.02 DEPRESSION reduc -0.5 0.01 AGGRESSION decr -0.5 0.02 ANXIETY reduc -0.5 0.01 BEHAVIOR improv -0.5 0.03 SLEEP improv -0.4 0.01 DEMENTIA prevent -0.4 -0 APATHY improv -0.4 0.01 INSOMNIA reduc -0.2 0.01 SEROTONIN incr -0.2 -0 MELATONIN restor -0.2 0.01 NOREPINEPHRINE incr -0.1 -0 FACTOR 1B - AD PREVENTION THROUGH IMMUNOTHERAPY AD prevent 0.32 ABETA reduc 0.25 ANTIBOD enhanc 0.14 FACTOR 2 - EPIGENETIC MODIFICATION HDAC inhibit 0.03 -0.7 HISTONE ACETYL incr 0.02 -0.7 DNA METHYLAT incr 0.02 -0.4 TUBULIN restor -0 -0.3 SIRT1 incr -0 -0.2 HISTAMINE incr 0.01 -0.2 WT1 reduc 0.01 -0.2 HISTONE H3K9 incr 0.01 -0.2 PGRN incr -0 -0.1

The initial factor matrix consisted of twenty factors. For each factor, the factor theme is determined by the tail of the factor that contains factor loadings with the highest absolute values. In Figure 2-1, the treatment benefits phrases shown under each factor heading (e.g., FACTOR 1A - MOOD/BEHAVIOR IMPROVEMENT) are those whose factor loadings have (relatively) high absolute values. In most factors, the absolute values of one tail's factor loadings completely dominated the absolute values of the other tail's factor loadings. However, for three of the factors, both tails contained factor loadings with high absolute values. These three additional tails were added to the initial list of twenty factors, for a final total of 23 factors.

The factor numbers are shown in green at the top of the matrix. The themes associated with each factor (e.g., FACTOR 1A - MOOD/BEHAVIOR IMPROVEMENT) are shown (in reddish brown) in the row preceding the factor items. The colors of the factor loadings reflect the importance of the particular treatment benefit in determining the theme of the factor. Bright red color signifies the most important, dark green signifies secondary importance, and no color signifies lesser importance.

Not unexpectedly, there is a reasonable amount of overlap between the factor matrix classification of Figure 2-1, and the manual classification of Table 2-4. Both of these classifications address many/most of the pathologies associated with the myriad AD causal hypotheses in the Introduction.

Not all the treatment benefits from Table 2-4 were included the the factor matrix of Figure 2-1. Most of the treatment benefits shown below the end of Factor 20B in Figure 2-1 had factor loadings too small to influence the theme of any factor. This should not be interpreted as their being unimportant. A treatment benefit that has a very modest impact across multiple factors could be just as valuable (or even more so) as a treatment benefit that has a strong impact on one or two factors.

Table 2-5 contains a listing of the AD treatment benefits ordered by decreasing numbers of records in which they appear. The highest frequency benefit types are mainly at the highest hierarchical levels, and accepted lab tests tend to expand dramatically as frequency approaches unity. Almost 1/3 of the categories have record frequencies of five or less. An expanded study would probably increase the lower frequency items substantially.

2C. AD Treatments

2C1. Existing AD treatments list

Existing AD treatments are treatments that appear in the AD literature. The linking term approach in the present monograph was used to identify both existing AD treatments and their benefits. The existing AD treatments identification process was performed at an earlier time than the existing AD benefits identification process. Many potential linking terms for identifying existing treatments were generated. Relatively few of the total number of generated linking terms were used for the existing AD treatment identification component, since the number of existing AD treatments identified was becoming overwhelming. An expanded study could increase greatly the number of existing AD treatments identified.

Table 2-6 lists the existing AD treatment phrases identified in the present study, arranged in order of decreasing numbers of records in which these phrases appear. The highest frequency phrases (top of table) tend to be existing AD treatments used most widely. While most of the existing AD treatments shown tend to be relatively specific, some generic categories are included in the upper portions of Table 2-6. As will be seen below, these generic AD treatment categories are of assistance in developing classes of related treatment types.

A factor analysis was performed on the list of existing AD treatments from Table 2-6, and the resulting factor matrix is presented in Figure 2-2. These existing AD treatments cover a wide range of dietary, medicinal plant, drug, vaccine, etc, approaches. If we deconvolve AD into three temporal phases (pre-AD diagnosis/preventive, post-AD diagnosis, and late-stage AD maintenance), then different existing AD treatments could apply to one or more of these three phases. A truncated version of Figure 2- 2 is presented below, to illustrate the figure's structure. The complete Excel spreadsheet containing Figure 2-2 is presented in the attached Excel workbook (see file FIGURES_FINAL.xlsx); click on the Excel workbook tab containing Figure 2-2.

Figure 2-2 (truncated)

Figure 2-2 (truncated) FACTOR MATRIX OF AD TREATMENTS (Factors 1-29 reflect 29 factor matrix; Factors 30-32 extracted from 50 factor matrix) CODE: Dark shading: absolute value >0.3; Light shading: 0.2clozapine 1 0 -0 0 0 0 -0 -0 ziprasidone 1 0 -0 0 0 0 0 0 Aripiprazole 1 0 -0 0 0 0 0 0 antipsychotic agents 1 0 0 0 0 0 -0 -0 Haloperidol 0 0 -0 0 0 -0 -0 -0 neuroleptic 0 0 0 0 0 0 -0 -0 Medication 0 0 0 0 0 0 -0 -0 anticholinergic medicat0 0 0 0 0 0 -0 -0 Carbamazepine 0 0 -0 0 0 -0 0 -0 clonazepam 0 0 0 0 0 0 -0 -0 amantadine 0 0 0 0 0 0 -0 -0 tiapride 0 0 0 -0 -0 0 0 0 trazodone 0 0 0 0 0 -0 -0 -0

2. ACHE INHIBITORS - NMDA RECEPTOR ANTAGONISTS (FDA-approved drugs for AD colored in aqua) acetylcholinesterase inhi- 1 0 0 0 0 -0 -0 drug therapy 0 0 0 0 -0 -0 -0 -0 donepezil -0 0 0 0 0 0 -0 -0 Rivastigmine -0 0 0 0 0 -0 -0 -0 galantamine -0 0 0 0 0 0 -0 -0 memantine -0 0 0 0 0 0 -0 -0 Tacrine -0 0 0 0 0 -0 -0 -0 anti-dementia agents -0 0 0 0 -0 0 -0 -0 NMDA receptor antagt- 0 0 0 0 0 0 -0 -0

To provide another perspective on existing AD treatment categorization, a text clustering approach was performed using the records that contained the existing AD treatments from Table 2-6. The high-level AD treatment categories from the text clustering approach are presented in Figure 2-3. At the highest level of AD treatment categorization, two main themes emerge:

 Laboratory and Clinical Research  Patient Management

 Laboratory and Clinical Research can be sub-divided further into o prevention or reversal of Abeta and tau buildup, and o acetylcholinesterase inhibition, oxidative stress reduction and neuroinflammation reduction.  Patient Management can be sub-divided further into o patient dementia prevention and treatment, and o patient caretaking drug and non-drug therapies.

If we define AD treatments as actions taken to modify AD characteristics in desired directions, then

1) removal of contributing factors to AD could be viewed as AD 'treatments' (e.g., cessation of smoking, cessation of excessive alcohol intake, cessation of high-fat diet, cessation of exposure to harmful chemicals, etc),

2) substitution of positive practices for contributing factors removed could be considered as AD 'treatments' (e.g., drinking more water as a substitute for high-fructose beverages, moving from high air pollution environments to low air pollution environments, replacing high-temperature cooking with low- temperature cooking, etc), in addition to what are normally considered AD treatments.

Under this perspective, combining the AD causes to be eliminated (identified in the April 2017 monograph [3]), along with the AD treatments identified in the present monograph, will result in well over 1000 existing AD treatments identified. An expanded study could easily double that number, and, if potential AD treatments and potential AD contributing factors are included, could triple that number!

In the text clustering algorithm, records were assigned to one category only. Thus, many of the AD lifestyle modification treatments (e.g., exercise, diet, improved vitamin and mineral intake, massage and other stress-reduction therapies, improved socialization approaches) were assigned to the broader Patient Management category in Figure 2-3. This category reflects patients in the mid-to-late AD stages, and many of the existing AD treatments shown in Figure 2-3 are aimed at increasing the patient's quality-of-life rather than attempting to reverse the AD. However, in the AD literature, some of these lifestyle modification therapies are also shown to have benefits in preventing AD and helping to alter the critical AD characteristics' values in the desired directions. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

For the existing AD treatment factor matrix and text clustering taxonomy presented, many of the pathological hypotheses for AD presented in the Introduction (e.g., Abeta, Hypothesis, Tau Hypothesis, Inflammation Hypothesis, Oxidative Stress Hypothesis, etc) are addressed by the AD treatments identified. Factor analyses with different numbers of factors were performed parametrically (e.g., eight factors, twenty factors, thirty factors, fifty factors), and the hierarchical levels from the text clustering taxonomy were examined at much lower levels (e.g., sixteen clusters, 32 clusters, 64 clusters). Examining these categorization results in greater detail showed that essentially all the AD pathological hypotheses were covered by the existing AD treatments, and all the pathological hypotheses were related to the existing AD characteristics from the existing AD literature (Table 2-1).

This is a crucial advantage of our comprehensive cause-effect approach, relative to approaches narrowly confined to specific AD pathogenic causal hypotheses. We are not tied to any particular AD hypothesis, but rather we address the effects from all the AD hypotheses that have been generated. Each AD hypothesis has merit in its own right, and its associated pathology contributes to AD, but each AD hypothesis must be viewed as one part of a much larger puzzle.

2C2. Potential AD treatments list

In the present literature-based study, potential AD treatments are defined as treatments that have been used for other diseases, but could conceivably be 're-purposed' for treating AD. They have exhibited favorable impacts on characteristics (in these other diseases) that are altered in the same direction in the AD literature as well. In some sense, the Literature-Related Discovery and Innovation (LRDI) [5] approach for 'discovering' potential AD treatments used in the present study (and, in fact, in our previous LRDI treatment discovery studies for other diseases [6-8]) can be viewed as 'treatment repurposing'. By linking two disparate literatures to identify novel concepts, we are conceptually extrapolating treatments used for one purpose (treating a non-AD disease) to be used for another purpose (treating AD, in the present case).

A query was developed to select potential AD treatments from treatments used in the non-AD literature (see Appendix 6-1). Basically, we searched the non-AD literature for records reflecting AD characteristics that moved in desired directions as a result of treatments (e.g., reduced Abeta; increased Bcl-2; reduced tau hyperphosphorylation; restricted NFKappaB signaling; reduced inflammation; reduced oxidative stress; enhanced Nrf2, etc.). Searching for records that had a threshold of including at least one of these desired characteristics alterations produced a voluminous retrieval. To keep the records retrieved at a manageable level, we imposed the requirement that a record in the non-AD literature must contain at least two AD characteristics (that moved in the appropriate direction in conjunction with a treatment) to be retrieved. Even then, the retrieval was voluminous, indicating the wealth of potential AD treatment discovery/re-purposing possible from an expanded study.

Since the present study is a proof-of-principle demonstration, and not a comprehensive documentation of potential AD treatments (discovery), we present five examples of potential AD treatment discoveries, to illustrate the process. The AD characteristics of interested are highlighted.

EXAMPLES OF POTENTIAL AD TREATMENT DISCOVERIES

 Fortunellin protects against high fructose-induced diabetic heart injury in mice by suppressing inflammation and oxidative stress via AMPK/Nrf-2 pathway regulation [9]

 Protective effects of sarains on H2O2-induced mitochondrial dysfunction and oxidative stress; improving mitochondrial function and decreasing reactive oxygen species levels; ability to block the mPTP and to enhance the Nrf2 pathway [10]

 Carboxyamidotriazole alleviates muscle atrophy in tumor-bearing mice by inhibiting NF-kappaB and activating SIRT1; CAI restricted the NF-kappaB signaling, downregulated the level of TNF- alpha in muscle and both TNF-alpha and IL-6 levels in serum, directly stimulated SIRT1 activity in vitro, and increased SIRT1 content in muscle [11]

 Protective effects and mechanism of meretrix meretrix oligopeptides (MMO) against nonalcoholic fatty liver disease; MMO inhibited the activation of cell death-related pathways, based on reduced p- JNK, Bax expression, tumor necrosis factor-alpha, caspase-9, and caspase-3 activity in the NAFLD model cells, and Bcl-2 expression was enhanced in the NAFLD model cells [12]

 Extract from Periostracum cicadae inhibits oxidative stress and inflammation induced by Ultraviolet B Irradiation; decreased reactive oxygen species (ROS) production. The extract attenuates the expression of interleukin-6 (IL-6), matrix metalloproteinase-2 (MMP-2), and MMP-9 in UVB- treated HaCaT cells. Also, P. cicadae abrogated UVB-induced activation of NF-kappaB, p53, and activator protein-1 (AP-1); accumulation and expression of NF-E2-related factor (Nrf2) were increased [13]

2D. AD Causes

Identifying and eliminating AD contributing factors/causes is the cornerstone of our AD treatment protocol. Table 2-7 (adapted from Chapter 8 of our April 2017 monograph [3]) presents the many hundreds of AD causes identified in reference [3] in detail (see Table 2-7C for the detailed list of AD causes), along with an analysis of these causes.

A sharply reduced version of the Table 2-7C causes is used in the present study for matrixing purposes. We extracted a few of the causes for each of the five major categories defined in Table 2-7C, and aggregated very detailed members of a class into a broader category, in some cases (e.g., pesticides). Table 2-8 is the list of fifty contributing factors/causes used for illustrative matrixing purposes in the present proof-of-principle demonstration.

2E. Matrices of AD Treatments and AD Characteristics Impacted by Treatments

Three matrices containing AD treatments and/or characteristics were generated (treatments- characteristics; treatments-treatments; characteristics-characteristics).

First, the list of existing AD treatments identified in the present study was matrixed against the list of existing AD characteristics impacted by these existing AD treatments, and the results are shown in Figure 2-4.

Second, the list of existing AD treatments was matrixed against itself, and the results are shown in Figure 2-5.

Third, the list of existing AD characteristics impacted by treatments was matrixed against itself, and the results are shown in Figure 2-6.

These matrices will now be described in more detail.

2E1. Matrix of AD Treatments vs. AD Characteristics Impacted by Treatments

Figure 2-4 contains a matrix of 722 existing AD treatments identified in the present study vs 259 existing AD characteristics impacted by these treatments. There are two versions of this matrix in Figure 2-4.

 The upper matrix contains the raw data, where the cell entries reflect the numbers of records that contain both the AD treatment and AD characteristic.  The lower matrix contains normalized data, where each cell entry has been normalized to the minimum value of o the number of AD treatment records or o the number of AD characteristics records.

A truncated version of Figure 2-4 is presented below, to illustrate the figure's structure. The complete Excel spreadsheet containing Figure 2-4 is presented in the attached Excel workbook (see file FIGURES_FINAL.xlsx); click on the Excel workbook tab containing Figure 2-4.

Figure 2-4 (truncated)

Figure 2-4 (truncated) TREATMENT-POTENTIAL BENEFITS MATRIX

UPPER MATRIX - RAW DATA - CELL ENTRIES ARE # RECORDS THAT CONTAIN BOTH TERMS 5 24 37 # CELLS # REC 3697 720 322 WITH # REC TREATMENT BENEFITS>>MEMORY improvROS decr BACE-1 reducENTRIES 3174 cholinesterase inhibitor 483 39 11 131 1481 donepezil 233 12 4 118 1392 antioxidant 276 367 24 154 1219 immunotherapy 164 8 13 126 958 memantine 130 13 4 106 874 Rivastigmine 104 10 3 94 734 galantamine 89 12 2 82 # CELLS WITH ENTRIES------>>>>574 245 149 18007

LOWER MATRIX - NORMALIZED - CELLS NORMALIZED TO MINIMUM RECORDS OF EITHER TERM 3697 720 322 #REC TREATMENT BENEFITS>>MEMORY improvROS decr BACE-1 reduc 3174 cholinesterase inhibitor 0.152174 0.054167 0.034161 1481 donepezil 0.157326 0.016667 0.012422 1392 antioxidant 0.198276 0.509722 0.074534 1219 immunotherapy 0.134537 0.011111 0.040373 958 memantine 0.135699 0.018056 0.012422 874 Rivastigmine 0.118993 0.013889 0.009317 734 galantamine 0.121253 0.016667 0.006211

The following example shows how to interpret the normalized cell entries in the lower matrix. For a hypothetical cell i,j, if the number of records for AD treatment i is 1000, the number of records for AD characteristic j is 500, and the cell entry i,j is 400 (which means there are 400 records that contain both AD treatment i and AD characteristic j), then the normalized value in the lower matrix would be 400/500, or 0.8. The normalization is useful for showing the closeness of linkages between the lower frequency partner and the higher frequency partner. In the hypothetical example above, whenever AD characteristic j appears in a record (in the AD literature) there is a strong likelihood it will appear in conjunction with AD treatment i. The cells are color-coded in the lower matrix, according to the normalized value.

At the right end of the upper matrix is a column titled: "# cells with entries". Essentially, the entries in this column reflect the number of AD characteristics impacted by the AD treatment of interest. For example, consider the second AD treatment listed, Donepezil (cell B10 in the complete Excel Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

spreadsheet). Its entry in the rightmost column (cell JB10 in the complete Excel spreadsheet) is 118, meaning that Donepezil impacted 118 AD characteristics (out of 259 characteristics that it could have theoretically impacted). Use of this metric can be helpful in determining the minimum number of AD treatments to impact all the AD characteristics of interest for a specific patient. It should be emphasized this metric focuses on the number of AD characteristics impacted, not the strength of the impact.

Immediately below the upper matrix is a row titled:"# cells with entries". The entries in this row reflect the number of AD treatments that impact the AD characteristic of interest. For example, consider the AD characteristic BACE-1 (cell AM8 in the complete Excel spreadsheet). The overwhelming majority of BACE-1 treatment-related records emphasize the desired reduction of this AD characteristic's measured value, since this beta-secretase enzyme contributes to Abeta formation through amyloid precursor protein cleavage. The BACE-1 entry in the row '# cells with entries' (cell AM731 in the complete Excel spreadsheet) is 149, meaning that 149 AD treatments impacted this AD characteristic. These AD treatments ranged from high-tech (BACE1 inhibitors, gene therapy, galantamine, etc) to low- tech (herbs, flavonoids, fruits, curcumin, resveratrol, ginseng, coffee, etc.). If multiple treatments are required to prevent and reverse AD, and if low-risk treatments are preferable in a multiple treatment protocol, then the above results indicate that therapies to reduce BACE-1 based mainly/entirely on low- risk treatments may be feasible. The same may hold true for addressing many other AD characteristics of interest.

2E2. Matrix of AD Treatments vs AD Treatments

Figure 2-5 contains a matrix of the 722 existing AD treatments (identified in the present study) on each axis. There are two versions of this matrix in Figure 2-5. The upper matrix contains the raw data, where the cell entries i,j reflect the number of records that contain both AD treatment i and AD treatment j. The lower matrix contains normalized data, where each cell entry has been normalized to the minimum value of the number of AD treatment i records or the number of AD treatment j records (as in Figure 2-4). A truncated version of Figure 2-5 is presented below, to illustrate the figure's structure. The complete Excel spreadsheet containing Figure 2-5 is presented in the attached Excel workbook (see file FIGURES_FINAL.xlsx); click on the Excel workbook tab containing Figure 2-5.

Figure 2-5 (truncated)

Figure 2-5 (truncated) TREATMENT-TREATMENT MATRIX UPPER MATRIX - RAW DATA - CELL ENTRIES ARE NUMBER OF RECORDS THAT CONTAIN BOTH TREATMENTS 1 2 3 # REC--> 3174 1481 1392 #REC TREAT/TREAT---->>>cholinesterasedonepezil inhibitorantioxidant 3174 cholinesterase inhibitor 3174 799 165 1481 donepezil 799 1481 48 1392 antioxidant 165 48 1392 1219 immunotherapy 74 17 30 958 memantine 512 284 34 874 Rivastigmine 552 451 19 734 galantamine 463 407 20

TREATMENT-TREATMENT MATRIX NORMALIZED LOWER MATRIX - NORMALIZED - CELL ENTRIES ARE NORMALIZED TO MINIMUM TOTAL RECORDS OF EITHER TREATMENT (CODE: DARK RED; >Ii 0.5; LIGHT RED: 0.3 3174 1481 1392 #REC TREATMENT cholinesterasedonepezil inhibitorantioxidant 3174 cholinesterase inhibitor 1 0.5395 0.118534 1481 donepezil 0.5395 1 0.034483 1392 antioxidant 0.118534 0.034483 1 1219 immunotherapy 0.060705 0.013946 0.02461 958 memantine 0.534447 0.296451 0.035491 874 Rivastigmine 0.631579 0.516018 0.021739 734 galantamine 0.63079 0.554496 0.027248

While there are myriad reasons for multiple AD treatments co-occurring in records, two of the main reasons seem to be 1) comparing the efficacy of one treatment against another, and 2) combining the treatments for more effective therapy. Thus, if a researcher/practitioner is interested in alternatives to a specific treatment, or synergies of individual treatments for more powerful results, this type of matrix may prove useful. Additionally, the normalized version of the treatment-treatment matrix can play a Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

similar role to that of the treatment factor matrix. Treatments that have some similarities will exhibit high values of the normalized values, as will treatments that are used most effectively in combination.

2E3. Matrix of AD Characteristics Impacted by AD Treatments vs AD Characteristics Impacted by AD Treatments

Figure 2-6 contains a matrix of the AD Characteristics (impacted by AD treatments identified in the present study) on each axis. There are two versions of this matrix in Figure 2-6. The upper matrix contains the raw data, where the cell entries i,j reflect the number of records that contain both AD characteristic i and AD characteristic j. The lower matrix contains normalized data, where each cell entry has been normalized to the minimum value of the number of AD characteristic i records or the number of AD characteristic j records (as in Figure 2-4). A truncated version of Figure 2-6 is presented below, to illustrate the figure's structure. The complete Excel spreadsheet containing Figure 2-6 is presented in the attached Excel workbook (see file FIGURES_FINAL.xlsx); click on the Excel workbook tab containing Figure 2-6.

Figure 2-6 (truncated)

Figure 2-6 (truncated) BENEFITS-BENEFITS MATRIX

UPPER MATRIX - RAW DATA - CELL ENTRIES ARE NUMBER OF RECORDS THAT CONTAIN BOTH BENEFITS #CELLS #REC-> 2220 1644 376 122 WITH #REC INFLAMM reducMETABOLISMSEROTONIN improvMDA incr decr ENTRIES 3697 MEMORY improv 464 286 58 71 211 720 ROS decr 176 95 3 33 136 322 BACE-1 reduc 39 26 1 3 117 #CELLS WITH ENTRIES----->>>>189 192 90 78

LOWER MATRIX - NORMALIZED TO TOTAL RECORDS OF THE SMALLEST OF THE TWO BENEFITS CODE: DARK RED; Ii>0.5; LIGHT RED; 0.3

#REC-> 2220 1644 376 122 #REC BENEFITS INFLAMM reducMETABOLISMSEROTONIN improvMDA incr decr 3697 MEMORY improv 0.209009 0.173966 0.154255 0.581967 720 ROS decr 0.244444 0.131944 0.007979 0.270492 322 BACE-1 reduc 0.121118 0.080745 0.003106 0.02459

Why is this matrix important? The effects of AD causes and treatments on the broad spectrum of AD characteristics can be represented as a complex network. There are direct interactions between

1) the exogenous AD causes and treatments that constitute the network boundary, and

2) the endogenous AD characteristics (at different hierarchical levels) that constitute the network interior.

There are direct relationships among the AD endogenous characteristics in the interior. Integrating these direct relationships along pathways that link causes or treatments to impacts yields voluminous pathways that link AD causes or treatments to their impacts indirectly. Identifying the complete pathways that link AD causes or treatments directly and indirectly to specific AD impacts requires the combination of

1) the direct interactions of the exogenous AD causes and treatments with the endogenous AD characteristics, and

2) the relationships among the AD characteristics that lead to the specific impacts desired.

For example, we may want to know whether/how treatment X could reduce Abeta, if there is no published evidence of a direct link between treatment X and the reduction of Abeta. Assume treatment X has been shown to reduce/inhibit BACE1 (beta secretase). Also assume there are (many) published papers showing that reduction/inhibition of BACE1 is associated with Abeta reduction. Then, combining

1) the direct interaction of treatment X with BACE1 inhibition/reduction with

2) the direct relationship between BACE1 inhibition/reduction and Abeta reduction, we can infer that treatment X may result in reduction of Abeta through the indirect treatment X-BACE1- Abeta pathway.

Given

1) the large numbers of AD characteristics impacted by many different AD treatments as shown on Figure 2-4, and

2) the large numbers of characteristic-characteristic relationships as shown on Figure 2-6, it is clear there may be very large numbers of indirect pathways that link specific AD treatments to desired higher-level target impacts. Delineation of these internal linkages that allow the full network pathway structure to be developed is a key benefit from the AD characteristics-characteristics matrix of Figure 2-6.

Additionally, the strong co-occurrences among the major AD pathology markers reflects the strong inter-relationships among the pathologies represented by the AD hypotheses. This supports our approach of addressing all AD pathologies, rather than those AD pathologies reflecting only one hypothesis.

2F. Matrix of AD Causes vs AD Characteristics Impacted

To keep the present monograph relatively self-sufficient in developing a treatment protocol that includes identifying AD characteristics, removing AD causes, and implementing AD treatments, some representation of AD causes needs to be included.

The specific representation of AD causes in Table 2-7C, taken from Table 8-3 of the previous AD causes-based monograph [3], is a combination of

1) MeSH terms,

2) text phrases, and

3) manually-assigned terms not precisely listed in the abstract phrases.

In addition, some of the AD causes identified were not in the title or abstract phrases of their records, but had to be obtained from reading the full-text version of the record. To convert these AD causes representations to a form that could be used in an abstract phrases-based matrix, the abstract phrases representation of these AD causes was required.

Because the present monograph is a proof-of-principle demonstration, a complete listing of the ~600 causes (depending on aggregation level) shown in Table 2-7C was not deemed necessary to illustrate the AD causes-impacts matrixing. Table 2-8 shows the fifty contributing factors that were extracted from Table 2-7C and used for illustrative matrixing purposes. Some of these contributing factors were aggregated (such as pesticides), and incorporated the many specific contributing factors (such as specific pesticides and herbicides) that are listed separately in Table 2-7C. These fifty existing AD causes have been matrixed with the existing AD characteristics impacted, and the results are shown in Figure 2-7. A truncated version of Figure 2-7 is presented below, to illustrate the figure's structure. The complete Excel spreadsheet containing Figure 2-7 is presented in the attached Excel workbook (see file FIGURES_FINAL.xlsx); click on the Excel workbook tab containing Figure 2-7.

Figure 2-7 (truncated)

Figure 2-7 AD CAUSES-IMPACTS MATRIX

UPPER MATRIX CONTAINS RAW DATA (CELL ENTRIES ARE NUMBERS OF RECORDS THAT CONTAIN BOTH TERMS) #CELLS # REC--> 24065 7388 5358 4418 WITH # REC CAUSE IMPACT--> COGNITIONMETABOLISM degrad INFLAMM decr incrOXIDATIVEENTRIES STRESS incr 547 SMOKING 223 41 27 29 101 446 EXCESS ALCOHOL 131 49 17 20 92 397 HIGH AGEs DIET 54 54 114 104 101 205 ANESTHETICS 83 12 18 7 75 129 PESTICIDES 23 19 5 25 61 117 HIGH FAT DIET 42 51 19 10 78 #CELLS WITH ENTRIES--->>> 47 46 41 38 2612

LOWER MATRIX - NORMALIZED BY INCLUSION INDEX Ii (CELL ENTRIES ARE NUMBERS OF RECORDS THAT CONTAIN BOTH TERMS DIVIDED BY THE MINIMUM OF EITHER TERM) CODE: DARK GREEN: Ii >0.499999; LIGHT GREEN: 0.299999 24065 7388 5358 4418 #REC CAUSE IMPACT--> COGNITIONMETABOLISM degrad INFLAMM decr incrOXIDATIVE STRESS incr 547 SMOKING 0.407678 0.074954 0.04936 0.053016 446 EXCESS ALCOHOL 0.293722 0.109865 0.038117 0.044843 397 HIGH AGEs DIET 0.13602 0.13602 0.287154 0.261965 205 ANESTHETICS 0.404878 0.058537 0.087805 0.034146 129 PESTICIDES 0.178295 0.147287 0.03876 0.193798 117 HIGH FAT DIET 0.358974 0.435897 0.162393 0.08547

There are two versions of this matrix in Figure 2-7. The upper matrix contains the raw data, where the cell entries reflect the number of records that contain both the AD cause and AD characteristic. The lower matrix contains normalized data, where each cell entry has been normalized to the minimum value of the number of AD causes records or the number of AD characteristics records, and has been color-coded in the same manner as the previously-shown normalized matrices.

At the right end of the upper matrix is a column titled: "# cells with entries". Essentially, the entries in this column reflect the number of AD characteristics impacted by the AD cause of interest, and have the same type of interpretation as their counterparts in the treatment-characteristics matrix of Figure 2-4. For example, consider the third cause listed on Figure 2-7 (truncated), High AGEs Diet (cell C19 of the complete Excel spreadsheet). Its entry in the rightmost column (cell HE19 of the complete Excel spreadsheet) is 101, meaning that it impacted 101 AD characteristics. There were substantial impacts on inflammation, oxidative stress, metabolism, and these impacts occurred in parallel many times. Use of this metric can be helpful in determining the breadth of potential AD causes that could produce abnormal AD characteristic values, and determining which existing AD causes are most relevant to the patient whose AD-related characteristics are being evaluated. It should be emphasized that this metric focuses on the number of existing AD characteristics impacted by particular existing AD causes, not the strength of the impact.

Immediately below the upper matrix is a row titled:"# cells with entries". The entries in this row reflect the numbers of existing AD causes that impact the AD characteristic of interest, and, again, have the same type of interpretation as their counterparts in the treatment-characteristics matrix (Figure 2-4).

For example (as was done in the illustrative example associated with Figure 2-4), consider the impact of AGEs on the more general AD characteristic Metabolism (cell I19 in the complete Excel spreadsheet). The overwhelming majority of Metabolism AD causes-related records emphasize the increase in dysfunction of this AD characteristic and its related biomarkers hypertension, defective insulin resistance and signaling, lipid dysregulation, glycemia, dysregulated glucose metabolism, high triglycerides and high cholesterol. The Metabolism entry in the row '# cells with entries' (cell I63) is 46, meaning that 46 existing AD causes (of the total of fifty used for the matrix) impacted this AD characteristic (~90% of the total number of existing AD causes listed). These AD causes ranged from high-tech (chemotherapy, ovariectomy, cyanobacteria, heavy metals, etc) to low-tech (high fat diet, high cholesterol diet, high AGEs diet, chronic stress, excess alcohol, etc).

Thus, in most cases, multiple AD causes need to be eliminated to prevent and reverse AD. Also, the most readily identifiable and easiest to remove AD causes (the 'low-hanging fruit') are preferable as a starting point in a multiple AD cause elimination protocol. The above results indicate that elimination of the lower tech AD causes responsible for increasing Metabolism dysregulation is within the control of a motivated individual. Taking this modest cause elimination step initially can ease the transition to elimination of the higher-tech AD causes that are harder to identify and may be less within an individual's control.

If, for many people (especially those not overexposed to many of the high-tech AD causes by virtue of their occupations or residence locations), the lower tech AD causes constitute the majority of their most important contributing factors to AD, cause elimination required to correct abnormal AD characteristic values based mainly/entirely on eliminating the 'low-hanging fruit' may be very feasible. In fact, this is essentially what Bredesen [13] and the Sherzais [14] have done. Their healing approaches emphasize mainly lifestyle-based AD cause removal, and substitution of positive lifestyle practices for negative lifestyle practices. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

2G. Under-representation of AD Causes, Treatments, and Characteristics

The previous sections of the present chapter have shown that, while the numbers of AD causes, treatments, and characteristics identified in the previous and present monographs of the AD study are massive compared to any other study in the literature, these numbers are

1) a modest fraction of what could theoretically be extracted from the existing AD literature and

2) a very modest fraction of what could be extracted from both the existing AD literature and non-AD literature.

There are two main reasons for this. First, numbers of AD causes, treatments, and characteristics are under-reported in the biomedical literature (especially AD causes). Second, resource limitations restricted the numbers of AD causes, treatments, and characteristics that could be extracted from what is reported in the biomedical literature.

There are myriad reasons for under-reporting of AD causes, treatments, and characteristics. These include:

 lack of incentives for industry and government to sponsor research on AD causes from industrial products  lack of incentives for some journals (especially those with sponsorship from industry or government) to publish research on AD causes from industrial products  limited scope and variables measured in many research projects

There are also myriad reasons that extraction of AD causes, treatments, and characteristics from those reported in the biomedical literature was limited in the present study. Most reasons for limited extraction from the reported data are based on resource and time limitations for the study, but process, software, and data limitations played a role as well. These issues are discussed in the remainder of this chapter. For those readers who want to access the AD treatment protocols directly at this point, they can be found in Chapter 3.

2G1. Under-reporting of AD Foundational Causes

2G1a. Reduced incentives for sponsoring and reporting AD foundational causes

Chapter 9 of reference [15], and reference [16], contain many caveats showing why the numbers of AD (or any other chronic disease) foundational causes presented in Table 2-7C and our previous monograph [3] may be vast under-representations of the numbers of AD operational foundational causes. Summarily, many adverse events are not reported and published in the literature (e.g., see references 70- 125 of reference [15]), or, if they are reported and published, many are not accessed due to inadequate search algorithms. The under-reporting occurs at the patient, doctor, researcher, journal, corporate, and Federal agency levels, mainly because of myriad incentives (and few disincentives) for under-reporting. See Chapter 9 of reference [15], or reference [16], for further examples. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Under-reporting can be disguised through selective reporting of adverse events. For example, in our April 2017 monograph focusing on AD causes [3], we considered an endogenous substance to be a foundational cause if it was administered exogeneously in lab tests for the purpose of better understanding its pathological mechanisms. There was a substantial amount of research reported on these intrinsically endogenous substances, and they were high-frequency in the literature (large numbers of records). These endogenous substances are typically not major industrial products, and therefore pose no threat to any industry if adverse effects are reported. As an example, there were many studies where Abeta was administered exogenously, in order to study its effects under more controlled conditions. Contrast this high level of effort on Abeta as an exogenous contributing factor to AD with the low level of research effort on the myriad harmful occupational and environmental substances and radiations.

In the same vein, for those foundational causes that are accepted as harmful (smoking, excess alcohol, etc), again, there is little reluctance for research funding into adverse effects. For potentially toxic substances that have not yet received public consensus as being harmful, industry and government research funds are sparse. This is reflected by the large number of very detailed foundational causes (typically specific chemicals, materials, or radiations) appearing in only one or two records in reference [15] and the present study.

So, while AD research on potential foundational causes may appear to be substantial based on overall funding and levels of effort, the research effort/funding is highly skewed toward 'safe' research on already known harmful substances, and away from substances important to industry and government not yet proven to be toxic.

2G1b. Resource limitations to identifying foundational causes

2G1b1. Existing foundational causes

Additionally, in the initial process of identifying the existing AD causes listed in Table 2-7C, identification of the higher-frequency causes (including some relatively general causes) was quite comprehensive. There were many lower frequency causes identified through the linking terms, but the latter process was truncated because of time considerations. Unfortunately, as the record frequency of AD causes decreases, the number of discrete AD causes increases drastically. These lower frequency AD causes tended to be highly specific in chemical and radiation exposures from industrial practices, medical treatments, everyday personal exposures, etc. Thus, over and above the existing AD causes that have not entered the AD literature for the reasons described in the previous section, there are probably many hundreds of low-frequency AD causes in the literature that were not accessed due to our time/resource limitations.

2G1b2. Potential foundational causes

Another constraint imposed by our resource limitations was identification of potential AD foundational causes. The LRDI approach for identifying potential AD foundational causes (aka literature-related discovery) is analogous to that used for identifying potential AD treatments, shown in section 2C2. Non-AD literatures are examined for causes that move the values of AD characteristics in some desired pre-determined direction, but these causes have not been identified in the AD literature. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

This LRDI-discovery approach was demonstrated in the chronic kidney disease (CKD) LRDI study [17]. It was clear from the voluminous retrievals in the CKD study that many hundreds of potential CKD contributing factors could be identified with the LRDI discovery process, and similar results for identifying AD causes would be expected from application of this LRDI discovery process to the biomedical literature.

2G1c. Limited research focus on identifying foundational causes

Further, in the epidemiological studies whose focus was on AD cause identification, only a finite number of AD causes to be identified were the objects of the research. AD causes that were operable, but not search targets, would not be identified.

2G1d. Research concentration on identifying foundational causes in isolation

Also, in both the epidemiology and laboratory studies, very few studies attempted to ascertain synergies resulting from combined potential contributing factors. These included factors that, when operating in isolation, produced no or miniscule harmful effects, but when operating in combination, produced very harmful effects.

2G2. Under-reporting of AD Treatments

It was shown in section 2G1 that under-reporting of causes had two major components: technical and disincentives for reporting. Under-reporting of treatments is mainly due to technical reasons, since there are many incentives for sponsorship and publication of AD treatment research.

2G2a. Resource constraints

2G2a1. Existing AD treatments limited

Existing AD treatments were identified in two ways primarily: visual examination of the high- frequency title and abstract phrases, and use of linking phrases (e.g., improve, restore, mitigate, etc) to identify low-frequency title and abstract phrases. As in the case of the foundational AD causes, the numbers of existing AD treatments increased drastically as the frequency of appearance in the literature decreased. So, most of the existing AD treatments to be identified were in the region that required linking phrases to access. Because of resource constraints and time limitations, only a few of the linking terms identified were used operationally. While this approach allowed identification of massive numbers of existing AD treatments, the limited use of linking terms meant that additionally massive numbers of existing AD treatments were not being identified. An expanded study could overcome this deficiency.

2G2a2. Potential AD treatments limited

Resource constraints also limited the number of potential AD treatments that could be identified. These are treatments that influence AD characteristics in directions desired for AD reversal, and are presently being used for non-AD diseases. Our LRDI discovery approach allows these potential AD treatments to be readily identified, and 're-purposed' for AD application. Exploratory analysis showed that voluminous treatments from non-AD literatures had potential to be 're-purposed' for AD, but only a handful of potential AD treatments were identified for the present proof-of-principle demonstration. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

2G2b. Process, software, and database limitations

While the linking term approach was indispensible for extracting existing AD treatments from the millions of AD abstract phrases, it had intrinsic limitations. While many AD treatment phrases were in close proximity to linking terms, not all AD treatment phrases were. Some AD treatment phrases were slightly outside the four-word range of the software abstract phrases, while other AD treatment phrases were not associated with any of the linking terms identified in the present study.

The titles were searched initially for existing AD treatments, and then the abstracts were searched. Unfortunately, there were records in which the existing AD treatment occurred in full-text only, and not in the title or abstract. Full-text searching would overcome this limitation. However, not all biomedical records are available in full-text on the main biomedical databases, and the complexity of searching full-text increases substantially over searching titles or abstracts [18].

2G3. Under-reporting of AD characteristics

The high-frequency AD characteristics were identified from visual examination of the abstract phrases in the retrieved AD database. The low frequency AD characteristics were identified and extracted with use of the linking terms developed for identifying and extracting treatments.

2G3a. Process, software, and database limitations

Although more linking terms were used to identify existing AD characteristics than were used to identify existing AD treatments, the identification process was terminated due to resource and time limitations. Many of the comments made in the previous AD treatments section apply to AD characteristics as well.

While many AD characteristics phrases were in close proximity to linking terms, not all AD characteristics phrases were. Some AD characteristics phrases were slightly outside the four-word range of the software abstract phrases. In many cases, this was because AD characteristics phrases were used in one long sentence following one linking term (e.g., treatment X attenuated characteristic A, characteristic B, characteristic C, etc, where only characteristic A would be in the range of the software phrase length). Other AD characteristics phrases were not associated with any of the linking terms identified in the present study.

The titles were searched initially for existing AD characteristics, and then the abstracts were searched. Unfortunately, there were records in which the existing AD characteristics occurred in full-text only, and not in the title or abstract. This occurred much more frequently than for treatments, since AD treatments tended to be the focus of the research more than the AD characteristics. Full-text searching would overcome this limitation. However, not all biomedical records are available in full-text on the main biomedical databases, and the complexity of searching full-text increases substantially over searching titles or abstracts [18].

2G3b. Experiment and epidemiology study limitations

In order for AD characteristics to be reported, they need to be identified and measured. Lab experiments targeted a handful of AD characteristics to be measured, typically selected for their relevance to the AD hypothesis being addressed by the researcher. Epidemiology studies used AD characteristics identified in medical records or stated on questionnaires. Every additional AD characteristic that is added to a lab experiment or epidemiology study translates into additional time and other resource expenditures. This effectively limits the number and scope of AD characteristics selected for any given lab experiment or epidemiological study.

The main point here is the AD characteristics that change based on AD causes or treatments will be a small fraction of all the AD characteristics that could have been measured and shown to have changed due to AD causes or treatments. This has strong implications on the populations of the AD causes-characteristics or AD treatments-characteristics matrices. It is our contention that the matrices presented above, massive as they are relative to any others that appear in the AD literature, are vastly under-populated because of the limited scope of the epidemiological studies or lab experiments relative to breadth of AD characteristics examined.

2G3c. Resource limitations on identifying potential AD characteristics

While many hundreds of existing AD causes and treatments were identified in the present study, many hundreds more could have been identified if the limitations described above were removed. Additionally, many more potential AD causes and treatments could have been identified by using the LRDI process to search non-AD literatures.

The same holds true for identifying potential AD characteristics. There are patterns/groupings of AD characteristics that could be used to search the non-AD literatures for groups of characteristics that include the AD group patterns, but may also contain other characteristics that were not included in the AD groups in the AD literature. Identifying potential AD characteristics was not explored in the present study, so it is not credible to make estimations of the magnitude of additional AD characteristics possible using this approach.

2G4. Impact of under-reporting of AD causes, treatments, and characteristics

What is the real-world impact from the under-reporting of AD causes, treatments, and impacts, as outlined above? As will be shown in the next chapter on AD treatment protocols, the AD protocols involve

1) measuring relevant AD characteristics for individual patients,

2) identifying causes to be removed based on that patient's AD characteristics' abnormalities, and

Any deficiencies in not identifying, or mis-identifying, AD characteristics, causes, and treatments will translate into deficiencies of these AD protocols' effectiveness.

In the results presented so far in the present chapter, the AD treatment-characteristics (Figure 2-4) and causes-characteristic matrixes (Figure 2-7) have their axes ordered starting with largest numbers of records at top left, and decreasing numbers of records when proceeding rightwards and downwards. Both types of matrices are dense in the upper left region and very sparse in the lower right region. The AD treatment-characteristics matrix has approximately ten percent of its cells populated with any records. Even for those cells that contain record numbers, the number of records they contain is a very small fraction (on average) of what they could theoretically contain, as the numerical entries in the normalized matrix cells show. While an expanded study could increase both the density of the matrix and the length of the axes (probably over 1000 existing AD foundational causes, over 1000 existing AD treatments, and over 500 existing AD characteristics), it would offer little if any insight on the magnitude of the AD causes being suppressed by sponsors, journals, and performers.

References - Chapter 2

Chapter 3

Treatment Protocol

3A. Overview

Our April 2017 monograph [1], which identified a wide spectrum of AD causes, also included a general protocol for preventing and reversing AD. The essence of this general protocol was removing as many of these identified AD causes as comprehensively, thoroughly, and rapidly as possible, and substituting positive replacements where possible. While we continue to believe this is an effective approach, the practicality of convincing practitioners and patients to remove perhaps hundreds of potential AD causes thoroughly and rapidly is open to question. Many of the AD causes, especially those related to lifestyle choices, can be viewed as addictions. We know from experience that eliminating even one or two addictions can be challenging, much less eliminating tens of addictions or more.

Some of the readers of reference [1] suggested that we perform a similar study to both identify a wide spectrum of AD treatments and develop an AD treatment protocol tailored to specific individuals. The present monograph is our response to these reader suggestions, and the present chapter contains the individually-tailored AD treatment protocol.

In our full AD study, reflected by combination of the April 2017 monograph [1] and the present monograph, we identified perhaps 500 AD causes (depending on how one aggregates AD causes at different levels), a similar number of AD treatments (again, depending on aggregation), and perhaps 250 AD characteristics. In the present monograph, we have made the point repeatedly that an expanded study (including recommendations for study process improvement outlined throughout this monograph) could double these numbers of existing AD causes, treatments, and characteristics identified, or more. Additionally, we have also stressed the point that the LRDI technique could be used to easily identify hundreds more potential AD causes, treatments, and characteristics.

Therefore, our challenge for developing a realistic AD treatment protocol is to

1) reduce the numbers of AD characteristics to be measured, AD causes to be eliminated, and AD treatments to be implemented from

2) the many hundreds of measurable existing and potential AD characteristics, AD causes, and AD treatments identified to

3) reasonable numbers of AD characteristics to be measured, AD causes to be eliminated, and AD treatments to be implemented.

The following sections of the present chapter outline the major components of the AD treatment protocol in chronological order. We believe adherence to this protocol will restore adequate functionality to a substantial number of AD patients; quantification of this hypothesis will require clinical trials for credible estimation. Strict adherence to this protocol will also prevent a substantial number of AD-prone cases from ever coming to fruition. A summary of the complete AD treatment protocol is contained in section 3B6. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

3B. AD Treatment Protocol in Chronological Order

There are five steps in the full treatment protocol:

FIVE-STEP PROTOCOL TO PREVENT AND REVERSE AD

These five steps will now be described in more detail.

3B1. Medical History Questionnaire

The first step in the protocol is to obtain a detailed medical and habit/exposure history from the AD patient. The patient would be provided a detailed questionnaire focusing mainly on practices and exposures that are potential AD contributing factors. The AD contributing factor component of the questionnaire would be based on Table 2-7C, or, preferably, on a similar table derived from an expanded study. In the latter case, there could be greater than 1,000 potential contributing factors identified.

Most of the questions would not be answerable. The patient (or caretaker) might be able to answer a number of questions related to the lifestyle and iatrogenic components of Table 2-7C, and perhaps a few of the questions related to the occupational exposures component if these exposures were significant. However, most patients would probably not be able to identify past and present exposures to many hundreds of chemicals and radiations that are contributing factors to AD. The questionnaire would yield some idea of past and present relevant AD contributing factors for the patient, with much to be determined by further testing.

Thus, the patient would probably be able to provide some estimate of dietary components, sedentary behavior, sleep quality, recreational drug use, major medications taken and surgeries experienced, and perhaps exposures to pesticides, ionizing radiation, asbestos, etc, as part of their job. The patient would probably not be able to identify food additives ingested when they ate out, chemicals in their home from cleaning and new furniture, exposure to non-ionizing radiations, etc.

For those patients whose major AD contributing factors are in the readily identifiable category, their chances of reversing AD are reasonable (assuming irreversible damage has not been done and they do not have an overwhelming genetic predisposition to AD). For those patients whose major AD contributing factors are in the non-identifiable category, complete reversal would be much more of a challenge. Reversal for them may in fact require identification and elimination of far more of the AD contributing factors. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

3B2. Assess Behaviors/Performance Observables

The second step in the protocol is to administer written and clinical performance and behavioral tests to assess the severity of the higher-level symptoms. This would include tests for memory, learning, cognition, etc, and for apathy, depression, anxiety, aggression, agitation, etc. The latter group of mood- related tests would have some overlap with the medical history on the initial questionnaire.

3B3. Administer Laboratory Tests

3B3a. Criteria for AD characteristics laboratory tests

The third step in the protocol is administration of laboratory tests (blood, urine, imaging, etc). Any abnormalities shown by these tests would help prioritize the AD contributing factors to be eliminated and AD treatments to be implemented in the streamlined protocol presented in this chapter.

In the present study, approximately 250 AD characteristics were identified. Perhaps twenty percent could be classified as behaviors and performances, whose abnormalities would be reflective of AD, and whose evaluation would be addressed by the procedures in section 3B2. The remaining ~eighty percent were estimated to be laboratory-measurable quantities. It was also estimated these numbers of measurable AD characteristics could be at least doubled in an expanded study. Therefore, for a non- streamlined protocol, this step in the protocol could involve the administration of ~400 lab tests (or more) to identify the full spectrum of abnormalities in these measured AD characteristics.

Given costs and other negative aspects of such tests, the number of tests would have to be reduced by almost an order of magnitude to be acceptable to both the patient and the healthcare practitioner. In other words, hundreds of laboratory tests are too large to be practical, at the present time. We propose a greatly reduced number of lab tests, selected for their ability to cover a wide swath of AD- related pathologies. Results from these core lab tests will help prioritize AD causes to be eliminated and AD treatments to be implemented.

Our approach is cause-and-effect based. We allow that many, if not all, of the (mainly) pathology-based AD hypotheses in the Introduction may be operable. We then ascertain whether the AD characteristics associated with these myriad AD hypotheses/pathologies could be useful for determining AD causes to be eliminated and/or AD treatments to be implemented.

To identify this abridged core group of critical lab-measured AD characteristics, we use concepts from surveillance theory and strategy. An often-used surveillance approach for identifying small-scale phenomena of interest in a large unexplored region is to

1) use a sampling strategy throughout the region to obtain a high-level perspective on areas of interest, and, after analyzing the samples,

2) sharpen the focus on those sub-regions that showed highest probability of containing the small- scale phenomena of interest. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

In the vernacular, it is known as starting with the view from 30,000 feet, and then focusing on the areas of interest at ground level.

In the present case, the large region is (at a minimum) the full list of AD characteristics shown on Table 2-1. These would be augmented substantially by the added AD characteristics from the expanded study recommended previously. Superimposed on the full list of AD characteristics would be the condition that sampling would be performed from categories generated by some combination of

1) the individual factors in the AD characteristics factor matrix of Figure 2-1 and

2) the myriad AD hypotheses listed in the Introduction.

While the factor matrix and AD hypotheses have some overlap, they each contain unique features. A few AD characteristics would be drawn from each unique factor and hypothesis category to insure coverage of the major pathologies reflected by the AD hypotheses and the factor matrix. If large abnormalities are shown in the values of the AD characteristics extracted, then other AD characteristics from these critical category factors and hypotheses could be sampled for further insights.

To reiterate, the final streamlined AD characteristics selected will encompass the pathologies viewed by the AD research community as important features of AD. Because of the inter-connectedness of major systemic networks (immune system, neural system, endocrine system, circulatory system, etc.), one would expect the myriad pathologies enumerated by the hypotheses and factors to have some relationship. Because of this ripple effect, important AD contributing factors and important AD treatments are expected to be systemic in their impact. This systemic impact would be reflected by

1) important AD contributing factors producing abnormalities in many of the hypothesis and factor-driven categories used as the basis for AD characteristics selection, and

2) important AD treatments removing abnormalities in many of the hypothesis and factor-driven categories used as the basis for AD characteristics selection.

3B3b. Sample recommendations for AD characteristics laboratory tests

Based on the criteria for selecting potential AD characteristics laboratory tests in the previous section, numbers of possible combinations were examined. Following is the combination selected for the present example. Different practitioners may interpret the source data differently, and modify the combinations. Other modifications and additions could be expected after an expanded study was conducted.

Table 3-1 contains the approximately seventy AD characteristics selected for initial laboratory tests in the AD protocol. These ~seventy AD characteristics reflect the approximately twenty AD pathological themes (Table 3-2) derived from the myriad AD hypotheses in the Introduction and the major themes from the AD characteristics factor matrix (Figure 2-1). The AD characteristics are typically not uniquely related to the pathological themes. Usually, any one of the AD characteristics in the selected group will be related to multiple AD pathologies, and any one of the AD pathologies will be related to many of the AD characteristics. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

3B4. Recommend AD Contributing Factors to be Eliminated

The fourth step in the AD treatment protocol is elimination of as many of the ongoing AD contributing factors as possible. Once the laboratory tests have been completed, the abnormalities in the AD characteristics' values can be identified. This allows causes to be eliminated and treatments to be implemented.

Figure 3-1 is a matrix of 1) the ~fifty heavily streamlined causes from Table 2-8 and 2) the ~seventy reduced AD characteristics from Table 3-1. The complete Excel spreadsheet containing Figure 3-1 is presented in the attached Excel workbook (see file FIGURES_FINAL.xlsx); click on the Excel workbook tab containing Figure 3-1. A truncated version of Figure 3-1 follows.

Figure 3-1 (truncated)

Figure 3-1 AD CAUSES-IMPACTS MATRIX (protocol)

UPPER MATRIX CONTAINS RAW DATA (CELL ENTRIES ARE NUMBERS OF RECORDS THAT CONTAIN BOTH TERMS) #CELLS #REC--> 6766 3692 2245 971 WITH #REC CAUSE IMPACT--> APOPTOSISHYPERPHOSPHORYLATION incr ROS incr CASPASE incr incrENTRIES 547 SMOKING 13 2 20 45 446 EXCESS ALCOHOL 27 3 7 2 44 397 HIGH AGEs DIET 60 20 42 7 53 205 ANESTHETICS 39 26 5 27 34 129 PESTICIDES 9 3 7 1 35 117 HIGH FAT DIET 5 13 1 1 35 #CELLS WITH ENTRIES 44 34 43 26

#REC--> 6766 3692 2245 971 #REC CAUSE IMPACT--> APOPTOSISHYPERPHOSPHORYLATION incr ROS incr CASPASE incr incr 547 SMOKING 0.023766 0.003656 0.036563 0 446 EXCESS ALCOHOL 0.060538 0.006726 0.015695 0.004484 397 HIGH AGEs DIET 0.151134 0.050378 0.105793 0.017632 205 ANESTHETICS 0.190244 0.126829 0.02439 0.131707 129 PESTICIDES 0.069767 0.023256 0.054264 0.007752 117 HIGH FAT DIET 0.042735 0.111111 0.008547 0.008547 Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

In the upper matrix (un-normalized), for example, High AGEs Diet impacts 53 AD characteristics, according to the column on the right labeled #Cells With Entries. Also, from the upper matrix, ROS (reactive oxygen species) is increased by 43 different causes. In some cases, there are many records describing a cause-impact relationship; in other cases, there are very few records. The latter may reflect a lack of research into the relationship or a suppression of the publication of the relationship rather than any intrinsic weakness of the causes-impact relationship.

Because most of the AD characteristics listed in the complete Table 3-1 are related to multiple causes, 'reverse-engineering' the abnormal AD characteristics values to identify candidate AD causes for elimination will be difficult. For example, if only one AD characteristic had abnormal values, there could be tens or hundreds of AD causes for this abnormality that could be identified through 'reverse- engineering' for potential elimination.

We propose a combined 'direct-identification' and 'reverse-engineering' approach that has the virtue of simplicity. The 'direct-identification' component consists of eliminating the AD contributing factors the patient listed on the initial medical/exposure questionnaire. The 'reverse-engineering' component

1) identifies all the patient's AD characteristics with abnormal laboratory test values,

2) identifies the number of these abnormal AD characteristics impacted by each AD contributing factor, then

3) prioritizes the AD contributing factors for elimination according to the number of AD characteristics impacted by the AD contributing factors.

For example, suppose five of the AD characteristics measured show abnormal values: high AGEs, low ATP, low BDNF, high Homocysteine, high IL-6. An analysis of Figure 2-7 yields the number of the above five AD characteristics impacted by each AD contributing factor (see Table 3-1A). The 'reverse-engineering' component suggested above would give highest priority for elimination to the first eight AD contributing factors listed in Table 3-1A (each of which impacted all five AD characteristics with abnormal values. Second highest priority for elimination would be the next four AD contributing factors listed (each with four AD characteristics impacted), and so on.

Table 3-1A

Number of Abnormal AD Characteristics impacted by AD Contributing Factors

Table 3-1A AD CONTRIBUTING #AD AD CONTRIBUTING #AD FACTOR CHARACTERISTICS FACTOR CHARACTERISTICS IMPACTED IMPACTED

Heavy Metals 5 Vit D Deficiency 1 Head Trauma 5 Air Pollution 1 Smoking 5 Rotenone 1 H2O2 5 Formaldehyde 1 Excitotoxins 5 Iron Deficiency 1 High AGEs Diet 5 Bulbectomy 1 Reactive Aldehydes 5 Cyanide 1 High Cholesterol Diet 5 Vit E Deficiency 1 Excess Alcohol 4 High Salt Diet 1 Anesthetics 4 Vit C Deficiency 1 Vit B Deficiency 4 Thapsigargin 0 Sedentary 4 Non-Ionizing Radiation 0 Viruses 3 Cyanobacteria 0 Chronic Stress 3 Nerve Agents 0 Chemotherapy 3 Organic Solvents 0 Ovariectomy 3 Zinc Deficiency 0 MPTP 3 Nanoparticles 0 High Fat Diet 3 High Meat Diet 0 Chlorinated Bypass Surgery 3 Solvents/PCBs 0 High Refined Carbo Diet 3 Lipophilic Chemicals 0 Pesticides 2 Magnesium Deficiency 0 OHDA/DHT 2 Dioxin 0 High Calorie Diet 2 MSG 0 Brominated Flame Recreational Drugs 1 Retardant 0 Ionizing Radiation 1 Mycotoxins 0

Within each group, further prioritization for AD contributing factor elimination is possible. The members of each group would be intersected with the full list of 'low-hanging fruit', and those would receive higher priority for elimination. For example, consider the top group of eight AD contributing factors, each impacting all five AD characteristics. The lowest-hanging fruit would be elimination of smoking, reduction of AGEs, and reduction of factors in the diet that raise serum cholesterol. These are well within the patient's/caretaker's control. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Heavy metals are almost the opposite. Who knows how much heavy metal we accumulate from the food we eat, the air we breathe, and the drugs/vaccines we take? Head trauma are in the middle ground. Head trauma from accidents are typically out of one's control. However, head trauma from myriad sports (football, boxing, etc) are well within one's control. Given the age at which such sports are played, avoidance of head trauma from those sports would be practiced as a preventive measure.

The next group of four AD characteristics impacted consists of almost all 'low-hanging fruit'. Excess alcohol can be reduced or eliminated, Vitamin B intake can be increased (if it is determined that the patient's low Vitamin B intake is a strong contributing factor to the patient's low Vitamin B in serum). Sedentary behavior can be reversed.

The recommended prioritization above is based on numbers of AD characteristics impacted by each AD contributing factor. It does not distinguish between one record describing the impact (for a particular AD contributing factor) or ten records describing the impact. Irrespective of the number of records describing the impact, it does not distinguish among the strengths of impact described in different records. This additional information could be used by the healthcare practitioner to modify the prioritization illustrated above.

The above prioritization approach would serve as a proxy for the more comprehensive elimination of all 'low-hanging fruit' recommended in reference [1].

3B5. Recommend AD Treatments to be Implemented

3B5a. AD treatment strategy

Figure 3-2 is a matrix of the treatments from Table 2-6 and the ~seventy reduced AD characteristics from Table 3-1. The complete Excel spreadsheet containing Figure 3-2 is presented in the attached Excel workbook (see file FIGURES_FINAL.xlsx); click on the Excel workbook tab containing Figure 3-2. A truncated version of Figure 3-2 is shown below. Not all the treatments from Table 2-6 are on the matrix axis of the full Figure 3-2, since some of the 700+ treatments from Table 2-6 were not linked to any of the strongly reduced numbers of AD characteristics on the other matrix axis.

Figure 3-2 (truncated)

Figure 3-2 AD TREATMENTS-IMPACTS MATRIX (protocol)

UPPER MATRIX CONTAINS RAW DATA (CELL ENTRIES ARE NUMBERS OF RECORDS THAT CONTAIN BOTH TERMS) #CELLS #REC--> 3579 1612 446 WITH #REC TREATMENT IMPACT> CHOLINESTERASEAPOPTOSIS GLUTAMATEinhibit ENTRIES 1481 donepezil 881 44 34 54 958 memantine 511 49 120 47 428 secretase inhibitors 21 29 9 48 232 Curcumin 22 32 1 47 188 DHA 2 29 1 44 100 resveratrol 8 16 1 41 #CELLS WITH ENTRIES 362 377 170

#REC--> 3579 1612 446 #REC TREATMENT IMPACT> CHOLINESTERASEAPOPTOSIS GLUTAMATEinhibit 1481 donepezil 0.5948683 0.0297097 0.0762332 958 memantine 0.5334029 0.0511482 0.2690583 428 secretase inhibitors 0.0490654 0.067757 0.021028 232 Curcumin 0.0948276 0.137931 0.0043103 188 DHA 0.0106383 0.1542553 0.0053191 100 resveratrol 0.08 0.16 0.01

There are six AD treatments shown on the truncated Figure 3-2. The top three are drugs, the bottom three are substances from plants/fruits or fish. The bottom three substances can be obtained from eating the appropriate foods, or they can be extracted from these foods and provided as supplements.

As the upper matrix shows, Donepezil appeared in 1481 records, and impacted 54 AD characteristics. Curcumin appeared in 232 records, and impacted 47 AD characteristics. Both these numbers should be viewed as lower bounds of impact, for reasons discussed previously. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Relatively speaking, the bottom three AD 'treatments' are low-risk, especially if obtained in physiological doses directly from eating foods. For AD multiple treatments, targeted to cover at least the AD characteristics that had abnormal test values redundantly, choosing the lowest-risk treatments is a desired conservative approach. Thus, from Figure 2-4, the low-risk treatments that cover the abnormal AD characteristics values would be identified and implemented. Additionally, those low-risk treatments which would serve as positive substitutes for the 'low-hanging fruit' causes to be eliminated would also be identified and implemented.

Even among low-risk AD treatments, some prioritization may be possible. The approach recommended parallels that for eliminating AD contributing factors. The approach is a hybrid of 'direct- identification' and 'reverse-engineering'. The 'direct-identification' component consists of identifying AD contributing factors from the medical/exposure questionnaire. Where applicable, AD treatments that are positive behaviors/habits would be substituted for the negative AD contributing factors under the patient's control. Thus, if the patient is eating a high AGEs diet, the 'treatment' would consist of substituting a low AGEs diet. If the patient is participating in minimal intellectually challenging activities, he/she would be encouraged to participate in more intellectually challenging activities.

The 'reverse-engineering' component' would be based on the laboratory tests. In parallel with the approach in the previous section, treatments would be prioritized based on the number of abnormal AD characteristics they would impact. The caveats of the previous section about relying on numbers of characteristics impacted would apply here as well.

3B5b. Examples of low-risk AD treatments

The low-risk AD treatments mentioned in section 3B5a would include, but not be limited to:

raspberries, grapes, flaxseeds, celery seeds, chestnuts, hazelnuts, pecans, almonds, walnuts, olives, artichokes, chicory, red onion, spinach, broccoli, apples, pomegranates, peaches, apricots, olive oil, canola oil), especially flavonoids (such as apples, blueberries, strawberries, red grapes, cabbage, broccoli, onions, capers, dark chocolate, cocoa, tea, red wine), isoflavones/genistein (such as soybeans, natto, tempeh, tofu, miso), and anthocyanins (such as blackberries, black currants, blueberries, strawberries, cranberries, eggplant, cherries, prunes, raisins, and the darker versions of raspberries, cabbage, plums, radish, grapes, plums, apples, beans, beets, cabbage, onions, pears, wines) o DHA/omega-3 fatty acid (such as salmon, herring, mackerel, anchovy, sardine, trout, shark, swordfish, mussel, sea bass, pollock, whiting, flounder, sole, lobster, halibut, carp, oyster, crab, mullet, tuna, perch, snapper, shrimp, octopus) o Vitamins B12/B6/Folate (such as meat [beef liver, lamb, beef], fish [sardines, mackerel, salmon], dairy [feta cheese, cottage cheese], eggs, legumes [chickpeas, fermented soy, pinto beans, lentils], fruit [banana, avocado], vegetables [spinach, parsley, broccoli, beets, turnip, asparagus,]) o Vitamin C (such as fruits [guavas, acerola cherry, kiwifruit, rose hips, strawberries, oranges, papayas, vegetables [bell peppers, broccoli, tomatoes, snow peas, kale]) o Vitamin D (such as fish [sardines, salmon, mackerel, tuna], liver [beef, calf, cod liver oil], dairy [milk, yogurt]; most importantly, sunlight on exposed skin) o Vitamin E (such as seeds [sunflower seeds, pumpkin seeds], nuts [almonds, hazelnuts, pine nuts], fish [abalone, salmon, trout], fruit [avocado, mango, kiwifruit], vegetables [red peppers, turnip greens, spinach, chard, squash, broccoli]) o lycopene (such as tomatoes, guavas, watermelon, papaya, grapefruit), o oleic acid (such as nuts [almonds, peanuts, pecans, cashews, pistachios, hazelnuts] seeds [sesame, sunflower], avocados, olives, and vegetable oils [safflower, almond, olive, sesame, sunflower]), o luteolin (such as dried oregano, celery seed, hot peppers, peppermint, sage, rosemary, juniper berries, thyme, radicchio, chinese celery), o quercetin (such as capers, lovage leaves, elderberry juice, dock leaves, raddish leaves, arugula, dill weed, coriander, and fennel, cilantro, banana peppers, juniper berries, oregano, onions, carob flour, radicchio, red leaf lettuce, onions, watercress, raw, asparagus, kale, okra, cocoa powder, chia seeds) o sulforaphane (such as broccoli sprouts, broccoli, cauliflower, kale, brussels sprouts, cabbage, collards, arugula, turnips) o resveratrol (such as red wine, red grapes, peanut butter, pistachios, cocoa powder, dark chocolate, strawberries, blueberries, bilberries, cranberries) o epigallocatechin-3-gallate (such as green tea, black tea, carob powder, apples, blackberries).

3B6. Treatment Protocol to Prevent and Reverse AD

This section summarizes the recommended treatment protocol for preventing and reversing AD. There are five steps in the full treatment protocol, as shown in the following:

FIVE-STEP TREATMENT PROTOCOL TO PREVENT AND REVERSE AD

These five steps will now be described in more detail.

Step 2. The second step in the protocol is to administer written and clinical performance and behavioral tests to assess the severity of the higher-level symptoms and degradation of executive functions. This would include tests for memory, learning, cognition, etc, and for apathy, depression, anxiety, aggression, agitation, etc. The latter group of mood-related tests would have some overlap with the medical history on the initial questionnaire.

Step 3. The third step in the protocol is administration of laboratory tests (blood, urine, imaging, etc). Any abnormalities shown by these tests would help prioritize the AD contributing factors to be eliminated and AD treatments to be implemented. Table 3-1 contains the approximately seventy AD characteristics selected for initial laboratory tests in the AD protocol. These ~seventy AD characteristics reflect the ~twenty AD pathological themes (Table 3-2) derived from the myriad AD hypotheses in the Introduction and the major themes from the AD characteristics factor matrix (Figure 2-1). Based on the laboratory test results, the health practitioner could require further tests to gain detailed information on problematic areas.

Step 4. The fourth step in the protocol is to eliminate ongoing AD contributing factors. Unfortunately, as Figure 3-1 shows, each AD contributing factor typically impacts many AD characteristics, and each AD characteristic is typically impacted by many AD contributing factors. Thus, in the general case, AD characteristic values abnormalities in the lab tests will not be uniquely related to specific AD contributing factors. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

To circumvent this problem, we propose a combined 'direct-identification' and 'reverse- engineering' approach that has the virtue of simplicity. The 'direct-identification' component consists of eliminating the AD contributing factors the patient listed on the initial medical/exposure questionnaire. The 'reverse-engineering' component

1) identifies all the patient's AD characteristics with abnormal laboratory test values,

2) identifies the number of these abnormal AD characteristics impacted by each AD contributing factor, then

3) prioritizes the AD contributing factors for elimination according to the number of AD characteristics impacted by the AD contributing factors.

See Table 3-1A and the surrounding narrative for an illustrative example of how this prioritization, and further sub-prioritizations, would operate.

The recommended prioritization above is based on numbers of AD characteristics impacted by each AD contributing factor. It does not:

1) distinguish between one record describing the impact (for a particular AD contributing factor) or ten records describing the impact,

2) distinguish among the strengths of impact described in different records, irrespective of the number of records describing the impact,

3) weight the AD characteristics by relative importance.

This additional information could be used by the healthcare practitioner to modify the prioritization illustrated above.

The above prioritization approach would serve as a proxy for the more comprehensive elimination of all 'low-hanging fruit' AD contributing factors recommended in reference [1]. To the degree possible, the patient should strive to eliminate as many of these 'low-hanging fruit' AD contributing factors as possible. The combination of 1) lack of knowledge about harmful exposures (limiting what can be answered on the initial medical/exposure questionnaire) and 2) incompleteness of AD characteristics measured will result in 3) AD contributing factors not being identified through the complete testing/evaluation process. Eliminating as many of the 'low-hanging fruit' AD contributing factors as possible will compensate partially for this lack of knowledge. Many of these items are under the patient's/caretaker's control, and can be readily eliminated. The details of this 'low-hanging fruit' recommendation are repeated here, because of their importance and centrality to the effectiveness of the overall protocol.

LOW-HANGING FRUIT RECOMMENDATIONS

There is an implicit assumption in some/many of these AD contributing factor elimination recommendations of a treatment implementation. For example, elimination of a high-fat diet (AD contributing factor) implies adoption of a low-fat diet (AD treatment).

Step 5. The fifth step in the protocol is to implement AD treatments. Because of risk associated with implementation of single AD treatments, and the lack of knowledge of how overall risk increases because of treatment combination synergies, it is highly recommended that the lowest-risk treatments be implemented initially. Higher-risk AD treatments can always be implemented at a later date, if the combination of AD contributing factor elimination and initial low-risk AD treatments is not achieving the desired results.

Even among low-risk AD treatments, some prioritization may be possible. The approach recommended parallels that for eliminating AD contributing factors in Step 4. The approach is a hybrid of 'direct-identification' and 'reverse-engineering'. The 'direct-identification' component consists of identifying the patient's AD contributing factors from the medical/exposure questionnaire. Where applicable, AD treatments that are positive behaviors/habits would be substituted for the negative AD contributing factors under the patient's control. Thus, if the patient is eating a high AGEs diet, the AD 'treatment' would consist of substituting a low AGEs diet. If the patient is participating in minimal Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

intellectually challenging activities, he/she would be encouraged to participate in more intellectually challenging activities.

The 'reverse-engineering' component' would be based on the laboratory tests. In parallel with the approach in Step 4, AD treatments would be prioritized based on the number of abnormal AD characteristics they would impact. The caveats of step 4 about relying on numbers of characteristics impacted would apply here as well.

The categories of AD treatments include:

CATEGORIES OF AD TREATMENTS  drugs  talk/behavior therapies,  exercise  touch therapies,  diet (including herbs/spices/plant extracts)  social interaction enhancement therapies,  vitamins/supplements  enhanced leisure/educational activities,  sleep  electromagnetic therapies,  stress reduction therapies  memory/cognitive training/environmental enrichment.

The specific AD treatments employed would be selected based on the medical questionnaire results, the neuropsychology evaluation, and the lab tests results. Some of the following AD treatments would (in practice) be substitutions for the AD contributing factors eliminated; others would be new activities implemented.

RECOMMENDED INITIAL LOW-RISK TREATMENTS (partial list)

 Enhanced Leisure/Educational Activities/ Memory Training/Cognitive Training/Environmental Enrichment (take college classes, mentor young students, learn new skills [art, music], play complex games)  Diet: choose foods high in o polyphenols (such as cloves, star anise, capers, curry powder, ginger, cinnamon, peppermint, oregano, sage, rosemary, thyme, basil, cocoa, tea, red wine, chokeberries, elderberries, blueberries, plums, cherries, black currants, blackberries, strawberries, raspberries, grapes, flaxseeds, celery seeds, chestnuts, hazelnuts, pecans, almonds, walnuts, olives, artichokes, chicory, red onion, spinach, broccoli, apples, pomegranates, peaches, apricots, olive oil, canola oil), especially flavonoids (such as apples, blueberries, strawberries, red grapes, cabbage, broccoli, onions, capers, dark chocolate, cocoa, tea, red wine), isoflavones/genistein (such as soybeans, natto, tempeh, tofu, miso), and anthocyanins (such as blackberries, black currants, blueberries, strawberries, cranberries, eggplant, cherries, prunes, raisins, and the darker versions of raspberries, cabbage, plums, radish, grapes, plums, apples, beans, beets, cabbage, onions, pears, wines) o DHA/omega-3 fatty acid (such as salmon, herring, mackerel, anchovy, sardine, trout, shark, swordfish, mussel, sea bass, pollock, whiting, flounder, sole, lobster, halibut, carp, oyster, crab, mullet, tuna, perch, snapper, shrimp, octopus) o Vitamins B12/B6/Folate (such as meat [beef liver, lamb, beef], fish [sardines, mackerel, salmon], dairy [feta cheese, cottage cheese], eggs, legumes [chickpeas, fermented soy, pinto beans, lentils], fruit [banana, avocado], vegetables [spinach, parsley, broccoli, beets, turnip, asparagus,]) o Vitamin C (such as fruits [guavas, acerola cherry, kiwifruit, rose hips, strawberries, oranges, papayas], vegetables [bell peppers, broccoli, tomatoes, snow peas, kale]) o Vitamin D (such as fish [sardines, salmon, mackerel, tuna], liver [beef, calf, cod liver oil], dairy [milk, yogurt]; most importantly, sunlight on exposed skin) o Vitamin E (such as seeds [sunflower seeds, pumpkin seeds], nuts [almonds, hazelnuts, pine nuts], fish [abalone, salmon, trout], fruit [avocado, mango, kiwifruit], vegetables [red peppers, turnip greens, spinach, chard, squash, broccoli]) o lycopene (such as tomatoes, guavas, watermelon, papaya, grapefruit), o oleic acid (such as nuts [almonds, peanuts, pecans, cashews, pistachios, hazelnuts] seeds [sesame, sunflower], avocados, olives, and vegetable oils [safflower, almond, olive, sesame, sunflower]), o luteolin (such as dried oregano, celery seed, hot peppers, peppermint, sage, rosemary, juniper berries, thyme, radicchio, chinese celery), o quercetin (such as capers, lovage leaves, elderberry juice, dock leaves, radish leaves, arugula, dill weed, coriander, and fennel, cilantro, banana peppers, juniper berries, oregano, onions, carob flour, radicchio, red leaf lettuce, onions, watercress, raw, asparagus, kale, okra, cocoa powder, chia seeds) o sulforaphane (such as broccoli sprouts, broccoli, cauliflower, kale, brussels sprouts, cabbage, collards, arugula, turnips) o resveratrol (such as red wine, red grapes, peanut butter, pistachios, cocoa powder, dark chocolate, strawberries, blueberries, bilberries, cranberries) o epigallocatechin-3-gallate (such as green tea, black tea, carob powder, apples, blackberries).

Additional important foods from Table 2-6 include curcumin, garlic, and ginseng.

Caveats on diet:  Many toxic/harmful substances enter the food supply during all phases of food growth, distribution, and processing. While foods should be selected to maximize the amounts of healing nutrients identified above, care must be taken to minimize the level of toxic additions to the food in parallel.  Low-temperature cooking should be used to minimize production of AGEs and other harmful products (nitrosamines, polycyclic aromatic hydrocarbons, and acrylamides) during the cooking process.  Only low-mercury wild-caught fish should be used; these tend to be smaller fish, lower on the food chain.  Grass-fed animals with no exogenous growth hormones or antibiotics should be used, if possible, since these harmful products could be passed through to the consumer.  For fruits and vegetables normally eaten with skin, those that have not been sprayed with harmful pesticides and other toxic chemicals should be used.  Heavy metals are a contributing factor for many neurodegenerative diseases, including AD. One source of heavy metal bioaccumulation in the body is through the food supply. Heavy metals can occur naturally in the soil in which food is grown, they can concentrate abnormally in soils from nearby industrial pollution or from precipitation of air pollution, they can preferentially absorb in different types of food, and, depending on the type of food, can be absorbed from the food processing and manufacturing process. Any of the above foods selected for AD prevention or treatment purposes should have heavy metal concentrations as low as possible.

A note about our dietary recommendations. In Table 2-6, herbs and plant extracts are associated with large numbers of records. One of the major reasons for this is their copious use in Traditional Chinese Medicine, which had significant representation in our AD database. Some of the concoctions that contained these substances had adverse side effects, which removed them from the desired low-risk category. Also, independent verification of many of these concoctions' impacts was not readily available. Therefore, they are not in the first-tier recommendations.

Additionally, many of these plant extracts, almost by definition, are not whole foods. In that regard, they are similar to supplements, vitamin and otherwise. We have recommended whole foods containing the desired chemicals and nutrients (listed in Table 2-6) preferentially in the above list. We believe the full spectrum of phytochemicals contained in whole foods act synergistically with the fragmented chemicals listed to provide far more protection. As stated in reference [2]: "the additive and synergistic effects of phytochemicals in fruit and vegetables are responsible for their potent antioxidant and anticancer activities, and that the benefit of a diet rich in fruit and vegetables is attributed to the complex mixture of phytochemicals present in whole foods."

3B7. Health policy impact on AD treatment protocol

The above AD treatment protocol has been developed based mainly on medical findings, especially as reported in the premier biomedical literature. Financial and political/policy considerations were not taken into account. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

The protocol contains implicit assumptions that patients will be able to

1) pay for any expensive drugs (if necessary),

2) afford pesticide and other harmful chemical-free foods,

3) leave jobs where the working environment is toxic,

4) move from residences where the environment is toxic, etc.

This flexibility might not be available to many patients with limited income and/or limited assets.

Probably the key exogenous contributing factor to the development of AD (and many other chronic diseases) is the incorporation of technology in all aspects of modern life without adequate regulation and safety testing. To compound the problem, some/many of these new technologies are effectively mandated, and impossible to avoid, even if the AD patient is wealthy.

For example, wireless radiation technology has become ubiquitous in modern life (cell phones, WiFi, smart meters, etc). Research has shown that wireless radiation in the cell phone radiofrequency part of the spectrum contributes to oxidative stress and inflammation of the brain [3, 4, 5, 6], among many other adverse effects. As our AD study results show, oxidative stress and inflammation are key AD characteristics. Chronic exposure to wireless radiation would be a factor contributing to increase the incidence of AD (and many other chronic diseases in which these two characteristics are important).

Wireless radiation technology requires an infrastructure. For cell phones, the major infrastructure is cell towers. The Telecommunications Act of 1996 effectively mandates the construction of cell towers with no opposition allowed based on health considerations. As of this writing, the FCC is attempting to implement similar effective mandates for the next generation of mobile wireless technology, known as 5G. A million or more 'short' cell towers (in the USA) would be required for 5G implementation, since the propagation of radiation energy at the high frequencies characteristic of 5G is poor, and the distances between 'short' cell towers is relatively small by necessity.

This means that populated areas will be blanketed (around the clock) with 3GHz-30GHz (or higher) radiofrequency radiation. This is a range of the frequency spectrum essentially untested for adverse health effects, especially over the long-term in humans, and especially in combination with other toxic stimuli [3]. It is no different in principle from a contractor proposing to spray the populated areas of the USA with Agent Orange around the clock, and the relevant government regulatory agency stating that no opposition to the spraying is allowed based on health considerations. In effect, the USA government is mandating an increase in rates of AD, with the potential of this increase being very large.

Thus, we have a dichotomy in the relevant USA Federal policy. On the one hand, the Federal government is investing heavily in biomedical research to treat and reverse AD. On the other hand, the Federal government is allowing essentially unrestricted and inadequately regulated expansion of technologies that are important contributing factors to AD. Metaphorically, the Federal government is drilling holes in the floor of the boat at the same time it is pumping water out of the boat! These policies are diametrically opposed, and will limit the effectiveness of any AD treatment protocol, no matter how strictly it is followed.

References - Chapter 3

Chapter 4

SUGGESTED FURTHER RESEARCH

4A. Identifying Additional AD Treatments

RECOMMENDATION FOR EXPANDED STUDY

This present monograph contains numerous recommendations for a follow-on expanded study. The context of the recommendations is typically to identify more (perhaps factors of two or three more) AD treatments, AD characteristics, and AD causes/contributing factors than are shown in the present monograph.

Some of the reviewers of this monograph have questioned why more AD treatments, characteristics, and causes are necessary. After all, the monograph has identified far more AD treatments than any other published paper, far more AD characteristics than any other published paper, and far more AD causes/contributing factors than any other published paper. Why are even more AD treatments, characteristics, and causes/contributing factors required and recommended?

The answer lies in the status of AD prevention and reversal. We have not solved the problem of preventing and reversing AD. We don't know the full extent of what is required to prevent and reverse the full spectrum of AD cases. How, then, can we make the assumptions that 1) the full spectrum of necessary diagnostics for every AD patient will be found within the ~250 AD characteristics we have identified in this study, 2) the full spectrum of necessary treatments for every AD patient will be found within the ~ 700 AD treatments we have identified in this study, 3) the full spectrum of necessary causes to be eliminated for every AD patient will be found within the ~500 AD causes/contributing factors we have identified in this study?

The AD protocol for preventing and reversing AD presented in this monograph represents a culling of the large numbers of diagnostics, treatments, and causes identified to more 'manageable' levels. It is imperative that this culling process 1) starts with the full complement of AD diagnostics, treatments, and causes identified in the biomedical literature, and then 2) proceeds to reduce these numbers to levels acceptable to both the healthcare and patient communities.

We believe that the large numbers of AD diagnostics, treatments, and causes identified in the present monograph will be adequate to prevent and reverse many AD cases. However, we cannot exclude the possibility that AD diagnostics, treatments, and causes existing in the biomedical literature, but not identified in the present monograph, will expand the number of AD cases that could be prevented or reversed.

4A1. Identifying Additional Existing AD Treatments

The present study is more comprehensive than any of its predecessors with respect to identifying potential AD treatments and their consequences, based on the premier biomedical literature. However, the study has identified only the tip of the iceberg of existing and potential AD treatments and their consequences.

First, only a modest number of AD treatment linking terms were identified due to time and resource limitations. More research could be done to identify additional AD treatment linking terms, as well as identify combinations of AD treatment linking terms for better precision.

Second, not all the AD treatment linking terms identified were used to extract AD treatments and their impacts from the VP abstracts' phrases. An arbitrary cutoff of ~800 AD treatments was set. This limit was deemed adequate to present a wide spectrum of AD treatments without overwhelming the reader. If more specific AD treatments are desired, the remaining linking terms can be used to query the VP abstracts for this purpose. Given the rate at which existing AD treatments were being identified with the linking term approach (especially at the lower frequencies of appearance in the biomedical literature), we would estimate the number of additional AD treatments possible using this approach would double or triple those identified presently.

The search for AD treatment impacts from abstract phrases was conducted separately from the search for AD treatments from abstract phrases. The linking terms identified more AD treatments than AD treatment impacts because AD treatment impacts tended to repeat in different sentences containing different AD treatments. Thus, more AD treatment linking terms were used to extract the AD treatment impacts than were used to extract the AD treatments. However, not all the identified AD linking linking terms were used, and further AD treatment linking terms could be identified to enhance retrieval of AD treatment impacts.

Additionally, in order to access the record containing the AD treatment and its consequence, the AD treatment linking term had to be physically relatively close to the AD treatment impact. There were numerous records where an abstract sentence was of the form 'treatment X reduced the occurrence of A, B, C, D..... The software would not have recognized the occurrence of B, C, and D because of phrase length limitations. This problem could be eliminated by the use of Concordance software, where all words within some pre-specified distance of the AD treatment linking term would be displayed, and the additional AD treatment consequences extracted. Section 7B provides examples of how Concordance software could improve this identification process.

4A2. Identifying Additional Potential AD Treatments

One straightforward way of identifying additional potential AD treatments is with use of the Discovery component of the literature-related discovery and innovation (LRDI) approach [1]. Only a handful of these potential AD treatments (obtained with the LRDI methodology outlined in Chapter 6, and shown in section 2C2) were identified in the present monograph. An expanded study could identify many hundreds more of these potential AD treatments using the LRDI methodology.

4B. Institute Clinical Trials Combining Removal of Potential AD Contributing Factors with Implementation of AD Treatments

The prevention and treatment protocol for AD described in Chapter 3 requires patient diagnostics measurements, removal of causes based on abnormal diagnostics measurements, and implementation of treatments to normalize the abnormal diagnostics measurements.

To gain operational experience with exploiting the findings in the present monograph and in its AD causes/contributing factors predecessor [2], clinical trials incorporating the above protocol should be started in the near future. One of the serious limitations in fully implementing the AD treatment protocol in section 3B6 is identifying the AD contributing factors to the AD characteristics that deviate from the norm. As was described in reference [2], there are many potential AD contributing factors in our environment and in our daily life to which we are exposed and of which we are unaware. We need to have the capability to measure the influx of these toxic substances on an individual, and section 4D describes a research opportunity (essentially repeated from reference [2]) to achieve this goal.

Given the limitations today in identification of personal exposures to many AD contributing factors, near-term clinical trials as recommended above could start with a broad-based removal of 'low- hanging fruit' AD causes/contributing factors identified in the previous study [2]. These would include:

LOW-HANGING FRUIT RECOMMENDATIONS

4C. Identifying Additional AD Characteristics

4C1. Identifying Additional Existing AD Characteristics

Existing AD characteristics were identified mainly using the text-based approach. The first step in this approach was visually inspecting thousands of higher frequency abstract phrases parsed from AD treatment records retrieved with the MeSH-based query, as described in section 6B2b. This step had two benefits: identifying the higher frequency AD characteristics, and identifying terms closely linked to those characteristics. Some of the more useful linking terms identified included the following: treat*, therap*, prevent*, protect*, improv*, reduc*, attenuat*, ameliorat*, enhanc*, revers*, promot*, alleviat*, inhibit*, remov*, suppress*, mitigat*, restor*, lower*, preserv*, regenerat*, rescu*, slow*, neuroprotect*, neurorestorati*, decreas*, increas*, eliminat*.

However,

1) additional linking terms could have been identified;

2) linking term patterns (combinations of linking terms) could have been identified for greater precision;

3) not all linking terms identified were used;

4) not all existing AD characteristics appeared in text in proximity to the identified linking terms;

5) software limitations on extracted phrase length excluded those existing AD characteristics not in very close proximity to the identified linking terms.

More linking terms could be identified by retrieving and evaluating a larger number of treatment record abstracts, and even full-text. Pattern analysis, including factor analysis, could identify groups of linking terms that would allow greater precision in identifying AD characteristics reflective of specific AD pathologies.

Expanding the number of credible linking terms allows expansion of the number of AD characteristics that could be identified. Some of the proximity limitation issues mentioned above could be overcome with use of Concordance software or searching the non-parsed abstracts or full-text for the linking terms. In both cases, the context in which the linking terms exist is expanded and observable, allowing more AD characteristics to be retrieved.

4C2. Identifying Additional Potential AD Characteristics (discovery)

The concept is to identify patterns of AD characteristics that tend to co-occur frequently in the AD literature, then use these patterns as a search query in the non-AD literature. New patterns may be identified in the non-AD literature consisting of the search query pattern plus additional characteristics not in the AD literature. These additional characteristics would then be candidates for discovery as new AD characteristics that not have been identified previously.

For example, IL-1 and IL-6 and TNF-alpha and NF-KappaB tend to co-occur in many AD articles relating to inflammation. These four terms would be combined as a query for the non-AD literature: "IL- 1 and IL-6 and TNF-alpha and NF-KappaB". Any records retrieved would be examined for additional characteristics, and these additional characteristics would be validated as potential AD characteristics if they did not occur in the AD literature.

Myriad other patterns are possible. For example, existing AD treatments and existing AD causes move AD characteristics in known directions. Non-AD literatures could be searched for characteristics impacted by these known AD treatments and AD causes, and not contained in the core AD literature. Combinations of these AD treatments and AD causes could be used to increase the likelihood that any new characteristics identified would have higher relevance to AD.

As a specific example, consider the following query: (high-fat-diet* NEAR/5 (increas* OR decreas*) AND chitosan NEAR/5 (increas* OR decreas*)) NOT alzheimer*. This query will retrieve all records reflecting an increase or decrease of characteristic values (in the non-AD literature) due to the presence of the existing AD cause "high-fat-diet" and the existing AD treatment "chitosan". Applying this query to the Medline database leads to the identification of a potential AD characteristic "mup17" (major urinary protein 17) [3]. This potential AD characteristic is not found in the AD literature, but it is altered in one direction by an existing AD cause, and is altered in the opposing direction by an existing AD treatment. It might be a valuable characteristic for AD researchers to track.

4D. Develop Measurement Devices for Potential AD Contributing Factor Exposures

As stated in section 4B, a key deficiency in implementating comprehensive AD cause removal for any individual is lack of knowledge of the myriad toxic stimuli to which the individual is being exposed continually. What is the full spectrum of potentially toxic chemicals in the water we drink, the air we breathe, the food we eat, and in contact with our skin? Further, what is the full spectrum of ionizing and non-ionizing, visible and non-visible, radiations to which we are exposed as a function of time? To answer these questions, we need devices that can measure the full range of these toxic stimuli and are convenient and portable. Producing such devices would require an extensive research and development effort, especially devices in a form that people would be motivated to wear and use.

References - Chapter 4

Chapter 5

BACKGROUND

5A. Overview

AD is a brain disease, and the most common form of dementia [1-3]. Presently, it affects overwhelmingly those 65 years old and above; incidence increases with age. The prevalence of AD in the USA was approximately 4.7 million people in 2010, and is projected to increase to 5.8 million in 2020, 8.4 million in 2030, and 11.6 million in 2040 [4]. According to reference [4], "A growing number of studies indicate that the age-specific risk of Alzheimer’s and other dementias in the United States and other higher-income Western countries may have declined in the past 25 years, though results are mixed. These declines have largely been attributed to increasing levels of education and improved control of cardiovascular risk factors." That positive assessment of declining incidence was questioned somewhat in a recent comprehensive meta-analysis: "We found no evidence to suggest that the current assumption of constant age-specific prevalence of dementia over time is ill-founded" [5].

Thus, these studies referenced conclude that age-adjusted AD incidence is either declining slightly or remaining approximately level. Projected prevalence is increasing rapidly, since the number of elderly is projected to increase rapidly.

The AD incidence projections may be highly misleading. They are based mainly on extrapolations from the past. The large causative technology component of these projections reflects the adverse effects of established technologies. The main body of our previous AD monograph [6] identifies many recently-implemented technologies that could potentially contribute to AD. Over the last couple of decades, the substantial growth in implementation of technologies potentially contributing to AD (or many other chronic diseases) portends ominously for the future. These new technologies have not been operational for sufficient time to display direct impacts on AD (or myriad other chronic diseases) in humans, because of potential decadal latency periods before serious diseases emerge. Additionally, the synergetic adverse effects resulting from combinations of these new technologies are unknown, especially when used for long time periods.

Thus, the appropriate future projections of AD incidence and prevalence should consist of superposition of 1) a declining/flat incidence trend line due to past personal health advances and 2) increasing incidence due to implementation of new potentially harmful technologies with decadal latency periods. The Precautionary Principle dictates that the impacts of these newer technologies on AD characteristics be considered when developing future incidence projections, especially in the longer-term.

Additional details on AD incidence, prevalence, pathology, causes, treatments, etc., can be found in the following books [7-16] and review articles [17-22].

This Background section consists of two parts: studies to identify a broad spectrum of causes and treatments for AD, and text mining approaches for identifying potential AD treatments.

5B. AD Causes and Treatments Studies

5B1. AD Causes/Contributing Factors Studies

As shown in Table 2-7C and the references contained therein, there are many published studies focusing on identifying one or a few contributing factors to AD. There are many fewer studies identifying a very broad spectrum of AD contributing factors, as was done in our previous AD monograph [6]. The focus in the present section is to summarize the results from credible broad spectrum or meta analysis studies identifying myriad AD contributing factors.

Results from significant review studies of AD contributing factors are as follows:

 Hazar et al [23] concluded: "Diabetes mellitus (DM) type 2, smoking, physical inactivity, overweight and obesity were significantly associated with increased risk of AD".  Grant [24-25] focused on dietary factors, and concluded that advanced glycation end products associated with high-temperature cooking, meat consumption, eggs, high-fat dairy, and low 25- hydroxyvitamin D concentrations are associated with increased risk of AD.  Li et al [26] concluded: "Patients with MCI with APOEepsilon4, abnormal CSF tau level, hippocampal and medial temporal lobe atrophy, entorhinal atrophy, depression, diabetes, hypertension, older age, female gender, lower MMSE score and higher ADAS-cog score, had a high risk for the progression to AD".  Xu et al [27] concluded that hyperhomocysteine, depression, frailty, carotid atherosclerosis, hypertension, low diastolic blood pressure, type 2 diabetes mellitus (Asian population), low education, and high body mass index (BMI) in mid-life increased AD risk.  Barnes and Yaffe [28] concluded that up to half the worldwide cases of AD can be attributed to seven "modifiable" risk factors: diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity, low educational attainment, and physical inactivity.  Meng et al [29] concluded that high blood pressure, hypercholesterolemia, obesity, diabetes mellitus in midlife, smoking, and hyperhomocysteinemia are AD risk factors.  Srisuwan [30] concluded that reducing dementia risk through "modifiable" risk factors requires cognitive activity, higher education, mentally demanding occupations, participation in mentally challenging leisure activities, more active socially, low saturated fat diet, high fruit and vegetable diet, smoking cessation, prevention of head injury with loss of consciousness, reduce high blood pressure, especially at midlife, reduce diabetes, reduce high serum cholesterol especially at midlife, and reduce depression.

There is a thread of common risk factors running through the above full spectrum surveys and meta-analyses. These include hypertension, diabetes, obesity, smoking, depression, physical inactivity, low education, and cognitive inactivity. Quasi-common risk factors include high meat diet, high saturated fat diet, high cholesterol, and hyperhomocysteine.

Superficially, this is a relatively low number of "modifiable" risk factors (the authors of these review articles view them as "modifiable"). However, this "low number" is deceptive. If we view the foundational causes as independent variables (those over which we have direct control, at least in theory), there are very few that have been identified in the studies above. Those that have been identified include Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

smoking, physical activity, cognitive activity, educational level, and the dietary factors of high fat, high meat, low fruit and vegetables. The non-foundational risk factors/contributing factors are in fact dependent variables, and include hypertension, diabetes, obesity, depression, hypercholesterolemia, and hyperhomocysteinemia.

Table 2-7C presents many hundreds of foundational causes/contributing factors for AD that can be identified from the published literature alone. As was shown in the first author's AD precursor study identifying foundational causes (and treatments) for chronic kidney disease (CKD) [31], there were also many hundreds of potential CKD foundational causes that could be identified. Additionally, in the first author's book on pervasive causes of disease [32], it was shown that there are many chronic diseases for which hundreds of potential foundational causes could be identified.

It is therefore reasonable to assume that hundreds of potential foundational causes could be identified for each of the above dependent variables/diseases (hypertension, diabetes, obesity, depression, hypercholesterolemia, and hyperhomocysteinemia). The surveys above, while valuable in their own right, do not work in the actionable coordinate system of foundational AD contributing factors, and cannot lead to an AD protocol whereby action could be taken to prevent or reverse AD in selected cases. The approach in the present monograph does indeed lead to such an actionable AD protocol!

5B2. AD Treatments Studies

The references listed in Chapter 10 reflect the wide range of AD treatment studies that have been performed and published. The present section will focus mainly on the larger-scale AD treatment review studies.

Mendiola-Precoma et al [33] focus on therapies for prevention and treatment of Alzheimer’s Disease. Their examination of pathogenesis and clinical features in AD yields six major AD Hypotheses that drive much of AD research today. These six major hypotheses are: the amyloid cascade hypothesis; the tau hypothesis; the cholinergic hypothesis; the mitochondrial cascade hypothesis; the metabolic hypothesis; the vascular hypothesis (we have tripled the number of AD hypotheses identified in our definitional section on AD Hypotheses, and explained the bases of these hypotheses in more detail).

Mendiola-Precoma et al [33] proceed to discuss AD pathology mechanisms and pathways, and then identify both genetic and non-genetic risk factors. They conclude that the main metabolic and nongenetic risk factors include hypercholesterolemia, obesity, hyperhomocysteinemia, hypertension, and type 2 diabetes mellitus (note that these are not foundational contributing factors, by our definition).

They then proceed to identify AD treatments, categorizing them into pharmacological and nonpharmacological. The pharmalogical treatments are further divided into

 Symptomatic (Acetylcholinesterase Inhibitors, N-Methyl-D-aspartate Receptor (NMDA) Antagonists,  Other Neurotransmitter Systems (serotonin, histamine)) and  Etiology-based (Secretase Inhibitors, Amyloid Binders, Anti-Abeta Aggregation Compounds, Tau Therapies, Other therapies (Statins, Insulin, Antioxidants, Anti-inflammatories)).

The non-pharmacological treatments include

 Lifestyle (physical activity, mental challenges, energy restriction, and socialization), and  Diet and Chemical Substances (e.g., vitamins, polyphenols, flavonoids, alkaloids, terpenoids, probiotics, Mediterranean Diet, Asiatic Diet, etc).

An excellent survey and categorization of past, present, and future AD treatments was performed by Anand et al [34]. Their initial graphic is a concise pictorial summary of the multiple mechanisms involved in the pathogenesis of AD, and the inter-relationships of these mechanisms. Their initial table is an outstanding representation of AD therapeutic strategies, and can be summarized as follows:

AD THERAPEUTIC STRATEGIES FROM ANAND ET AL [34]  neurotransmission modulation;  lipid modification;  tau based therapies;  growth factor supplementation;  amyloid based strategies;  metal chelation;  intracellular signaling cascades modulation;  epigenetic modification;  oxidative stress reduction;  caspase inhibition;  mitochondrial targeted therapy;  nitric oxide synthase modulation;  cellular calcium homeostasis modulation;  nucleic acid drugs;  anti-inflammatory therapy;  multi-target directed ligands.  gonadotropin supplementation;

A broad-ranging review of the major AD hypotheses by Amtul [35] delineates deficiencies in the amyloid cascade, tau, inflammatory, and oxidative stress hypotheses. It attempts to make the case that considerations from the neurovascular hypothesis of AD should be incorporated more broadly in present analyses of pathological mechanisms.

A comprehensive review by Godyn et al examines therapeutic strategies and agents for AD in clinical trials [36]. These include "agents acting upon the beta-amyloid, such as vaccines, antibodies and inhibitors or modulators of g- and b-secretase; agents directed against the tau protein as well as compounds acting as antagonists of neurotransmitter systems (serotoninergic 5-HT6 and histaminergic H3)." Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

The authors opine that "Ongoing clinical trials with Ab antibodies (solanezumab, gantenerumab, crenezumab) seem to be promising, while vaccines against the tau protein (AADvac1 and ACI-35) are now in early-stage trials."

The authors believe "Interesting results have also been achieved in trials involving small molecules such as inhibitors of b-secretase (MK-8931, E2609), a combination of 5-HT6 antagonist (idalopirdine) with donepezil, inhibition of advanced glycation end product receptors by azeliragon or modulation of the acetylcholine response of a-7 nicotinic acetylcholine receptors by encenicline."

They then conclude "Development of new effective drugs acting upon the central nervous system is usually a difficult and time-consuming process, and in the case of AD to-date clinical trials have had a very high failure rate. Most phase II clinical trials ending with a positive outcome do not succeed in phase III, often due to serious adverse effects or lack of therapeutic efficacy." This latter conclusion about poor performance in clinical trials has been echoed in many, if not most, of the credible reviews of AD treatment effectiveness we have examined.

A review of multi-target-directed ligands in AD treatment by Bajda et al [37] concludes that the largest group of these ligands "comprises cholinesterase inhibitors, acting as dual binding site inhibitors and/or inhibitors with additional properties. They are characterized by increased potency against AChE and Abeta plaque formation with additional properties such as antioxidant activity, neuroprotective and voltage-dependent calcium channel antagonistic activity, inhibitory activity against glutamate-induced excitotoxicity, histamine H3 receptor antagonism, cannabinoid CB1 receptor antagonism and BACE1 inhibition. A novel class of compounds includes multifunctional chelators or prochelators with additional properties, dual inhibitors of BACE1 with metal chelators, as well as dual modulators of gamma-secretase with peroxisome proliferator-ativated receptor gamma. In the course of designing novel compounds, heterodimeric molecules interacting with different targets were linked by chains of varying lengths and types with fused pharmacophore molecules."

The authors make the interesting point that "There are many attractive targets for the development of anti-AD drugs, and the multi-factor nature of this disease calls for multi-target-directed compounds which can be beneficial for AD treatment." More interestingly, they overlook the obvious conclusion that "the multi-factor nature of this disease" calls for eliminating the multiple AD contributing factors that result in much of the observed AD pathology.

An interesting review of personal intervention for AD treatment [38] concludes that "intervention strategies shall be tailored for subgroups of AD patients. Both demographic and in-depth information is needed for patient stratification. The demographic information includes primarily APOE genotype, age, gender, education, environmental exposure, life style, and medical history, whereas in-depth information stems from genome sequencing, brain imaging, peripheral biomarkers, and even functional assays on neurons derived from patient-specific induced pluripotent cells (iPSCs)."

Some of their non-drug recommendations [38] for prevention and early-stage AD treatment include "A good lifelong education can also help build a resilient brain network....it is necessary to avoid non-healthy living and working environment. It is equally important to stick to a healthy diet and stay away from bad habits such as cigarette smoking and alcohol drinking.....A good starting point is to have regular physical exercise. This can be supplemented with brain stimulating activities such as music and arts. Early stage patients should be actively involved in social communication with family, friends, or local community. Certain Chinese traditional medicine may also be helpful.....nutritional supplements such as coenzyme Q10 may provide more energy supply to the brain".

In a comprehensive review of drug treatments for AD [39], the authors conclude "Despite the significant public health issue that it poses, only five medical treatments have been approved for Alzheimer’s disease (AD) and these act to control symptoms rather than alter the course of the disease." This is a concise statement of the state-of-the-art of AD drug treatment, repeated in different terminology by many, if not most, of the credible review articles on mainline AD treatments we have examined. One should add the caveats that

1) not all patients receive such benefits,

2) the benefits tend to occur for a limited time period, and

3) the benefits are accompanied by side effects.

A study on AD biomarkers [40] concludes "The best-established AD biomarkers include PET measurements of Aβ plaque burden, PHF-tau burden and cerebral glucose metabolism; MRI measurements of brain atrophy and resting state functional connectivity; and cerebrospinal fluid (CSF) Aβ42, Aβ40, total tau and phospho-tau levels. These and additional brain imaging, spinal fluid and other biomarker methods continue to be developed, tested and considered for inclusion"

Additional reviews cover current and emerging therapies for AD [41-43], disease-modifying treatments for AD [44], and discovering new treatments for AD by 'repurposing' approved medications [45-47]. These additional reviews tend to re-enforce the findings of the major reviews discussed in some detail.

None of these reviews approach the wide spectrum of AD contributing factors and treatments identified in the present monograph. The closest techniques to our wide spectrum approach are those delineated in the 2017 books by Bredesen [48] and the Sherzais [49]. Even these approaches tend to focus on correcting mainly the lifestyle components of AD contributing factors, and can be viewed as a sub-set of our more comprehensive approach.

5C. Text Mining to Identify Causes and Treatments for Disease

5C1. Overview

The two main literature-based approaches for identifying potential contributing factors to AD (or any other disease) are "direct" and "indirect", where "direct" can be viewed as analogous to Innovation, and "indirect" can be viewed as analogous to Discovery [31]. The direct approach identifies contributing factors that appear in the same article as AD (e.g., smoking increases the risk for AD) and link directly to AD. The indirect approach identifies potential contributing factors to some disease/symptom other than AD, then links this disease/symptom to AD (e.g., high-salt diet increases the risk for hypertension, hypertension is strongly linked to AD). The same arguments used for classifying AD contributing factors into 'direct' and 'indirect' can be used for classifying AD treatments into 'direct' and 'indirect'.

The bulk of our previous AD monograph [6] focused on direct contributing factors to AD, and included conceptual discussion, but not examples, of indirect contributing factors. The latter include linkages between a potential contributing factor and a disease/symptom where AD is mentioned in the article as being related to the disease/symptom (Case 1), and linkages between a potential contributing factor and a disease/symptom where AD is not mentioned in the article (Case 2). Case 1) is, e.g., typical of AD characteristics papers. In Case 2), identifying another article where the disease/symptom is linked to AD is required to close the loop. Case 2) is usually described in the text-mining literature as literature- based discovery or literature-related discovery. Case 1) could also be viewed as "soft" discovery, and Case 2) as "hard" discovery [31]. Case 2) examples were not provided in our previous AD monograph because of length considerations, but, based on past experience, voluminous discoveries of potential AD contributing factors are possible (e.g., [31]).

The 'hard discovery'/'soft discovery' distinction holds for AD treatments as well. In the present AD monograph, a handful of Case 2 examples was presented. Based on the retrieval of potential discovery candidates by the query that was used for Case 2 discovery, voluminous discoveries of potential AD treatments are possible.

5C2. Literature Survey

The published text mining approach related most closely to that used in the present monograph can be found in our previous AD monograph [6] and reference [32]. In reference [32], three approaches were used to develop queries for identifying foundational causes for all diseases. The first approach used MeSH Qualifiers relevant to identifying foundational causes of disease (e.g., adverse effects, toxicity, pathogenicity, poisoning) to retrieve records from Pubmed for analysis. The second approach used generic MeSH terms related relatively unambiguously to foundational causes (e.g., "Drug-Related Side Effects AND Adverse Reactions"; Abnormalities, Drug Induced; Air Pollutants, Occupational; Amphetamine Related Disorders; Carcinogens; Chemical Warfare Agents; Chemically-Induced Disorders, etc) to retrieve the records from Pubmed for analysis. The third approach used text terms (applied to the title field) to retrieve the records from Pubmed for analysis. This title query consisted of two parts: standalone terms (e.g., cardiotoxic*, genotoxic*, mutagenic, adverse-outcome, adverse- metabolic-effect*, etc) and terms that are intersected with diseases (e.g., (expos* OR induc*) AND (cancer* OR dermatitis)). Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Other text mining approaches have been developed for generating literature-based discovery. They have been used mainly for identifying potential new treatments for disease, but the approaches used for identification of new treatments could be easily modified for identification of potential new foundational causes as well (e.g., [31]). In the past decade, a number of these semantic relation-based approaches have been promulgated:

 Cohen et al [50] use semantic indexing to identify empirically sequences of relationships known as 'discovery patterns', such as "drug x INHIBITS substance y, substance y CAUSES disease z" that link pharmaceutical substances to diseases they are known to treat. These sequences are derived from semantic predications extracted from the biomedical literature, and subsequently utilized to direct the search for known treatments for a held out set of diseases.  Hu et al [51] present a biomedical semantic-based association rule system that significantly reduces spurious/useless/biologically irrelevant connections through semantic filtering.  Miller et al [52] advance the hypothesis of "cortisol as part of a mechanistic link elucidating the observed correlation between decreased testosterone in aging men and diminished sleep quality".  Hristovski et al [53] emphasize semantic relations approaches to literature-based discovery.  Sang et al [54] develop a supervised learning based approach to generate hypotheses from biomedical literature, splitting the traditional processing of hypothesis generation with classic ABC model into AB model and BC model.  Cameron et al [55] implement a context-driven, automatic subgraph creation method that captures multifaceted complex associations between biomedical concepts; given a pair of concepts, the method automatically generates a ranked list of subgraphs, which provide informative and potentially unknown associations between such concepts.  Kastrin et al [56] mimic the process of literature-based discovery as a classification problem on a graph of MeSH terms, using unsupervised and supervised link prediction methods for predicting previously unknown connections between biomedical concepts.

These approaches achieve neither the breadth nor the volume of Innovation and Discovery found in references [31-32, 57].

Other information technology approaches have been used to identify potential risk factors/contributing factors for specific diseases. They differ from the Discovery approaches above because of their focus on identifying the direct causes of disease as defined above. Examples of these information technology approaches include:

 training neural networks to identify risk factors for specific diseases/conditions [58-61],  machine learning-based methods to quantify risk factors for diseases/conditions [62-63],  data based clustering and rule based prediction to identify risk factors for diseases/conditions [64-66],  Bayesian networks to identify risk factors [67-72],  association rules to identify risk factors [73-75],  decision trees to identify risk factors [76-80],  text/data mining approaches [81-83], and  information technology approaches for identifying adverse events resulting from drugs and surgery [84-96]. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

5D. Definitions

5D1. AD Foundational Cause definition

The myriad causes of AD reported in this monograph are termed "foundational". An AD foundational cause is a tangible stimulus or behavior that can contribute to an AD symptom or an AD biomarker/characteristic change that reflects AD progression.

Thus, excesses of calcium, water, exercise, drugs, environmental exposures, etc, can contribute to an AD symptom(s) and/or negative AD biomarker/characteristic change, and severe deficiencies of calcium, water, or exercise can contribute to AD symptom(s) and/or negative AD biomarker/characteristic changes as well. Abuse, poverty, educational status, etc., can contribute to AD symptoms and/or negative AD biomarker/characteristic changes, even though categorizations into excesses and deficiencies may be less applicable. The expression 'contributing factor' is used interchangeably with 'cause' throughout the monograph.

A symptom(s)/disease(s) in a person exposed to toxic stimuli is the result of imbalance between the strength of the toxic stimuli and the person's innate ability to neutralize the effects of the toxic stimuli, including the genetic factors that were not included in this monograph. The two are not independent; the toxic stimuli can affect the capabilities of the defensive system to neutralize incoming toxic stimuli. Thus, the incoming toxic stimuli can be viewed as a "signature" of individual toxic stimuli, with different weightings assigned to each toxic stimulus, and the defense can also be viewed as a "signature", with different weightings assigned to the health of the body's defensive mechanisms. Whether a symptom will materialize as a result of one or more toxic stimuli depends on whether the defensive "signature" is able to neutralize the "signature" of the incoming toxic stimuli.

Thus, not every person who eats a high-fat diet or undergoes surgery with inhalation anesthetics develops AD, but some (more than expected randomly) do. There were a number of cases in the literature where relatively few people were reported to have adverse reactions to a given toxic stimulus. Identifying the offensive-defensive "signature" relationships that allow toxic stimuli to translate into symptoms (within the context of understanding genetic polymorphisms and the resulting variations in biological pathways) will play a significant role in explaining why some people develop a disease and others do not when exposed to the same agent(s). Understanding the complex web of gene-environment interactions is the central challenge of modern medicine; our identification of myriad individual toxic stimuli and defensive system deficiencies is the first step in this long journey.

For purposes of this monograph, we term a toxic stimulus a (foundational) cause if the research author stated/implied/inferred the toxic stimulus was a cause and the information presented supported the research author's conclusion. We recognize, however, that this toxic stimulus was in all probability one component of a more complex offensive-defensive "signature" imbalance that resulted in the symptom(s) of interest.

5D2. AD Treatment definition

AD treatments are actions taken to modify AD characteristics/symptoms/biomarkers in desired directions. The most widely used AD treatments are myriad drugs for attenuating undesired symptoms and/or modifying undesired biomarker/characteristics changes. However, removal of AD contributing factors could be viewed as AD 'treatments' (e.g., cessation of smoking, cessation of excessive alcohol intake, cessation of high-fat diet, cessation of exposure to harmful chemicals, etc), since this action would modify AD characteristics in desired directions. Also, substitution of positive practices for AD contributing factors removed could be considered as AD 'treatments' (e.g., drinking more water as a substitute for high-fructose beverages, moving from high air pollution environments to low air pollution environments, replacing high-temperature cooking with low-temperature cooking, etc), again, since they modify AD characteristics in desired directions.

5D3. AD Characteristics definition

An AD characteristic is a measurable quantity associated with a test subject/patient whose changes in value may reflect changes in the progression or reversal of AD. The AD characteristics can be divided into five categories as follows:

 behaviors (e.g., aggression, agitation, delerium, etc);  performance (e.g., cognition, memory, learning, etc);  psychological states (e.g., apathy, anxiety, etc);  biomarker/metabolic function (e.g., oxidative stress, neuroinflammation, Abeta, tau phosphorylation, mitochondrial function, synaptic plasticity, etc); and  biomarker/metabolic metrics (e.g., acetylcholine, ABCA1, BCL-2, BDNF, ADAM10, GSK-3, homocysteine, BACE1, etc).

5D4. Linking Term definition

Linking terms are words/phrases strongly associated with specific text concepts of interest. Linking terms tend to be more generic than the specific terms that are the main targets of text searching. There are relatively few linking terms compared to the large numbers of characteristics, causes, and treatments. Searching text for the known linking terms will allow the desired concepts of interest to be identified.

For the causes, treatments, and characteristics of interest in the AD study, linking terms are verbs strongly associated with AD causes, treatments, and characteristics. For AD treatments and characteristics in particular (the main targets of the present monograph), some of the more useful linking terms identified included the following: treat*, therap*, prevent*, protect*, improv*, reduc*, attenuat*, ameliorat*, enhanc*, revers*, promot*, alleviat*, inhibit*, remov*, suppress*, mitigat*, restor*, lower*, preserv*, regenerat*, rescu*, slow*, neuroprotect*, neurorestorati*, decreas*, increas*, eliminat*.

Not all these terms are of equal value, or efficiency in identifying the desired text concepts. Some of these terms had higher efficiencies of identifying the AD treatment consequences of interest (AD characteristics) than others. Terms like prevent*, protect*, improv*, restor*, alleviat*, ameliorat*, Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

mitigat*, etc, almost always gave the desired AD characteristics and the direction in which they changed as a result of AD treatment. Terms like decreas*, increas*, reduc*, etc, could go either way. The former group of terms had the 'sense' of improvement, while the latter group of terms reflected change (positive or negative).

Linking terms for identifying AD causes are summarized in section 9A4C1. These AD causes linking terms include: -induced; caused by; induced by; -contaminated; exposure to; exposure(s) [at end of phrase]; exposed to; poisoning [at end]; -exposed [at end]; -related; -associated; -infected; abuse*; toxicity.

5D5. Text Mining definition

Text mining is the extraction of useful information from large volumes of text.

5D6. AD Hypothesis definition

An AD hypothesis is a mechanistic description of the pathophysiology of AD development and progression. Selection of a specific hypothesis by a specific researcher typically guides and motivates the selection of AD characteristics that researcher will use for diagnostic purposes, AD treatment research, and AD treatment implementation.

The most widely used AD hypotheses are shown in the block below. Because they are centered around AD pathology, the AD treatments that result from these AD hypotheses focus on removing/suppressing pathological symptoms, rather than removing the causes of these symptoms.

Interestingly, there are no foundational causes-based hypotheses of AD, e.g., the Deficient-Diet Hypothesis, the Iatrogenic Hypothesis, the Sedentary Lifestyle Hypothesis, the Radiation Exposure Hypothesis, the Toxic Chemical Exposure Hypothesis, etc. As a result, there are many articles in the biomedical literature questioning the validity of each of these pathology-based hypotheses, and showing the deficiencies in their associated treatments on reversing AD.

COMPREHENSIVE SUMMARY OF AD HYPOTHESES (numbered references can be found in Chapter 1 reference list)

Other AD hypotheses have been proposed as well, including, but not limited to  the calcium hypothesis (disruption of calcium signaling as the underlying cause of neuronal dysfunction) [5,6],  the inflammatory hypothesis (inflammatory mechanisms play an important role in the pathogenesis of AD) [7],  the oxidative stress hypothesis (oxidative stress associated with the onset and progression of AD) [8],  the aluminum hypothesis (human exposure to aluminum linked to AD) [9],  the metal hypothesis (neuropathogenic effects of Abeta in AD are promoted by, and possibly even dependent on, Abeta-metal interactions) [10]  the cognitive reserve hypothesis (persons with greater education begin to experience acceleration in cognitive decline closer to the time of diagnosis than persons with lower reserve, but that their rate of decline is more rapid after the time of acceleration due to increased disease burden) [11],  the cell cycle/mitosis failure hypothesis (cell cycle reentry is an early event in AD and produces apoptosis) [12],  the deleterious network hypothesis (close interactions among abnormal amyloid precursor protein metabolism, oxidative damage, compromised energy metabolism and impaired calcium homeostasis is the common pathway of AD) [13],  the aminopeptidase hypothesis (aminopeptidase-catalyzed proteolysis of Abeta may limit the rate of Abeta catabolism whose reduction would lead to Abeta dyscatabolism and thus to deposition [14],  the ammonia hypothesis (ammonia is a factor able to produce symptoms of AD) [15],  the attrition hypothesis (activation of the effector caspase-6 in AD due to one or a variety of insults is responsible for the breakdown of the cytoskeletal structure of neurites and damages proper trafficking of proteins and organelles thus resulting in the observed clinical and pathological features of AD) [16], and  the protein cancer hypothesis (abnormal or malignant proteins--such as prion proteins--generated in a cell grow and propagate from cell to cell by converting normal proteins, and this propagation causes disease progression) [17].

Chapter 6

METHODOLOGY

6A. Overview and Strategy

6A1. Overview

There are two main goals of the present study: identify the full spectrum of treatments for AD, and develop an individually-tailored treatment protocol that could be used for prevention and reversal of AD.

The operational objectives that contribute to these goals include:

1) comprehensive identification of the existing treatments available for AD,

2) comprehensive identification/discovery of potential treatments for AD,

3) comprehensive identification of specific existing AD characteristics impacted by each of these existing and potential treatments,

4) comprehensive identification of specific potential AD characteristics impacted by each of these existing and potential treatments, and

5) integration of the AD treatments and their impacts with the AD causes and their impacts [1] to generate a protocol that will prevent and reverse AD, in selected cases.

Assume the existing and potential AD treatments can be related to their effects on the AD characteristics identified above, existing and potential AD causes can be related to their effects on the same AD characteristics, and these AD characteristics are amenable to measurement. Then, a treatment protocol can be generated that identifies 1) the amount that measured AD characteristics deviate from the norm for each AD patient, 2) the causes that have to be eliminated to restore the AD characteristic measurements back to the norm, and 3) the treatments required to restore the AD characteristics back to the norm. This individually tailored protocol is discussed in more detail in Chapter 3.

Existing and potential causes for AD were identified in reference [1], and are shown in Table 2- 7C. The methodology employed in the present monograph identifies existing and potential AD treatments that impact one or more of the myriad characteristics associated with AD, and existing and potential AD characteristics whose values can move in predictable directions when stimulated by AD causes and treatments.

A summary list of the existing AD characteristics identified for the present study is shown in Table 2-1.

6A2. Strategy

The overall strategy for identifying AD causes, treatments, and characteristics was essentially the same, although the implementation of the strategy differed slightly as we gained knowledge during the evolution of the study. The strategy components are:

 Select source database (Medline/Pubmed was selected as the primary source database, although the Thomson-Reuters version was used when proximity searching was performed).  Generate a core AD database (a Pubmed query was used to generate a core AD database).  Retrieve records relevant to AD treatments (or AD causes or AD characteristics) from the core AD database (a combination of MeSH-based, text-based, and visual examination approaches was used to retrieve records relevant to AD treatments, AD causes, and AD characteristics, and to extract the desired AD treatments, AD causes, and AD characteristics from these retrieved records).

6B. Methodology for Identifying Existing AD Treatments

6B1. Overview

To identify existing AD treatments, a query consisting of MeSH terms and text terms was developed to retrieve Medline records that had high probability of describing AD treatments. These retrieved Medline records were imported into our VP text mining software [2] and parsed into phrases. Many of these parsed record abstract phrases were visually inspected to identify existing AD treatments and identify consequences of those treatments (e.g., increased cerebral blood flow, reduced Abeta, reduced tau hyperphosphorylation, etc).

6B2. Identifying Existing AD Treatments

6B2a. MeSH-based Approach

The MeSH-based approach consisted of two components: MeSH Qualifiers related to treatments/therapies relatively strongly (e.g., diet therapy, drug therapy, prevention & control, therapeutic use, therapy, etc), and MeSH Headings related to treatments/therapies relatively unambiguously (e.g., Treatment Outcome, Neuroprotective Agents, Nootropic Agents, Plant Extracts, Phytotherapy, Dietary Supplements, Drugs, Chinese Herbal, etc). Each of the two components was intersected with a core AD Medline query (e.g., Alzheimer* OR dementia OR "mild cognitive impairment") to retrieve records describing AD treatments. The retrieved records were inspected visually, and the relevant articles extracted.

As a very simple example of the above, a query term might be "diet therapy" in the MeSH Qualifier field, AND "Alzheimer's" in the title field.

6B2b. Text-based Approach

The text-based approach was developed and used because of the following MeSH-based approach limitations:

1) not all Medline records have MeSH terms assigned;

2) for those records with MeSH terms, the terms do not always form a comprehensive set;

3) for records with MeSH terms, the Qualifiers appended to the Heading are not always complete.

Thus, the text-based approach complements (and overlaps) the MeSH-based approach.

Fundamentally, the text-based approach 1) identified linking terms that were strongly associated with AD treatments and their consequences, and then 2) used these linking terms to search for the AD treatments and consequences of interest. These linking terms were obtained from reading the records retrieved with the MeSH-based approach, and selecting those terms strongly associated with AD treatments and their consequences. Some of the more useful linking terms identified included the following: treat*, therap*, prevent*, protect*, improv*, reduc*, attenuat*, ameliorat*, enhanc*, revers*, promot*, alleviat*, inhibit*, remov*, suppress*, mitigat*, restor*, lower*, preserv*, regenerat*, rescu*, slow*.

The text-based approach was used at three distinct points in the study:

1) It was used as part of the total AD Medline database query to retrieve records strongly associated with AD treatments.

2) It was applied to the parsed abstract phrases of the retrieved records imported into the VP software to surgically extract the existing AD treatments and their consequences.

3) It was used to develop patterns of terms for searching the non-AD Medline literature to generate literature-based discovery of potential AD treatments.

The main text mining advance in this study was development and demonstration of this AD treatment pattern filter for

1) querying the Medline database,

2) extracting AD treatments and their consequences from the parsed abstract phrases, and

3) discovering potential AD treatments from the non-AD biomedical literature.

The first chronological application of the linking terms was to help generate the initial query used for retrieving the AD treatment records from the Medline database. In the query, the linking terms were added to the MeSH terms described in 6B2a. The linking terms were only applied to the title field to minimize retrieval of excessive non-relevant records. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

The second chronological application of the linking terms was to help extract existing AD treatments and their consequences from the parsed abstract phrases of the retrieved AD treatment records in the VP software. Approximately 52,000 records constituted the retrieved Medline AD treatments database, and approximately 3.5 million abstract phrases were parsed from the abstracts by the VP software. There was a dramatic increase in the number of phrases as the frequency of their appearance decreased. For example, there were 20,000 phrases that appeared in 22 records or more (roughly the number of phrases that were examined visually). There were 3,437,961 phrases that appeared in 21 records or less. In particular, there were 3,322,873 phrases that appeared in three records or less! It is these lower frequency phrases that may represent promising emerging AD treatments, or AD treatments that for one reason or another may have been suppressed in the literature.

The higher frequency phrases could be inspected visually, but a text mining filtering approach was necessary to extract the desired treatment and treatment consequence information from the millions of lower frequency phrases. Linking terms were used to search these lower frequency phrases and efficiently extract the requisite treatment and consequences information.

As a very simple example, we might search the ~3.5 million abstract phrases in the database of AD treatment records using the linking term "improv*". Typically, this term might appear in the larger text string of e.g. "substance X improved Abeta clearance". Thus, "substance X" would be the AD treatment identified, "Abeta" would be the AD characteristic of interest, and "Abeta clearance" would show the AD characteristic having moved in the desired direction. As the next paragraph will show, if the above text sub-string "improved Abeta clearance" were used to query the non-AD literature, then treatments/mechanisms from non-AD literatures could be identified and extrapolated ('re-purposed') for possible use in treating/understanding AD pathology.

6C. Identify Potential AD Treatments (Discovery)

The third chronological application of the linking terms was for use as a query in literature-based discovery of potential AD treatments. Linking phrases that formed patterns characteristic of successful AD treatments were generated, and applied to the Medline non-AD literature. These linking phrases consisted of linking terms combined with the AD characteristics to which they were linked (e.g., increase glutathione, inhibit GSK-3, increase CREB phosphorylation, etc.) In practice, the linking phrases were constructed more broadly, such as increas* NEAR/3 glutathione, inhibit* NEAR/3 GSK-3, etc. For the literature-based discovery application, combinations of the more fundamental and less AD-specific linking phrases were used

(e.g., (((increas* OR enhanc* OR restor*) NEAR/3 "norepinephrine") AND ((increas* OR enhanc* OR restor*) NEAR/3 "Nrf2")) NOT ((alzheimer* OR dementia OR "mild cognitive impairment") OR {existing AD treatments}).

While terms such as 'reduce Abeta' or 'reduce tau phosphorylation' may be efficient for extracting existing AD treatments from the AD literature, they are very inefficient, either in isolation or especially in combination, for AD treatment discovery from the non-AD literature. It is difficult to imagine people doing research in reducing Abeta or reducing tau hyperphosphorylation not emphasizing the AD/dementia applications in their publications. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

6D. Identify Existing AD Characteristics

Existing AD characteristics were identified mainly using the text-based approach. The first step in this approach was reading thousands of higher frequency abstract phrases parsed from treatment records retrieved with the MeSH-based query, as described in section 6B2b. This step had two benefits: identifying the higher frequency AD characteristics, and identifying terms closely linked to those characteristics.

Some of the more useful linking terms identified included the following: treat*, therap*, prevent*, protect*, improv*, reduc*, attenuat*, ameliorat*, enhanc*, revers*, promot*, alleviat*, inhibit*, remov*, suppress*, mitigat*, restor*, lower*, preserv*, regenerat*, rescu*, slow*, neuroprotect*, neurorestorati*, decreas*, increas*, eliminat*. Some of these terms had higher efficiencies of identifying the treatment consequences of interest than others. Terms like prevent*, protect*, improv*, restor*, alleviat*, ameliorat*, mitigat*, etc, almost always gave the desired AD characteristics and the direction in which they changed as a result of treatment. Terms like decreas*, increas*, reduc*, etc, could go either way. The former group of terms had the 'sense' of improvement, while the latter group of terms reflected change (positive or negative). In all cases, each retrieved phrase was validated before it could be included as an AD characteristic.

The second step was identifying the lower frequency AD characteristics. Many of the linking terms obtained in the first step were applied to all the abstract phrases in the full AD core Medline database, and ~250 major and semi-major existing AD characteristics were identified.

However,

 additional linking terms could have been identified;  linking term patterns (combinations of linking terms) could have been identified for greater precision;  not all linking terms identified were used;  not all existing AD characteristics appeared in text in proximity to the identified linking terms;  software limitations on extracted phrase length excluded those existing AD characteristics not in very close proximity to the identified linking terms.

An expanded study could easily overcome these limitations, and possibly double the number of existing AD characteristics identified.

6E. Identify Potential AD Characteristics (Discovery)

1 and IL-6 and TNF-alpha and NF-KappaB". Any records retrieved would be examined for additional characteristics, and these additional characteristics would be validated if they did not occur in the AD literature.

As a specific example, consider the following query: (high-fat-diet* NEAR/5 (increas* OR decreas*) AND chitosan NEAR/5 (increas* OR decreas*)) NOT alzheimer*. This will retrieve all records reflecting an increase or decrease of characteristic values (in the non-AD literature) due to the presence of the existing AD cause "high-fat-diet" and the existing AD treatment "chitosan". Applying this query to the Medline database leads to the identification of a potential AD characteristic "mup17" (major urinary protein 17) [3]. This potential AD characteristic is not found in the AD literature, but it is altered in one direction by an existing AD cause, and is altered in the opposing direction by an existing AD treatment. So, it might be a valuable characteristic for AD researchers to track.

The focus of the present monograph is on AD treatments. Further, the number of existing AD characteristics identified appeared to be far more than could be used in practice. Therefore, identification of additional potential AD characteristics was not deemed a first-order priority in the present study. No attempt was made to identify specific potential AD characteristics, beyond the illustrative example above.

6F. Identify Existing and Potential AD Contributing Factors

The detailed methodology for identifying existing and potential AD contributing factors is contained in reference [1]. For purposes of self-containment, the AD contributing factors identification methodology is adapted from reference [1], and is presented in Chapter 9.

Appendices - Chapter 6

Appendix 6-1 - AD Treatment Discovery Query

6-1a. General strategy

The basic concept is to generate textual patterns consisting of

1) existing AD treatments,

2) existing AD characteristics impacted by these AD treatments,

3) phrases that link these AD treatments to desired changes in the AD characteristics and apply these linking phrases and desired AD characteristics changes to the Medline non-AD literature to identify potential AD treatments.

6-1b. Specific approach

The specific highly streamlined approach used for illustrative proof-of-principle demonstration purposes was the following. Search for records in the non-AD literature that contain combinations (of two at first) of linking phrases-AD characteristics (AD targets). Metaphorically, use three windows in Medline. The top window contains one AD target, expressed broadly. The middle window (separated from the top window by AND) contains the remaining AD targets, separated by OR. The bottom window (separated from the middle window by NOT) contains the query for retrieving the broad AD literature and existing AD treatments.

Twenty AD target-linking term units were selected. Each of these AD target-linking term units was entered as a query, and the query was run in Thompson-Reuters-Medline. The results were stored in the Thompson-Reuters -Medline Search History. This occupied twenty slots of the forty slot Search History limit imposed by Thompson-Reuters -Medline. Then, twenty queries were run of the form #1 AND (#2 OR #3 OR #4 OR.....#20) NOT (#21 OR #22) (where #21 is the AD core query, and #22 is the existing AD treatments). Each result was saved in Endnote and Marked List, and deleted after saving. This insured remaining under the forty result limit of Thompson-Reuters -Medline.

6-1b1. AD Characteristic-Linking Term units

#1 - (reduc* OR decreas* OR prevent* OR attenuat* OR suppress* OR alleviat* OR ameliorat*) near/3 "oxidative stress"

#2 - (reduc* OR decreas* OR prevent* OR attenuat* OR suppress* OR alleviat* OR ameliorat*) near/3 "apoptosis"

#3 - ((protect* OR improv* OR enhanc* OR restor* OR preserv*) near/3 "mitochondrial function") OR ((reduc* OR decreas* OR prevent* OR attenuat* OR suppress* OR alleviat* OR ameliorat*) near/3 "mitochondrial dysfunction")

#5 - (modulat* OR attenuat* OR reduc* OR inhibit* OR decreas*) near/3 "gamma-secretase"

#6 - (enhanc* OR increas* OR improv* OR protect*) near/3 "autophagy"

#7 - (attenuat* OR reduc* OR prevent* OR inhibit*) near/3 ("caspase* activ*" OR "caspase* express*")

#8 - (increas* OR restor* OR enhanc*) near/3 "Bcl-2"

#9 - (attenuat* OR reduc* OR inhibit* OR decreas* OR prevent*) near/3 "NF-kappaB"

#10 - (increas* OR enhanc* OR restor*) near/3 "ADAM10"

#11 - (increas* OR restor* OR enhanc*) near/3 "CREB"

#12 - (inhibit* OR decreas* OR reduc* OR attenuat*) near/3 "GSK-3"

#13 - (increas* OR enhanc* OR restor*) near/3 "GLP-1"

#14 - (increas* OR enhanc* OR restor*) near/3 "ABCA1"

#15 - (increas* OR enhanc* OR restor*) near/3 "norepinephrine"

#16 - (increas* OR enhanc* OR restor*) near/3 "Nrf2"

#17 - (increas* OR enhanc* OR restor*) near/3 "seladin-1"

#18 - (increas* OR enhanc* OR restor*) near/3 "LRP1"

#19 - (increas* OR enhanc* OR restor*) near/3 "SIRT1"

#20 - (attenuat* OR reduc* OR inhibit* OR decreas*) near/3 "beclin1"

NOT

#21 - alzheimer* OR dementia OR "mild cognitive impairment"

Existing Treatments

#22 - ("donepezil" OR "memantine" OR "Rivastigmine" OR "galantamine" OR "Tacrine" OR "hormone replacement therapy" OR "vitamin E" OR "risperidone" OR "Curcumin" OR "melatonin" OR "docosahexaenoic" OR "olanzapine" OR "walking" OR "nicotine" OR "folate" OR "17 beta-estradiol" OR "physostigmine" OR "lithium" OR "vitamin B-12" OR "neurotrophin" OR "quetiapine" OR "omega-3 fatty acid" OR "Haloperidol" OR "huperzine" OR "psychotherapy" OR "music therapy" OR "occupational therapy" OR "acupuncture" OR "social interaction" OR "resveratrol" OR "polyunsaturated fatty acids" OR "neural stem cells" OR "transcranial magnetic stimulation" OR "vitamin D" OR "selegiline" OR "piracetam" OR "citalopram" OR "Testosterone" OR "folic acid" OR "vitamin C" OR Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

"muscarinic agonist" OR "clioquinol" OR "ibuprofen" OR "Nimodipine" OR "simvastatin" OR "Carbamazepine" OR "electroconvulsive therapy" OR "rapamycin" OR "clozapine" OR "caffeine" OR "cannabinoid" OR "extract EGb 761" OR "tetrahydroaminoacridine" OR "alpha tocopherol" OR "ECT" OR "leisure activity" OR "Ginseng" OR "Mediterranean diet" OR "acetyl-L-carnitine" OR "metrifonate" OR "Aricept" OR "Bapineuzumab" OR "mesenchymal stem cells" OR "trazodone" OR "Cerebrolysin" OR "Epigallocatechin-3-gallate" OR "humanin" OR "reminiscence therapy" OR "B vitamin" OR "sertraline" OR "solanezumab" OR "Ginsenoside" OR "aerobic exercise" OR "pioglitazone" OR "Retinoic acid" OR "deep brain stimulation" OR "indomethacin" OR "leptin" OR "aromatherapy" OR "Cognitive Stimulation Therapy" OR "insulin therapy" OR "Intravenous immunoglobulin" OR "L- deprenyl" OR "turmeric" OR "galanin" OR "selenium" OR "treadmill" OR "coffee" OR "DHEA" OR "progesterone" OR "Atorvastatin" OR "massage" OR "electroacupuncture" OR "fluoxetine" OR "memory training" OR "phosphatidylserine" OR "rosiglitazone" OR "phosphatidylcholine" OR "semagacestat" OR "Green tea" OR "nicotinamide" OR "physical therapy" OR "Aripiprazole" OR "rTMS" OR "bright light therapy" OR "quercetin" OR "fish oil" OR "phenserine" OR "S-adenosylmethionine" OR "saponin" OR "alpha lipoic acid" OR "amylin" OR "environmental enrichment" OR "Propentofylline" OR "social activity" OR "vitamin B-6" OR "cobalamin" OR "flurbiprofen" OR "methylene blue" OR "metformin" OR "rasagiline" OR "Group Therapy" OR "catechin" OR "coumarin" OR "lipoic acid" OR "lovastatin" OR "berberine" OR "ferulic acid" OR "small interfering RNA" OR "cognitive behavioral therapy" OR "DNA vaccine" OR "Reminyl" OR "velnacrine" OR "bexarotene" OR "carotenoid" OR "Citicoline" OR "desferrioxamine" OR "Huperzia serrata" OR "Liraglutide" OR "Thiamine" OR "morphine" OR "N- acetylcysteine" OR "amantadine" OR "ascorbic acid" OR "caloric restriction" OR "Dimebon" OR "erythropoietin" OR "genistein" OR "grape" OR "lamotrigine" OR "red wine" OR "behavioral therapy" OR "curcuminoid" OR "medroxyprogesterone" OR "methylphenidate" OR "pravastatin" OR "scyllo- inositol" OR "Xanomeline" OR "divalproex" OR "gabapentin" OR "lavender" OR "levetiracetam" OR "raloxifene" OR "transcranial direct current stimulation" OR "validation therapy" OR "ziprasidone" OR "arecoline" OR "idebenone" OR "ladostigil" OR "minocycline" OR "nicergoline" OR "PBT2" OR "perindopril" OR "soy" OR "Chondroitin sulfate" OR "etanercept" OR "hydergine" OR "piperidine" OR "sodium valproate" OR "sulfonamide" OR "animal-assisted therapy" OR "clonazepam" OR "Cognex" OR "deferoxamine" OR "multisensory stimulation" OR "allopregnanolone" OR "buspirone" OR "clonidine" OR "coenzyme Q10" OR "cyclophilin" OR "fluvoxamine" OR "garlic" OR "Imipramine" OR "tarenflurbil" OR "transcutaneous electrical nerve stimulation" OR "AF102B" OR "anthocyanin" OR "citrus" OR "embryonic stem cell" OR "escitalopram" OR "Higher education level" OR "Alpha2 macroglobulin" OR "Amaryllidaceae" OR "aminoguanidine" OR "art therapy" OR "benzothiazole" OR "Caffeic acid" OR "doxycycline" OR "Eptastigmine" OR "exendin-4" OR "gelsolin" OR "Icariin" OR "M30" OR "resistance training" OR "Tai Chi" OR "tanshinone" OR "Vinpocetine" OR "Yizhi" OR "Bacopa" OR "bisdemethoxycurcumin" OR "cocoa" OR "Colostrinin" OR "gantenerumab" OR "Geniposide" OR "hydrogen sulfide" OR "moxibustion" OR "oxiracetam" OR "Reality orientation therapy" OR "rifampicin" OR "strength training" OR "9-Amino-1,2,3,4-tetrahydroacridine" OR "apigenin" OR "cinnamon" OR "cognitive therapy" OR "D-cycloserine" OR "propargylamine" OR "rosmarinic acid" OR "telmisartan" OR "topiramate" OR "Tramiprosate" OR "blueberry" OR "Fortasyn" OR "hyperforin" OR "Kampo" OR "mirtazapine" OR "N-benzylpiperidine" OR "Panax notoginseng" OR "Salvia miltiorrhiza" OR "Taurine" OR "yoga" OR "aniracetam" OR "CHF5074" OR "colostrum" OR "dantrolene" OR "Ghrelin" OR "grape seed" OR "hyperbaric oxygen" OR "linopirdine" OR "oleic acid" Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

OR "propranolol" OR "pyridostigmine" OR "retinoid*" OR "saffron" OR "trehalose" OR "AF150" OR "captopril" OR "Crocus sativus" OR "demethoxycurcumin" OR "H2S" OR "latrepirdine" OR "lycopene" OR "piperazine" OR "Polygala tenuifolia" OR "ramelteon" OR "Riluzole" OR "tiapride" OR "beer" OR "clomipramine" OR "dance therapy" OR "Doll therapy" OR "gold nanoparticles" OR "Huannao Yicong" OR "lentiviral vectors" OR "Luteolin" OR "memoquin" OR "Nefiracetam" OR "pitavastatin" OR "pomegranate" OR "Puerarin" OR "scFv antibody" OR "zolpidem" OR "acupressure" OR "AF267B" OR "anandamide" OR "apomorphine" OR "ASS234" OR "Curcuma longa" OR "dihydrotestosterone" OR "glatiramer acetate" OR "horticultural therapy" OR "ketogenic diet" OR "L-3-n-butylphthalide" OR "losartan" OR "rutin" OR "tea polyphenols" OR "Zingiber" OR "7,8-dihydroxyflavone" OR "Aducanumab" OR "aged garlic extract" OR "amiridin" OR "apocynin" OR "baicalein" OR "Centella asiatica" OR "Danshen" OR "edaravone" OR "focused ultrasound" OR "HP 029" OR "Huprine" OR "milieu therapy" OR "natural origin" OR "paeoniflorin" OR "R-flurbiprofen" OR "retinoic acid receptor" OR "Selenate" OR "single-chain antibody" OR "Withania somnifera" OR "Acori graminei" OR "akatinol" OR "beta-asarone" OR "cotinine" OR "cryptotanshinone" OR "cyproterone" OR "dronabinol" OR "ganstigmine" OR "laser therapy" OR "Lavandula angustifolia" OR "naringenin" OR "Noopept" OR "oleocanthal" OR "pepper" OR "pet therapy" OR "ponezumab" OR "Pyritinol" OR "Rehmannia glutinosa" OR "Salidroside" OR "Salvianolic acid" OR "silymarin" OR "T0901317" OR "Tauroursodeoxycholic acid" OR "thalidomide" OR "triflusal" OR "Triptolide" OR "valsartan" OR "AMPK activation" OR "Colivelin" OR "fullerene*" OR "gastrodin" OR "hesperidin" OR "JWH-133" OR "Naftidrofuryl" OR "naringin" OR "neuroglobin" OR "nobiletin" OR "Oleuropein aglycone" OR "sodium butyrate" OR "talsaclidine" OR "Tannic acid" OR "Tetrahydrohyperforin" OR "Tiaoxin" OR "Uncaria rhynchophylla" OR "4-Phenylbutyrate" OR "asiatic acid" OR "benzylpiperidine" OR "Capsaicin" OR "Carnosic acid" OR "Catalpol" OR "D609" OR "Danggui-Shaoyao-San" OR "dihydroergotoxine" OR "ellagic acid" OR "fingolimod" OR "FLZ" OR "glycosaminoglycan polysulfate" OR "granulocyte colony-stimulating factor" OR "graphene" OR "IKKbeta" OR "mifepristone" OR "osthole" OR "protocatechuic acid" OR "Qingxin Kaiqiao" OR "rhynchophylline" OR "S14G-HN" OR "Selenomethionine" OR "Sodium selenate" OR "umbilical cord blood cells" OR "vagus nerve stimulation" OR "Wuzi Yanzong" OR "Xanthoceras" OR "xanthoceraside" OR "Xiusanzhen" OR "yi- gan" OR "Abeta12-28P" OR "carvedilol" OR "Choto-san" OR "cyclandelate" OR "cytidinediphosphocholine" OR "ebselen" OR "fucoidan" OR "H-89" OR "Hericium erinaceus mycelia" OR "JTP-4819" OR "L-theanine" OR "low molecular weight heparin" OR "Namaste Care" OR "Naoling" OR "neotrofin" OR "Noninvasive Brain Stimulation" OR "Oligonol" OR "red mold" OR "retinoid x receptor alpha" OR "S-allyl-l-cysteine" OR "Scutellaria baicalensis" OR "spatial training" OR "SuHeXiang" OR "Tolfenamic acid" OR "Tong Luo Jiu Nao" OR "touch intervention" OR "Valeriana amurensis" OR "15-deoxy-Delta(12,14)-PGJ(2)" OR "17-AAG" OR "4-O-methylhonokiol" OR "alpha- Mangostin" OR "Anatabine" OR "angiotensin-(1-7)" OR "Arundic acid" OR "bee venom" OR "betaine" OR "Cinnamomum" OR "coconut" OR "coptisine" OR "corticotropin-releasing factor receptor" OR "Cranberry" OR "diallyl disulfide" OR "Emblica officinalis" OR "Fucoxanthin" OR "Fuzhisan" OR "Gamma-hydroxybutyrate" OR "intermittent fasting" OR "isorhynchophylline" OR "Isradipine" OR "morin" OR "neural stem cell transplantation" OR "neuritin" OR "Nicotinamide mononucleotide" OR "pifithrin-alpha" OR "PQCA" OR "s-Ethyl cysteine" OR "s-propyl cysteine" OR "scFv-h3D6" OR "sulforaphane" OR "synj1" OR "tamibarotene" OR "targretin" OR "tenuifolin" OR "Tetrandrine" OR "Thymoquinone" OR "tropisetron" OR "vildagliptin" OR "3,6'-dithiothalidomide" OR "4% figs" OR "6- Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

shogaol" OR "A-887755" OR "Activated protein C" OR "AF151" OR "Agmatine" OR "aminopyridazines" OR "apple juice concentrate" OR "arachidonic acid ARA" OR "AVP-786" OR "benfotiamine" OR "BMP9 administration" OR "BMS-299897" OR "compound-1" OR "CREB-binding protein CBP" OR "crocetin" OR "cyclophilin A." OR "Cystatin B deletion" OR "dasatinib" OR "delta-9- tetrahydrocannabinol" OR "derivative of benzothiazole aniline" OR "diazoxide" OR "Dl-PHPB" OR "Drp1 inhibitors" OR "Enoxaparin" OR "ergothioneine" OR "Fbx2" OR "glycyrrhizic acid" OR "Gossypium herbaceam" OR "Human amniotic epithelial cells" OR "hunger" OR "Hydroxysafflor yellow" OR "ICI 118,551" OR "IL-33" OR "ILEI" OR "indirubin-3'-monoxime" OR "iododiflunisal" OR "isoliquiritigenin" OR "L803-mts" OR "linagliptin" OR "Memogain" OR "Meserine" OR "mithramycin" OR "MMP9 gene" OR "Ophiopogon japonicus" OR "PEI-conjugated R8-Abeta(25-35)" OR "phloroglucinol" OR "PLD2 ablation" OR "protein-iPSCs" OR "rexinoid*" OR "RNS60" OR "Safflower yellow" OR "salubrinal" OR "saxagliptin" OR "Sendai virus" OR "single-walled carbon nanotubes" OR "Smart Soup" OR "sodium benzoate" OR "sulfomucopolysaccharide" OR "T-817MA" OR "tetrathiomolybdate" OR "WAY-100635" OR "WIN55212-2" OR "2-methyl-5-(3-{4-[(S)- methylsulfinyl]phenyl}-1-benzofuran-5-yl" OR "2-phenylethynyl-butyltellurium" OR "2S -neoeriocitrin" OR "3,4-dihydroxyphenylethanol" OR "3-alpha-akebonoic acid" OR "40 Hz light-flickering regime" OR "AA3E2" OR "AAD-2004" OR "AAV-p75ECD" OR "Abeta-HBc VLPs" OR "ACAT1 gene ablation" OR "acetate extract of Centipedegrass" OR "Activase rt-PA" OR "activation-inhibitory Lactobacillus pentosus" OR "AD-35" OR "adipose-derived stem cell-conditioned medium" OR "allicin" OR "alpha- chymotrypcin" OR "alpha-tocopherol quinine" OR "alpha-Zearalanol" OR "Anhydroexfoliamycin" OR "anthoxanthin" OR "anti-dementia effects of s-limonene" OR "anti-TLR2 antibody" OR "arctigenin" OR "AS2030680" OR "AS2674723" OR "ASP5736" OR "AVP-923" OR "beta-caryophyllene" OR "Bis(9)-(- )-nor-meptazinol" OR "BMS-289948" OR "BMS-708,163" OR "BRET-Qdot-emitted NIR" OR "butyrolactone" OR "C-30-27" OR "Cardiotrophin-1" OR "Cassia obtusifolia" OR "catechin hydrate" OR "chitosan oligosaccharides" OR "chloroquine derivatives" OR "chronic intranasal treatment" OR "ciproxifan" OR "collagen VI" OR "Cudrania cochinchinensis" OR "cyclophilin B" OR "Cyperus rotundus" OR "cytosine-guanosine-containing DNA oligodeoxynucleotides" OR "DA-JC4" OR "Dalesconol B" OR "Daucosterol palmitate" OR "DcR3" OR "Dehydroevodiamine" OR "deleting Nogo" OR "Dendrobium Nobile Lindl" OR "deoxyschisandrin" OR "dexamethasone exposure during pregnancy" OR "Dietary niacin" OR "Dihydromyricetin" OR "dipotassium N-stearoyltyrosinate" OR "dynorphin A-(1-13)" OR "dZip1 inhibition" OR "ephrinB1/Fc" OR "Eugenia jambolana" OR "EUK1001" OR "exogenous Abeta fibrillar seeds" OR "fenugreek seed powder" OR "Fructus mume" OR "Fumanjian" OR "Gami-Chunghyuldan" OR "genetic deletion of 12/15LO" OR "Genetic deletion of eIF2alpha" OR "Gfa2-VIVIT" OR "GSM-2" OR "Harpagoside" OR "hemizygous deletion of Synj1" OR "high potassium intakes" OR "hunger-inducing drug" OR "HX630" OR "hypericin" OR "IL-1R blocking Ab" OR "illite" OR "Inhibition of GIVA-PLA(2)" OR "Interleukin-34" OR "iso-alpha-acids" OR "JC- 124" OR "JM6" OR "Jujuboside" OR "K6Abeta1-30[E18E19]" OR "kallikrein 7" OR "Kamikihi-to" OR "kappacarrageenanderived pentasaccharide" OR "L-NNNBP" OR "laminin 1" OR "Lentiviral ABN" OR "low-intensity pulsed LIP ultrasound" OR "LX2343" OR "Magnesium sulfate treatment" OR "maltolyl p- coumarate" OR "Marapuama" OR "MER5101" OR "MOG45D" OR "MS-275" OR "murine pathogen- free" OR "MW01-2-069A-SRM" OR "MW01-2-151SRM" OR "N-butylidenephthalide" OR "NButGT" OR "Neuropep-1" OR "ninjin'yoeito" OR "NRG1" OR "P. frutescens extract" OR "P11-hEGF" OR "Paeng-Jo-Yeon-Nyeon-Baek-Ja-In-Hwan" OR "Pantethine" OR "pBri-peptide-based Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

immunomodulation" OR "PD146176" OR "pentamidine" OR "peoniflorin" OR "pharmacological inducer of HO-1" OR "PHF13" OR "Pleurotus ostreatus" OR "PP-3copy-Abeta1-6-loop123" OR "pratensein" OR "proteolytic nanobodies" OR "Pterocarpus marsupium" OR "pulsed ultrasound" OR "Qifu-Yin" OR "recombinant brain-targeted neprilysin ASN12" OR "reduced InsP3R1 expression" OR "reduction in mTOR signaling" OR "Reduction of exosome secretion" OR "repeated cognitive enrichment" OR "replace the endogenous apoE" OR "Rhizophora mucronata" OR "RP-1" OR "S1 peptide" OR "Saengshik" OR "Salvia sahendica" OR "Satureja bachtiarica" OR "scanning ultrasound" OR "Schisantherin B" OR "selenofuranoside" OR "Shengmai" OR "shRNA in the dentate" OR "Sia hydroxamate" OR "skeletal analogues of gambierol" OR "ST09" OR "SUN11602" OR "TAK-070" OR "tangeretin" OR "TAT-BDNF peptide" OR "TAT-haFGF" OR "tenascin-C-deficient" OR "TG101209" OR "TNFSF10 neutralizing antibody" OR "Tongmai Yizhi Decoction" OR "Transplantation of neural progenitor" OR "tri-lithium pyrroloquinoline quinone" OR "tricyclodecan-9-xanthogenate" OR "unmethylated DNA CpG motif" OR "Wen-Dan-Tang" OR "Y-29794" OR "yonkenafil" OR "Zataria multiflora Boiss" OR "zinc/copper chelators")

6-1b2. Final Query

(#1 AND (#2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#2 AND (#3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#3 AND (#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#4 AND (#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#5 AND (#6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#6 AND (#7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

#7 AND (#8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#8 AND (#9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#9 AND (#10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#11 AND (#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#12 AND (#13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#13 AND (#14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#14 AND (#15 OR #16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#15 AND (#16 OR #17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#16 AND (#17 OR #18 OR #19 OR #20)) NOT (#21 OR #22)

(#17 AND (#18 OR #19 OR #20)) NOT (#21 OR #22)

(#18 AND (#19 OR #20)) NOT (#21 OR #22)

(#19 AND (#20)) NOT (#21 OR #22)

6-1b3. Discovery Validation

Each candidate potential AD treatment retrieved using the above query required validation before becoming a potential AD treatment. The candidate potential AD treatment was intersected with the core AD literature, and was validated only after this intersection showed orthogonality.

For example, the candidate potential AD treatment "fortunellin" was retrieved because it satisfied the query combination of reducing inflammation and oxidative stress. Fortunellin also had the additional benefits of reducing the pro-inflammatory cytokines and the expression of p-IkappaB kinase alpha, p- IkappaBalpha, and p-nuclear factor-kappaB, while significantly enhancing superoxide dismutase, catalase, heme oxygenase-1and p-AMP-activated protein kinase. Fortunellin was intersected with (alzheimer* OR dementia OR "mild cognitive impairment"), and no records were retrieved. Fortunellin was therefore validated as a potential AD treatment (Discovery).

Chapter 7

Tables and Concordance Software

7A. Tables

Table 2-1

AD Characteristics

(arranged by # of records when used for treatment benefits)

AD DEMENTIA COGNITION ABETA MEMORY CHOLINERGIC BEHAVIOR INFLAMM NEURON NEUROTOXICITY METABOLISM APOPTOSIS OXIDATIVE STRESS MMSE DEPRESSION LEARNING PLASTICITY NEURODEGENERAT ANTIBOD HYPERPHOSPHORYLATION NFT AGITATION ALPHA-SECRETASE ROS MICROGLIAL ACTIV INSULIN SIGNAL MITOCHONDRIA TAU PATHOLOGY reduc NMDA antagon ESTROGEN replac ASTROGLIOSIS reduc ANXIETY reduc AGGRESSION decr SLEEP improv SEROTONIN incr NEUROGENESIS incr Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

BACE-1 reduc NGF incr GLUTATHIONE incr BDNF incr CASPASE reduc GSK-3 decr TNF-alpha decr MULTIPLE PATHWAYS activat IL-1 decr EXCITOTOXICITY reduc glut APATHY improv MELATONIN restor LTP incr MAO inhibit CEREB BLOOD FLOW incr DHA incr FOLATE amelior VIT B12 amelior HOMOCYSTEINE decr COPPER decr MOBILITY improv Akt incr AGEs reduc Bcl-2 incr ATTENTION improv DENDR SPINE rescu NF-kappaB reduc IL-6 decr MDA decr CHOLESTEROL lower MAPK inhibit INSOMNIA reduc GPX incr Bax decr NONAMYLOIDOGENIC incr NEUR NET regen MISFOLD prevent NEP incr IADL restor ATP incr PHAGOCYTOSIS enhanc IDE incr iNOS reduc QUALITY OF LIFE improv TESTOSTERONE incr ANTIOXIDANT DEFENSE improv cAMP incr Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

CREB incr JNK reduc PHF inhibit MUSCAR M1 activat PGE2 reduc VIT B6 amelior HDAC inhibit NOREPINEPHRINE incr MTOR reduc ANTI-TAU ANTIBOD incr HISTAMINE incr BRAIN ATROPHY reduc Cdk5 inhibit HMGCoAr incr ADAM10 incr CORTISOL decr GLP-1 incr sAPP incr LEPTIN incr COX-1 inhib DHEA incr PPAR-gamma incr PROGESTERONE incr SIRT1 incr Nrf2 incr IL-4 incr ANDROGEN incr VEGF incr HYPERLIPIDEMIA ameliorat Pgp restor IGF-1 incr NAA incr TrkB restor MoCA improv NITROTYROSINE decr PP2A incr BRAIN ACTIVAT incr ATAXIA allev CALCIUM decr TTR incr DNA METHYLAT incr DOPAMINE incr LRP1 incr AMPK incr BrdU incr LXR incr LDL decr Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

HISTONE ACETYL incr CALCINEURIN decr Hsp70 incr HYPERGLYCEMIA improv STRESS reduc ABCA1 incr ENDOTHEL FUNCT improv ADDL inhibit CATHEPSIN-B inhibit MAC inhibit PS1 reduc ALLOPREGNANOLONE incr AUTOPHAGY enhanc DCX restor METAL HOMEOSTAS restore PSD95 incr Seladin-1 incr SLAI restor 25-OHD incr GELSOLIN incr LH reduc c-fos incr LDH reduc PGRN incr IRS-1 reduc PGC-1alpha incr s100B reduc CMRglc incr AXONAL DYSTROPHY decr Beclin-1 decr ADIPONECTIN incr PAI-1 inhibit SNAP-25 restor GABA incr p38MAPK reduc PREGNENOLONE incr TYROSINE HYDROXYLASE incr ADAM9 incr Drp1 decr HDL incr BBB restor ECE incr Egr-1 incr NFAT attenuat PICALM decr TLR-4 reduc NEUROTROPHIN incr Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Ngb incr PLASMA VITAMIN E incr 27-OHC decr GCSF incr HSF1 incr MENOPAUSAL allev O-GlcNAc incr PCNA incr Ras ACTIVITY incr RESOLVIN D1 incr ATF4 decr CD33 inhibit EAAT2 incr GSAP reduc iPLA2 incr LR11 incr MEGALIN enhanc PAK decr 24-OHC decr ABCA7 incr ADMA reduc CNPase incr HSV REP prevent IGFBP3 restor LYSOSOMAL ACIDIFICATION restor miR-339-5p incr miRNA-146a decr MYOINOSITOL reduc SIR1 incr Synj1 decr TERT restor TUBULIN restor Wnt3 incr BH4 restor CHROM MIS-SEGR reduc CLAUDIN-5 incr CRP decr CXCR2 reduc cyclinD1 incr DYSPHAGIA amelior EphB2 incr GLYMPHATIC DRAINAGE restor MAGNESIUM incr mir-206 decr NAAG incr p75ECD incr PI(4,5)P(2) rescu Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

PRAS40 reduc S6K1 reduc SOCE reduc TGF-beta1 rescu UCH-L1 incr B1R incr B2R incr BAG3 incr BRN-4 incr C3 CONVERTASE reduc CEREBROVASC DYSFUNCT amelior CX3CR1 reduc CXCL1 incr Ephexin5 reduc EXCESSIVE NO amelior GEPHYRIN restor GLUT4 incr HISTONE H3K9 incr HSP90ALPHA inhibit HYPERVASCULARITY revers IL-12p40/p70 decr MAP1B incr METHIONONE incr miR-30a-5p decr MKL1 reduc p16 decr PALMITOLEIC ACID reduc Pr-SSG reduc RLT incr RORgammat decr SQSTM1 decr SREBP2 reduc T-MEHA incr TOMOSYN reduc TPI incr TRPM2 reduc WT1 reduc

Table 2-2

AD Causes Impacts

(arranged by # records; abbreviations as shown in VP software)

# RECORDS AD CAUSES IMPACTS 80759 AD enhance 26726 ABETA incr 25423 DEMENTIA incr 24065 COGNITION degrad 12234 MEMORY degrad 7388 METABOLISM decr 6879 APOPTOSIS incr 6732 CHOLINERGIC decr 6307 BEHAVIOR degrad 5946 NEUROTOXICITY incr 5582 PLASTICITY reduc 5358 INFLAMM incr 5075 NFT incr 5011 ANTIBOD reduc 4418 OXIDATIVE STRESS incr 4403 DEPRESSION incr 3992 MMSE decr 3701 LEARNING reduc 3687 HYPERPHOSPHORYLATION incr 3652 NEURON degrad 2835 ASTROGLIOSIS incr 2669 MICROGLIAL ACTIV incr 2663 TAU PATHOLOGY incr 2610 MITOCHONDRIA degrad 2437 ANTIOXIDANT DEFENSE reduc 2328 ROS incr 2300 ALPHA-SECRETASE decr 1623 NEURODEGENERAT incr 1213 EXCITOTOXICITY incr glut 1194 NMDA enhanc 1132 NEUROGENESIS incr 1121 PHF enhanc 1081 MISFOLD incr 1062 ANXIETY incr 988 ESTROGEN reduc 979 CEREB BLOOD FLOW decr 971 CASPASE incr 856 SLEEP decr 820 NGF decr 809 AGITATION incr Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

770 SEROTONIN decr 761 DENDR SPINE degrad 736 BACE-1 incr 732 IL-1 incr 700 STRESS incr 683 GLUTATHIONE decr 667 TNF-alpha incr 666 AGGRESSION incr 652 COPPER incr 632 GSK-3 incr 615 NEUR NET degen 607 LTP decr 588 AGEs incr 567 APATHY incr 567 BRAIN ATROPHY incr 536 ATP decr 520 BDNF decr 497 HOMOCYSTEINE incr 487 IL-6 incr 433 PS1 incr 423 MAPK enhanc 388 NF-kappaB incr 360 Akt decr 358 Cdk5 enhanc 344 NONAMYLOIDOGENIC decr 333 ATAXIA incr 330 CALCIUM incr 327 ATTENTION decr 322 INSULIN SIGNAL reduc 317 CHOLESTEROL incr 316 MELATONIN decr 309 MAO enhanc 307 Bcl-2 decr 305 NEP decr 276 PHAGOCYTOSIS reduc 275 FOLATE degrad 273 cAMP decr 269 MULTIPLE PATHWAYS reduc 261 IDE decr 254 MOBILITY reduc 253 JNK incr 250 AXONAL DYSTROPHY incr 248 DHA decr 236 CORTISOL incr 231 NOREPINEPHRINE decr 223 iNOS incr 223 PGE2 incr Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

222 NAA decr 213 VIT B12 decr 211 GPX decr 204 Bax incr 196 HISTAMINE decr 194 TTR decr 185 IADL reduc 173 INSOMNIA incr 162 DOPAMINE decr 160 TESTOSTERONE decr 155 ADAM10 decr 137 PP2A decr 136 ENDOTHEL FUNCT decr 135 Hsp70 decr 134 HDAC incr 133 DNA METHYLAT decr 132 CREB decr 127 BRAIN ACTIVAT decr 122 CALCINEURIN incr 122 VEGF decr 118 ANDROGEN decr 117 BBB degrad 116 TYROSINE HYDROXYLASE decr 109 MDA incr 108 COX-1 stimulat 105 DHEA decr 104 Pgp decr 101 PROGESTERONE decr 100 HYPERLIPIDEMIA incr 96 HYPERGLYCEMIA incr 96 LRP1 decr 96 MoCA decr 96 MTOR incr 96 PGRN decr 95 IGF-1 decr 93 LEPTIN decr 93 NITROTYROSINE incr 92 CATHEPSIN-B enhanc 91 VIT B6 decr 90 LXR decr 85 ABCA1 decr 85 CMRglc decr 84 GLP-1 decr 83 Nrf2 decr 82 c-fos decr 81 LDL incr 81 SIRT1 decr Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

80 TrkB reduc 76 s100B incr 75 LH incr 71 CEREBROVASC DYSFUNCT incr 71 IL-4 decr 69 PPAR-gamma decr 67 MAC enhanc 63 METAL HOMEOSTAS decr 59 HMGCoAr decr 57 PICALM incr 56 O-GlcNAc decr 54 MUSCAR M1 decr 53 BrdU decr 50 QUALITY OF LIFE reduc 49 ADDL stimulat 49 AUTOPHAGY reduc 48 GELSOLIN decr 47 AMPK decr 44 SNAP-25 decr 41 HISTONE ACETYL decr 40 27-OHC incr 40 ECE decr 38 ALLOPREGNANOLONE decr 34 Beclin-1 incr 33 DCX degrad 33 Drp1 incr 32 25-OHD decr 32 PSD95 decr 31 EAAT2 decr 31 PGC-1alpha decr 31 Seladin-1 decr 30 IRS-1 incr 30 MYOINOSITOL incr 30 sAPP decr 29 PAI-1 enhanc 26 NFAT incr 26 PREGNENOLONE decr 25 ADIPONECTIN decr 25 MENOPAUSAL worsen 23 SLAI reduc 22 ABCA7 decr 22 LDH incr 20 p38MAPK incr 19 ADAM9 decr 19 LR11 decr 19 MAP1B decr 18 24-OHC incr Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

17 CD33 enhanc 17 GABA decr 17 HDL decr 17 Ngb decr 17 PCNA decr 17 UCH-L1 decr 16 ATF4 incr 16 HSF1 decr 16 PAK incr 15 GLUT4 decr 15 MEGALIN reduc 15 miRNA-146a incr 15 TLR-4 incr 14 CRP decr 14 Egr-1 decr 13 BH4 degrad 13 PLASMA VITAMIN E decr 12 ADMA incr 12 CLAUDIN-5 decr 12 CNPase decr 12 CX3CR1 incr 11 LYSOSOMAL ACIDIFICATION reduc 11 NAAG decr 10 CXCR2 incr 10 GSAP incr 10 Wnt3 decr 9 EphB2 decr 8 PI(4,5)P(2) decr 7 Ras ACTIVITY decr 7 SOCE incr 6 GEPHYRIN decr 6 TPI decr 5 EXCESSIVE NO incr 5 GCSF decr 5 GLYMPHATIC DRAINAGE reduc 5 iPLA2 decr 5 NEUROTROPHIN decr 5 p16 incr 5 TUBULIN reduc 4 BAG3 decr 4 C3 CONVERTASE incr 4 CXCL1 decr 4 IGFBP3 decr 4 RESOLVIN D1 decr 4 Synj1 incr 4 TERT reduc 3 B1R decr Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

3 CHROM MIS-SEGR incr 3 cyclinD1 decr 3 MAGNESIUM decr 3 mir-206 incr 3 Pr-SSG incr 3 SIR1 decr 3 TRPM2 incr 2 B2R decr 2 DYSPHAGIA incr 2 HSV REP prevent 2 HYPERVASCULARITY incr 2 PALMITOLEIC ACID incr 2 RLT decr 2 SREBP2 incr 2 T-MEHA decr 2 WT1 incr 1 BRN-4 decr 1 IL-12p40/p70 incr 1 METHIONONE decr 1 miR-30a-5p incr 1 miR-339-5p decr 1 S6K1 incr 1 TOMOSYN incr

Table 2-3

Taxonomy of Benefits from AD Treatment

AD TREATMENT BENEFITS IMPROVE MAINLINE BIOMARKER DEFICITS 1. Neurotransmission modulation 1.1 Enhance cholinergic neurotransmission 1.15 Improve synapse plasticity 1.2 Antagonize NMDA receptors 1.3 GABAergic modulation 1.4 Serotonin receptor modulation 1.5 Histamine receptor modulation 1.6 Adenosine receptor modulation 1.7 Other neurotransmitter modulation 2. Tau modulation 2.1 Tau phosphorylation inhibition 2.2 Microtubule stabilization 2.3 Reducing Tau oligomerization/pathology 3. Abeta modulation 3.1 Reduce Abeta 3.2 Modulate amyloid transport 3.3 Prevent amyloid aggregation 3.4 Promote amyloid clearance 3.5 Amyloid based immunotherapy 3.6 Secretase enzymes modulation 3.7 Improve structural deficits 3.8 Other

IMPROVE METABOLISM BIOMARKERS 4. Insulin and energy metabolism 4.1 Insulin metabolism 4.2 Energy metabolism 5. Oxidative stress reduction 5.1 Augment endogenous defense 5.2 AGEs reduction 6. Mitochondrial function improvement 7. Modulation of cellular calcium homeostasis 8. Inflammation alleviation 9. Others 9.1 Hormone dyshomeostasis improvement 9.2 Lipid dyshomeostasis improvement 9.3 Growth factor restoration 9.4 Metal homeostasis improvement Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

9.5 Epigenetic modification 9.6 Caspase inhibition 9.7 Nitric oxide synthase modulation 9.8 Combinatorial improvements

IMPROVE PERFORMANCE DEFICITS 10. Cognition/Memory/Learning 10.1 Cognition 10.2 Memory 10.3 Learning

IMPROVE BEHAVIORAL DEFICITS 11. Behavioral problems 11.1 Behavior 11.2 Quality of Life 11.3 Agitation 11.4 Aggression 11.5 Anxiety 11.6 Depression 11.7 Attention 11.8 Apathy 11.9 Sleep

IMPROVE NEUROPATHOLOGY AND AD/DEMENTIA 12. Prevent and reverse neuropathology 12.1 ameliorate neurodegeneration 12.2 attenuate neurotoxicity 12.3 prevent apoptosis 12.4 protect neurons 12.5 promote neurogenesis 13. Prevent and reverse AD/dementia 13.1 prevent and reverse AD 13.2 prevent and reverse dementia

Table 2-4

DETAILED TAXONOMY OF AD TREATMENT BENEFITS

BENEFITS FROM AD TREATMENT IMPROVE MAINLINE BIOMARKER DEFICITS 1. Neurotransmission modulation 1.101 incr cholinergic 1.102 restor SLAI 1.15 Improve synapse plasticity 1.1501 improv PLASTICITY 1.1502 reduc SREBP2 1.1503 regen neural network 1.1504 incr PSD95 1.1505 incr Ras activity 1.1506 incr CMRglc 1.1507 incr MAP1B 1.1508 reduc TOMOSYN 1.1509 reduc myoinositol 1.151 reduc S6K1 1.1511 rescu PI(4,5)P(2) 1.1512 restor SNAP-25 1.1513 decr PAK 1.1514 amelior excessive NO 1.1515 incr magnesium 1.1516 incr EAAT2 1.1517 reduc glut excitotoxicity 1.1518 decr calcineurin 1.2 Antagonize NMDA receptors 1.201 antag NMDA 1.3 GABAergic modulation 1.301 incr GABA 1.302 restor gephyrin 1.4 Serotonin receptor modulation 1.401 incr SEROTONIN 1.402 inhibit MAO 1.5 Histamine receptor modulation 1.501 incr histamine 1.502 incr T-MEHA 1.6 Adenosine receptor modulation 1.601 incr ATP 1.7 Other neurotransmitter modulation 1.701 incr norepinephrine 1.702 activat M1 Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

1.703 incr N-acetylaspartate 1.704 incr NAAG 1.705 incr brain activation 2. Tau modulation 2.1 Tau phosphorylation inhibition 2.101 reduc hyperphosphorylation 2.2 Microtubule stabilization 2.201 restor tubulin 2.202 decr NFT 2.203 incr glutathione 2.3 Reducing Tau oligomerization/pathology 2.301 reduc tau pathology 2.302 decr paired helical filament 2.303 inhibit Hsp90alpha 2.304 prevent hsv 2.305 incr anti-tau antibod 3. Abeta modulation 3.1 Reduce Abeta 3.101 reduc Abeta 3.102 reduc mTOR 3.103 incr AMPK 3.104 incr Brn-4 3.105 incr p75ECD 3.106 incr LR11 3.107 inhibit CatB 3.108 reduc PRAS40 phosphorylation 3.109 restor glymphatic drainage 3.2 Amyloid transport 3.201 restor BBB 3.202 incr Claudin-5 3.3 Preventing amyloid aggregation 3.302 incr iPLA2 3.303 inhibit ADDL 3.304 reduc C3 convertase 3.305 incr TTR 3.306 incr LRP1 3.307 incr NEP 3.308 incr ECE-2 3.309 incr tyrosine hydroxylase 3.4 Promoting amyloid clearance 3.401 enhanc phagocytosis 3.402 restor lysosomal acidification 3.403 incr ABCA1 Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

3.404 incr ABCA7 3.405 inhibit CD33 3.406 incr LXR 3.407 enhanc megalin 3.408 incr gelsolin 3.409 restor Pgp 3.5 Amyloid based immunotherapy 3.501 enhanc antibod 3.6 Secretase enzymes modulation 3.601 incr alpha-secretase 3.602 incr sAPP 3.603 incr nonamyloidogenic 3.604 reduc GSAP 3.605 reduc PS1 3.606 incr ADAM10 3.607 incr ADAM9 3.608 reduc BACE1 3.609 incr SIRT1 3.61 decr PICALM 3.7 Improve structural deficits 3.701 decr brain atrophy 3.8 Other 3.801 decr homocysteine 3.802 incr methionone IMPROVE METABOLISM BIOMARKERS 4. Insulin and Energy metabolism 4.1 Insulin metabolism 4.101 allev diabet 4.102 reduc IRS-1 4.103 improv hyperglycemia 4.104 incr IDE 4.105 incr GLP-1 4.106 incr Akt 4.107 incr BAG3 4.108 incr GLUT4 4.2 Neuronal metabolism 4.201 improv metabol 4.202 incr O-GlcNAc 5. Oxidative stress reduction 5.1 Augmenting endogenous defense 5.101 improv antioxidant defense 5.102 reduc oxidative stress 5.103 incr glutathione peroxidase Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

5.104 decr nitrotyrosine 5.105 incr plasma Vitamin E 5.106 reduc Pr-SSG 5.107 decr ROS 5.108 incr Nrf2 5.109 incr IGF-1 5.11 reduc ADMA 5.111 decr GSK-3 5.112 improv endotheli 5.113 restor BH4 5.114 incr cerebral blood flow 5.2 AGEs reduction 5.201 reduc AGEs 6. Mitochondrial function improvement 6.101 protect mitochondria 6.102 incr SIR1 6.103 incr PGC-1alpha 6.104 decr Drp1 7. Modulation of cellular calcium homeostasis 7.101 decr calcium 7.102 reduc SOCE 8. Inflammation alleviation 8.101 reduc inflamm 8.102 decr TNF-alpha 8.103 decr CRP 8.104 incr cAMP 8.105 decr IL-1 8.106 decr IL-6 8.107 incr IL-4 8.108 reduc NF-kappaB 8.109 decr p16 8.11 incr cyclinD1 8.111 incr PPAR-gamma 8.112 inhib cyclooxygenase-1 8.113 incr resolvin D1 8.114 reduc CXCR2 8.115 reduc TLR-4 8.116 reduc MKL1 8.117 reduc s100B 9. Others 9.1 Hormone dyshomeostasis 9.101 incr progesterone 9.102 incr testosterone Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

9.103 replace estrogen 9.104 incr androgen 9.105 reduc luteinizing hormone 9.106 incr DHEA 9.107 incr Allopregnanolone 9.108 incr pregnenolone 9.2 Lipid dyshomeostasis 9.201 reduc cholesterol level 9.202 decr 24-hydroxycholesterol 9.203 decr 27-hydroxycholesterol 9.204 incr HDL 9.205 decr LDL 9.206 incr HMGCoAr 9.207 reduc chromosome mis-segregation 9.208 ameliorat hyperlipidemia 9.209 incr leptin 9.3 Growth factor restoration 9.301 incr NGF 9.302 incr VEGF 9.4 Metal homeostasis improvement 9.401 restor metal homeostasis 9.402 decr copper 9.403 inhib MAPK 9.5 Epigenetic modification 9.501 incr DNA methylation 9.502 amelior B6 9.503 amelior B12 9.504 amelior folate 9.511 inhib HDAC 9.512 incr histone acetylation 9.513 incr histone H3K9 9.521 incr miR-339-5p 9.522 decr miR-30a-5p 9.523 decr mir-206 9.524 decr miRNA-146a 9.6 Caspase inhibition 9.601 reduc caspase 9.602 reduc JNK 9.603 restor IGFBP3 9.7 Nitric oxide synthase modulation 9.701 reduc iNOS 9.8 Combinatorial improvements 9.801 activat multiple pathways Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

IMPROVE PERFORMANCE DEFICITS 10. Cognition/Memory/Learning 10.1 Cognition 10.101 improv cogniti 10.102 amelior cerebrovascular dysfunction 10.103 revers hypervascularity 10.104 incr CXCL1 10.105 improv MoCA 10.106 improv MMSE 10.107 reduc palmitoleic acid 10.108 incr DHA 10.109 incr c-fos 10.11 incr Egr-1 10.111 incr adiponectin 10.112 incr TPI 10.2 Memory 10.201 improv memory 10.202 incr B2R 10.203 incr B1R 10.204 incr GCSF 10.205 incr LTP 10.206 incr RLT 10.207 inhib Cdk5 10.208 inhib MAC 10.209 restor TrkB 10.21 restor melatonin 10.211 reduc CX3CR1 10.212 decr ATF4 10.213 incr dopamine 10.214 incr EphB2 10.3 Learning 10.301 improv learning 10.302 decr RORgammat IMPROVE BEHAVIORAL DEFICITS 11. Behavioral problems 11.1 Behavior 11.101 improv behavior 11.2 Quality of Life 11.201 prevent nutritional deficien 11.201 improv quality of life 11.201 improv quality-of-life 11.202 allev menopausal 11.203 amelior dysphagia Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

11.204 restor IADL 11.205 allev ataxia 11.206 improv mobility 11.207 incr 25-OHD 11.208 reduc reduce stress 11.3 Agitation 11.301 reduc agitat 11.302 decr cortisol 11.4 Aggression 11.401 decr aggressi 11.5 Anxiety 11.501 reduc anxiety 11.6 Depression 11.601 reduc depression 11.7 Attention 11.701 improv attention 11.8 Apathy 11.801 reduc apathy 11.9 Sleep 11.901 improv sleep 11.902 reduc insomnia REVERSE NEUROPATHOLOGY AND AD/DEMENTIA 12. Prevent and reverse neuropathology 12.1 Ameliorate neurodegeneration 12.101 reduc neuro degenerat 12.102 reduc astrogli 12.103 suppress activation microgli 12.104 attenuat NFAT 12.105 incr CNPase 12.106 incr Bcl-2 12.107 decr Bax 12.108 decr MDA 12.109 incr BDNF 12.11 incr neurotrophin 12.111 incr UCH-L1 12.112 inhibit PAI-1 12.113 rescu TGF-beta1 12.114 decr axonal dystrophy 12.115 incr PP2A 12.116 reduc LDH 12.117 incr PGRN 12.2 Attenuate neurotoxicity 12.201 alleviat neurotoxic Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

12.202 incr Ngb 12.3 Prevent apoptosis 12.301 inhib apopto 12.302 rescu dendritic spine 12.303 reduc Ephexin5 12.304 incr seladin-1 12.305 incr Hsp70 12.306 reduc TRPM2 12.307 reduc WT1 12.308 restor TERT 12.309 reduc p38MAPK 12.4 Protect neurons 12.401 protect neuron 12.402 enhanc autophagy 12.403 decr Beclin-1 12.404 decr SQSTM1 12.405 reduc synj1 12.406 incr CREB 12.407 decr IL-12p40/p70 12.5 Promote neurogenesis 12.501 incr neurogenesis 12.502 restor DCX 12.503 incr PCNA 12.504 incr 5-bromo-2'-deoxyuridine 12.505 incr heat shock transcription factor 12.506 incr Wnt3 PREVENT AND REVERSE AD/DEMENTIA 13. AD and Dementia 13.1 AD/Dementia 13.101 prevent AD 13.102 reduc prostaglandin 13.103 prevent dementia

Table 2-5

AD Treatment Benefits

(ordered by # records; abbreviations as shown in VP software)

# RECORDS AD TREATMENT BENEFIT 15766 AD prevent 8299 DEMENTIA prevent 8245 COGNITION improv 6592 ABETA reduc 3697 MEMORY improv 3557 CHOLINERGIC enhanc 2765 BEHAVIOR improv 2220 INFLAMM reduc 2053 NEURON protect 2048 NEUROTOXICITY allev 1644 METABOLISM improv 1612 APOPTOSIS inhibit 1467 OXIDATIVE STRESS reduc 1456 MMSE improv 1455 DEPRESSION reduc 1335 LEARNING improv 1331 PLASTICITY improv 1190 NEURODEGENERAT reduc 1152 ANTIBOD enhanc 924 HYPERPHOSPHORYLATION reduc 800 NFT decr 759 AGITATION reduc 752 ALPHA-SECRETASE incr 720 ROS decr 715 MICROGLIAL ACTIV suppress 648 INSULIN SIGNAL restor 562 MITOCHONDRIA protect 545 TAU PATHOLOGY reduc 532 NMDA antagon 526 ESTROGEN replac 480 ASTROGLIOSIS reduc 471 ANXIETY reduc 439 AGGRESSION decr 390 SLEEP improv 376 SEROTONIN incr 364 NEUROGENESIS incr 322 BACE-1 reduc 306 NGF incr 305 GLUTATHIONE incr 297 BDNF incr Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

256 CASPASE reduc 250 GSK-3 decr 239 TNF-alpha decr 237 MULTIPLE PATHWAYS activat 212 IL-1 decr 211 EXCITOTOXICITY reduc glut 207 APATHY improv 195 MELATONIN restor 190 LTP incr 190 MAO inhibit 185 CEREB BLOOD FLOW incr 185 DHA incr 163 FOLATE amelior 160 VIT B12 amelior 159 HOMOCYSTEINE decr 153 COPPER decr 152 MOBILITY improv 145 Akt incr 143 AGEs reduc 139 Bcl-2 incr 138 ATTENTION improv 134 DENDR SPINE rescu 134 NF-kappaB reduc 123 IL-6 decr 122 MDA decr 121 CHOLESTEROL lower 119 MAPK inhibit 117 INSOMNIA reduc 112 GPX incr 109 Bax decr 109 NONAMYLOIDOGENIC incr 107 NEUR NET regen 106 MISFOLD prevent 106 NEP incr 100 IADL restor 96 ATP incr 96 PHAGOCYTOSIS enhanc 93 IDE incr 93 iNOS reduc 91 QUALITY OF LIFE improv 85 TESTOSTERONE incr 80 ANTIOXIDANT DEFENSE improv 79 cAMP incr 76 CREB incr 74 JNK reduc 74 PHF inhibit 69 MUSCAR M1 activat Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

66 PGE2 reduc 65 VIT B6 amelior 64 HDAC inhibit 62 NOREPINEPHRINE incr 61 MTOR reduc 60 ANTI-TAU ANTIBOD incr 59 HISTAMINE incr 57 BRAIN ATROPHY reduc 56 Cdk5 inhibit 56 HMGCoAr incr 53 ADAM10 incr 51 CORTISOL decr 51 GLP-1 incr 51 sAPP incr 49 LEPTIN incr 47 COX-1 inhib 46 DHEA incr 46 PPAR-gamma incr 46 PROGESTERONE incr 42 SIRT1 incr 41 Nrf2 incr 40 IL-4 incr 39 ANDROGEN incr 39 VEGF incr 36 HYPERLIPIDEMIA ameliorat 35 Pgp restor 34 IGF-1 incr 34 NAA incr 34 TrkB restor 33 MoCA improv 31 NITROTYROSINE decr 31 PP2A incr 30 BRAIN ACTIVAT incr 29 ATAXIA allev 28 CALCIUM decr 28 TTR incr 27 DNA METHYLAT incr 27 DOPAMINE incr 27 LRP1 incr 26 AMPK incr 26 BrdU incr 25 LXR incr 23 LDL decr 22 HISTONE ACETYL incr 21 CALCINEURIN decr 21 Hsp70 incr 21 HYPERGLYCEMIA improv Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

21 STRESS reduc 20 ABCA1 incr 20 ENDOTHEL FUNCT improv 19 ADDL inhibit 19 CATHEPSIN-B inhibit 19 MAC inhibit 19 PS1 reduc 18 ALLOPREGNANOLONE incr 18 AUTOPHAGY enhanc 18 DCX restor 18 METAL HOMEOSTAS restore 18 PSD95 incr 17 Seladin-1 incr 17 SLAI restor 16 25-OHD incr 16 GELSOLIN incr 16 LH reduc 15 c-fos incr 15 LDH reduc 15 PGRN incr 14 IRS-1 reduc 14 PGC-1alpha incr 14 s100B reduc 13 CMRglc incr 12 AXONAL DYSTROPHY decr 12 Beclin-1 decr 11 ADIPONECTIN incr 11 PAI-1 inhibit 11 SNAP-25 restor 10 GABA incr 10 p38MAPK reduc 10 PREGNENOLONE incr 10 TYROSINE HYDROXYLASE incr 9 ADAM9 incr 9 Drp1 decr 8 HDL incr 7 BBB restor 7 ECE incr 7 Egr-1 incr 7 NFAT attenuat 7 PICALM decr 7 TLR-4 reduc 6 NEUROTROPHIN incr 6 Ngb incr 6 PLASMA VITAMIN E incr 5 27-OHC decr 5 GCSF incr Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

5 HSF1 incr 5 MENOPAUSAL allev 5 O-GlcNAc incr 5 PCNA incr 5 Ras ACTIVITY incr 5 RESOLVIN D1 incr 4 ATF4 decr 4 CD33 inhibit 4 EAAT2 incr 4 GSAP reduc 4 iPLA2 incr 4 LR11 incr 4 MEGALIN enhanc 4 PAK decr 3 24-OHC decr 3 ABCA7 incr 3 ADMA reduc 3 CNPase incr 3 HSV REP prevent 3 IGFBP3 restor 3 LYSOSOMAL ACIDIFICATION restor 3 miR-339-5p incr 3 miRNA-146a decr 3 MYOINOSITOL reduc 3 SIR1 incr 3 Synj1 decr 3 TERT restor 3 TUBULIN restor 3 Wnt3 incr 2 BH4 restor 2 CHROM MIS-SEGR reduc 2 CLAUDIN-5 incr 2 CRP decr 2 CXCR2 reduc 2 cyclinD1 incr 2 DYSPHAGIA amelior 2 EphB2 incr 2 GLYMPHATIC DRAINAGE restor 2 MAGNESIUM incr 2 mir-206 decr 2 NAAG incr 2 p75ECD incr 2 PI(4,5)P(2) rescu 2 PRAS40 reduc 2 S6K1 reduc 2 SOCE reduc 2 TGF-beta1 rescu Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

2 UCH-L1 incr 1 B1R incr 1 B2R incr 1 BAG3 incr 1 BRN-4 incr 1 C3 CONVERTASE reduc 1 CEREBROVASC DYSFUNCT amelior 1 CX3CR1 reduc 1 CXCL1 incr 1 Ephexin5 reduc 1 EXCESSIVE NO amelior 1 GEPHYRIN restor 1 GLUT4 incr 1 HISTONE H3K9 incr 1 HSP90ALPHA inhibit 1 HYPERVASCULARITY revers 1 IL-12p40/p70 decr 1 MAP1B incr 1 METHIONONE incr 1 miR-30a-5p decr 1 MKL1 reduc 1 p16 decr 1 PALMITOLEIC ACID reduc 1 Pr-SSG reduc 1 RLT incr 1 RORgammat decr 1 SQSTM1 decr 1 SREBP2 reduc 1 T-MEHA incr 1 TOMOSYN reduc 1 TPI incr 1 TRPM2 reduc 1 WT1 reduc

Table 2-6

Existing AD Treatments

(arranged in decreasing order of number of records in database)

# RECORDS TREATMENT 3174 cholinesterase inhibitor 1481 donepezil 1392 antioxidant 1219 immunotherapy 1154 antiinflammatory agents 958 memantine 903 antipsychotic agents 874 Rivastigmine 734 galantamine 661 anti-Abeta therapy 642 antidepressant 600 exercise 526 Tacrine 428 secretase inhibitors 421 psychotropic agents 408 NSAID 402 statin therapy 381 neuroleptic 333 herb 322 chelator 312 plant extract 295 nerve growth factor 294 stem cell 285 vitamin E 284 risperidone 235 antihypertensive agents 232 Curcumin 212 nicotine 210 hormone replacement therapy 210 polyphenol 209 brain-derived neurotrophic factor 195 melatonin 192 cognitive therapy 189 vitamin supplementation 188 DHA 183 olanzapine 183 walking 179 transplanted 170 flavonoids 168 anti-oxidant Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

163 folate 159 17 beta-estradiol 157 NMDA receptor antagonist 152 physostigmine 148 lithium 147 estrogen replacement therapy 146 vitamin B-12 144 serotonin reuptake inhibitor 143 neurotrophin 142 BACE1 inhibitor 142 quetiapine 134 omega-3 fatty acid 133 Haloperidol 131 gene therapy 130 huperzine 128 fish 123 fruit 123 psychotherapy 122 aggregation inhibitor 121 music therapy 118 ACE inhibitor 110 occupational therapy 105 acupuncture 104 social interaction 102 phenol 100 resveratrol 97 polyunsaturated fatty acids 96 neural stem cells 96 transcranial magnetic stimulation 92 vitamin D 91 selegiline 90 anticonvulsant 86 piracetam 85 citalopram 85 Testosterone 83 folic acid 83 vitamin C 82 electroconvulsive therapy 81 MAO-B inhibitor 80 muscarinic agonist 77 Epigallocatechin-3-gallate 76 clioquinol 72 ibuprofen 71 Nimodipine 70 simvastatin 69 Carbamazepine 68 rapamycin Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

67 clozapine 66 caffeine 66 calcium channel blocker 66 cannabinoid 64 EGB 761 62 tetrahydroaminoacridine 61 alpha tocopherol 61 antiepileptic drugs 61 leisure activity 60 Ginseng 60 Mediterranean diet 60 Phytochemical 59 acetyl-L-carnitine 59 metrifonate 58 Aricept 58 Bapineuzumab 57 mesenchymal stem cells 56 trazodone 55 Retinoic acid 54 Cerebrolysin 54 GSK-3 inhibitor 53 humanin 53 reminiscence therapy 52 B vitamin 52 sertraline 52 solanezumab 51 Ginsenoside 50 aerobic exercise 50 pioglitazone 49 deep brain stimulation 49 indomethacin 49 leptin 48 aromatherapy 48 deprenyl 48 insulin therapy 48 Intravenous immunoglobulin 47 antidiabetic agents 47 galanin 47 selenium 47 treadmill 46 coffee 46 DHEA 46 diuretic 46 progesterone 45 Atorvastatin 45 massage 44 electroacupuncture Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

44 fluoxetine 44 memory training 44 phosphatidylserine 44 rosiglitazone 43 phosphatidylcholine 43 semagacestat 42 cholesterol-lowering agents 41 COX-2 inhibitor 41 Physiotherapy 40 Aripiprazole 38 bright light therapy 38 quercetin 37 fish oil 36 phenserine 36 S-adenosylmethionine 36 saponin 35 spice 34 alpha lipoic acid 34 amylin 34 environmental enrichment 34 PPARgamma agonist 34 Propentofylline 34 social activity 34 vitamin B6 33 cobalamin 33 flurbiprofen 33 methylene blue 33 sensory stimulation 32 anti-tau treatments 32 metformin 32 rasagiline 31 Group Therapy 30 catechin 30 coumarin 30 lipoic acid 30 lovastatin 29 berberine 29 ferulic acid 29 latrepirdine 29 small interfering RNA 27 velnacrine 26 bexarotene 26 carotenoid 26 Citicoline 26 desferrioxamine 26 Liraglutide 26 neurosteroid Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

26 Thiamine 25 morphine 25 N-acetylcysteine 25 transcutaneous electrical nerve stimulation 24 amantadine 24 anti-diabetic 24 ascorbic acid 24 caloric restriction 24 erythropoietin 24 genistein 24 grape 24 lamotrigine 24 red wine 23 behavioral therapy 23 histone deacetylase inhibitor 23 medroxyprogesterone 23 methylphenidate 23 pravastatin 23 scyllo-inositol 23 Xanomeline 22 divalproex 22 gabapentin 22 isoflavone 22 lavender 22 levetiracetam 22 lipid lowering 22 raloxifene 22 RXR agonist 22 transcranial direct current stimulation 22 validation therapy 22 ziprasidone 21 arecoline 21 idebenone 21 minocycline 21 nicergoline 21 PBT2 21 perindopril 21 polysaccharide 21 soy 20 angiotensin receptor blockers 20 anti-depressant 20 Chondroitin sulfate 20 etanercept 20 genetic deletion 20 hydergine 20 piperidine 20 sodium valproate Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

20 sulfonamide 19 animal-assisted therapy 19 clonazepam 19 Colostrinin 19 deferoxamine 19 multisensory stimulation 18 allopregnanolone 18 buspirone 18 butyrylcholinesterase inhibitor 18 clonidine 18 coenzyme Q10 18 cyclophilin 18 fluvoxamine 18 garlic 18 Imipramine 18 tarenflurbil 17 AF102B 17 anthocyanin 17 citrus 17 embryonic stem cell 17 escitalopram 17 Higher education level 17 hydrogen sulfide 16 Alpha2 macroglobulin 16 Amaryllidaceae 16 aminoguanidine 16 art therapy 16 benzothiazole 16 Caffeic acid 16 Crocus sativus 16 doxycycline 16 Eptastigmine 16 exendin-4 16 gelsolin 16 Icariin 16 M30 16 resistance training 16 Tai Chi 16 tanshinone 16 Vinpocetine 16 Yizhi 15 anti-amnesic 15 Bacopa 15 cocoa 15 gantenerumab 15 Geniposide 15 moxibustion Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

15 oxiracetam 15 Reality orientation therapy 15 rifampicin 15 strength training 14 9-Amino-1,2,3,4-tetrahydroacridine 14 apigenin 14 cinnamon 14 D-cycloserine 14 propargylamine 14 rosmarinic acid 14 telmisartan 14 topiramate 14 Tramiprosate 13 blueberry 13 Fortasyn 13 hyperforin 13 Kampo 13 ladostigil 13 mirtazapine 13 N-benzylpiperidine 13 Panax notoginseng 13 Salvia miltiorrhiza 13 Taurine 13 TV3326 13 yoga 12 aniracetam 12 anti-epileptic 12 CHF5074 12 dantrolene 12 Ghrelin 12 hyperbaric oxygen 12 linopirdine 12 multinutrient 12 oleic acid 12 propranolol 12 pyridostigmine 12 trehalose 11 AF150 11 anticoagulant therapy 11 captopril 11 lycopene 11 nootropic agents 11 piperazine 11 Polygala tenuifolia 11 ramelteon 11 Riluzole 11 tiapride Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

10 antibiotic therapy 10 beer 10 clomipramine 10 dance therapy 10 Doll therapy 10 fatty acid supplementation 10 gold nanoparticles 10 Huannao Yicong 10 lentiviral vectors 10 Luteolin 10 memoquin 10 Nefiracetam 10 pitavastatin 10 pomegranate 10 Puerarin 10 rhynchophylline 10 zolpidem 9 acupressure 9 AF267B 9 anandamide 9 apomorphine 9 ASS234 9 butylphthalide 9 dihydrotestosterone 9 glatiramer acetate 9 horticultural therapy 9 ketogenic diet 9 losartan 9 rutin 9 Zingiber 8 7,8-dihydroxyflavone 8 Aducanumab 8 amiridin 8 apocynin 8 baicalein 8 Centella asiatica 8 Danshen 8 edaravone 8 focused ultrasound 8 HP 029 8 Huprine 8 milieu therapy 8 paeoniflorin 8 R-flurbiprofen 8 Sodium selenate 8 Withania somnifera 7 Acori graminei Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

7 akatinol 7 beta-asarone 7 cotinine 7 cryptotanshinone 7 cyproterone 7 dronabinol 7 ganstigmine 7 genetic reduction 7 laser therapy 7 Lavandula angustifolia 7 naringenin 7 Noopept 7 oleocanthal 7 pepper 7 pet therapy 7 ponezumab 7 Pyritinol 7 Rehmannia glutinosa 7 Salidroside 7 Salvianolic acid 7 silymarin 7 T0901317 7 Tauroursodeoxycholic acid 7 thalidomide 7 triflusal 7 Triptolide 7 valsartan 6 Colivelin 6 fullerene 6 gastrodin 6 hesperidin 6 JWH-133 6 Naftidrofuryl 6 naringin 6 neuroglobin 6 nobiletin 6 Oleuropein aglycone 6 sodium butyrate 6 talsaclidine 6 Tannic acid 6 Tetrahydrohyperforin 6 Tiaoxin 6 xanthoceraside 5 4-Phenylbutyrate 5 asiatic acid 5 benzylpiperidine 5 Capsaicin Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

5 Carnosic acid 5 Catalpol 5 D609 5 Danggui-Shaoyao-San 5 dihydroergotoxine 5 ellagic acid 5 fingolimod 5 FLZ 5 glycosaminoglycan polysulfate 5 granulocyte colony-stimulating factor 5 graphene 5 IKKbeta 5 mifepristone 5 osthole 5 protocatechuic acid 5 Qingxin Kaiqiao 5 S14G-HN 5 Selenomethionine 5 umbilical cord blood cells 5 vagus nerve stimulation 5 Wuzi Yanzong 5 Xiusanzhen 5 yi-gan 4 Abeta12-28P 4 carvedilol 4 Choto-san 4 cyclandelate 4 cytidinediphosphocholine 4 ebselen 4 fucoidan 4 H-89 4 Hericium erinaceus 4 JTP-4819 4 L-theanine 4 low molecular weight heparin 4 Namaste Care 4 Naoling 4 neotrofin 4 Noninvasive Brain Stimulation 4 NRG1 4 Oligonol 4 red mold 4 S-allyl-l-cysteine 4 Scutellaria baicalensis 4 spatial training 4 SuHeXiang 4 Tolfenamic acid Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

4 Tong Luo Jiu Nao 4 touch intervention 4 Valeriana amurensis 3 15d-PGJ2 3 17-AAG 3 4-O-methylhonokiol 3 alpha-Mangostin 3 Anatabine 3 angiotensin-(1-7) 3 Arundic acid 3 bee venom 3 betaine 3 Cinnamomum 3 coconut 3 coptisine 3 corticotropin-releasing factor receptor 3 Cranberry 3 diallyl disulfide 3 Emblica officinalis 3 Fucoxanthin 3 Fuzhisan 3 Gamma-hydroxybutyrate 3 intermittent fasting 3 Isradipine 3 morin 3 neuritin 3 pifithrin-alpha 3 PQCA 3 s-Ethyl cysteine 3 s-propyl cysteine 3 sulforaphane 3 tamibarotene 3 targretin 3 tenuifolin 3 Tetrandrine 3 Thymoquinone 3 tropisetron 3 vildagliptin 2 3,6'-dithiothalidomide 2 4% figs 2 6-shogaol 2 A-887755 2 Activated protein C 2 AF151 2 Agmatine 2 aminopyridazines 2 apple juice concentrate Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

2 arachidonic acid ARA 2 AVP-786 2 benfotiamine 2 BMS-299897 2 bone morphogenetic protein 9 2 compound-1 2 CREB-binding protein CBP 2 crocetin 2 Cystatin B deletion 2 dasatinib 2 delta-9-tetrahydrocannabinol 2 derivative of benzothiazole aniline 2 diazoxide 2 Dl-PHPB 2 Drp1 inhibitors 2 Enoxaparin 2 ergothioneine 2 Fbx2 2 glutaminyl cyclase inhibitor 2 glycyrrhizic acid 2 Gossypium herbaceam 2 Human amniotic epithelial cells 2 hunger 2 Hydroxysafflor yellow 2 ICI 118,551 2 IL-33 2 ILEI 2 indirubin-3'-monoxime 2 iododiflunisal 2 isoliquiritigenin 2 L803-mts 2 linagliptin 2 Memogain 2 Meserine 2 mithramycin 2 MMP9 gene 2 Ophiopogon japonicus 2 PEI-conjugated R8-Abeta(25-35) 2 phloroglucinol 2 PLD2 ablation 2 prolyl endopeptidase inhibitor 2 protein-iPSCs 2 RNS60 2 Safflower yellow 2 salubrinal 2 saxagliptin 2 Sendai virus Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

2 single-walled carbon nanotubes 2 Smart Soup 2 sodium benzoate 2 T-817MA 2 tetrathiomolybdate 2 WAY-100635 2 WIN55212-2 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1- 1 benzofuran-5-yl 1 2-phenylethynyl-butyltellurium 1 2S -neoeriocitrin 1 3,4-dihydroxyphenylethanol 1 3-alpha-akebonoic acid 1 40 Hz light-flickering regime 1 AA3E2 1 AAD-2004 1 AAV-p75ECD 1 Abeta-HBc VLPs 1 ACAT1 gene ablation 1 Activase rt-PA 1 activation-inhibitory Lactobacillus pentosus 1 AD-35 1 adipose-derived stem cell-conditioned medium 1 allicin 1 alpha-chymotrypcin 1 alpha-Zearalanol 1 Anhydroexfoliamycin 1 anthoxanthin 1 anti-dementia effects of s-limonene 1 arctigenin 1 AS2030680 1 AS2674723 1 ASP5736 1 AVP-923 1 beta-caryophyllene 1 Bis(9)-(-)-nor-meptazinol 1 BMS-289948 1 BMS-708,163 1 BRET-Qdot-emitted NIR 1 butyrolactone 1 C-30-27 1 Cardiotrophin-1 1 Cassia obtusifolia 1 Centipedegrass 1 chitosan oligosaccharides 1 chloroquine derivatives 1 ciproxifan Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

1 collagen VI 1 Cudrania cochinchinensis 1 Cyperus rotundus cytosine-guanosine-containing DNA 1 oligodeoxynucleotides 1 DA-JC4 1 Dalesconol B 1 Daucosterol palmitate 1 DcR3 1 Dehydroevodiamine 1 deleting Nogo 1 Dendrobium Nobile Lindl 1 deoxyschisandrin 1 dexamethasone exposure during pregnancy 1 Dietary niacin 1 Dihydromyricetin 1 dipotassium N-stearoyltyrosinate 1 dynorphin A-(1-13) 1 dZip1 inhibition 1 ephrinB1/Fc 1 Eugenia jambolana 1 EUK1001 1 exogenous Abeta fibrillar seeds 1 fenugreek seed powder 1 Fructus mume 1 Fumanjian 1 Gami-Chunghyuldan 1 genetic deletion of 12/15LO 1 Genetic deletion of eIF2alpha 1 Gfa2-VIVIT 1 GSM-2 1 Harpagoside 1 hemizygous deletion of Synj1 1 high potassium intakes 1 human ApoE4 allele 1 HX630 1 hypericin 1 IL-1R blocking Ab 1 illite 1 Inhibition of GIVA-PLA(2) 1 Interleukin-34 1 iso-alpha-acids 1 JC-124 1 JM6 1 Jujuboside 1 K6Abeta1-30[E18E19] 1 kallikrein 7 Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

1 Kamikihi-to 1 kappacarrageenanderived pentasaccharide 1 L-NNNBP 1 laminin 1 1 Lentiviral ABN 1 low-intensity pulsed LIP ultrasound 1 LX2343 1 Magnesium sulfate treatment 1 maltolyl p-coumarate 1 Marapuama 1 MER5101 1 MOG45D 1 MS-275 1 murine pathogen-free 1 MW01-2-069A-SRM 1 MW01-2-151SRM 1 N-butylidenephthalide 1 NButGT 1 Neuropep-1 1 ninjin'yoeito 1 P. frutescens extract 1 P11-hEGF 1 Paeng-Jo-Yeon-Nyeon-Baek-Ja-In-Hwan 1 Pantethine 1 pBri-peptide-based immunomodulation 1 PD146176 1 pentamidine 1 peoniflorin 1 pharmacological inducer of HO-1 1 PHF13 1 Pleurotus ostreatus 1 PP-3copy-Abeta1-6-loop123 1 pratensein 1 proteolytic nanobodies 1 Pterocarpus marsupium 1 pulsed ultrasound 1 Qifu-Yin 1 recombinant brain-targeted neprilysin ASN12 1 reduced InsP3R1 expression 1 Reduction of exosome secretion 1 repeated cognitive enrichment 1 Rhizophora mucronata 1 RP-1 1 S1 peptide 1 Saengshik 1 Salvia sahendica 1 Satureja bachtiarica Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

1 scanning ultrasound 1 Schisantherin B 1 selenofuranoside 1 Shengmai 1 shRNA in the dentate 1 Sia hydroxamate 1 skeletal analogues of gambierol 1 ST09 1 sulfo-muco-polysaccharides 1 sulfomucopolysaccharide 1 SUN11602 1 TAK-070 1 tangeretin 1 TAT-BDNF peptide 1 TAT-haFGF 1 tat-VIVIT 1 tenascin-C-deficient 1 TG101209 1 Tongmai Yizhi Decoction 1 tri-lithium pyrroloquinoline quinone 1 tricyclodecan-9-xanthogenate 1 unmethylated DNA CpG motif 1 Wen-Dan-Tang 1 Y-29794 1 yonkenafil 1 Zataria multiflora Boiss (to access multiple AD treatment references, either

1) go to section 10C, or

2) use Medline query:

{treatment name from list} AND (Alzheimer's OR dementia OR "mild cognitive impairment")

Table 2-7

DETAILED AD FOUNDATIONAL CAUSES

(adapted from reference [1])

2-7A. Taxonomy of AD Causes

Table 2-7A presents a detailed taxonomy of AD foundational causes.

Table 2-7A - Detailed Taxonomy of AD Foundational Causes

CODE CATEGORY I LIFESTYLE I-A Diet I-A1 Excesses I-A2 Deficiencies I-A3 Food Additives/Pollutants I-B Activity I-B1 Sedentary Lifestyle

I-B2 Sleep I-C Substance Abuse I-C1 Recreational Drugs I-C2 Smoking I-C3 Alcohol I-D Other II IATROGENIC II-A Drugs II-A1 Anti-Neoplastic Agents II-A2 Anti-Infective Agents II-A2a Anti-Bacterial/Anti-Fungal/Anti-Parasitical Agents II-A2b Anti-Viral/Anti-Retroviral Agents II-A3 Anti-Inflammatory Agents II-A4 Cardiovascular Agents II-A5 Central Nervous System Agents II-A5a Analgesics and Pain Relievers II-A5b Movement Stabilizers II-A5c Depressants/Anti-Depressants and Stimulants II-A5d Mood Stabilizers II-A6a Immunosuppressive Agents/Immunosuppression II-A6b Immunostimulation Agents Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

II-A6b1 Vaccines/Vaccination II-A7 Hematologic Agents II-A7a Coagulants II-A7b Anti-Coagulants II-A7c Other II-A8 Steroids/Hormones II-A9 Anti-Hypertensive Agents II-A10 Gastrointestinal Agents II-A11 Lipid Regulating Agents II-A12 Dermatologic Agents II-A13 Anti-Bone-Loss Agents II-A14 Anti-Diabetic Agents II-A15 Anti-Rheumatic Agents II-A16 Anti-Allergic Agents II-A17 Anti-Hypotensive Agents II-A18 Anti-Thyroid Agents II-B Radiotherapy II-C Surgery/Invasive Treatments II-C1 Transplantation II-C2 CardioVascular II-C3 Orthopedic II-C4 Gastrointestinal II-C5 Kidney/Urologic II-C6 Brain/Neural II-C7 Dental/Oral/Nose/Ear II-C8 Gynecologic II-C9 Respiratory/Thorax II-C10 Liver/Spleen II-C11 Ocular II-C12 Breast II-C13 Dermal/Tissue/Neck II-C14 Thyroid II-C15 Pancreas II-C16 General II-C17 Other II-D Diagnostic Agents/Procedures II-D1 Contrast Media II-D2 Radiation II-D2a Ionizing Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

II-D2b Non-Ionizing II-D3 Invasive II-D4 Other III BIOTOXIC AGENTS III-A Mycotoxins III-B Exotoxins III-C Bacteria/Fungi/Parasites III-D Viruses III-E Other IV OCCUPATIONAL/ENVIRONMENTAL EXPOSURES IV-A Chemicals/Materials IV-A1 Industrial/Household Chemicals/Materials IV-A1a Hydrocarbons IV-A1b Solvents IV-A1c Chemical Compounds IV-A1d Other IV-A2 Agricultural Chemicals IV-A3 Materials IV-A3a Heavy Metals IV-A3b Particulates IV-A3c Nanotechnology IV-B Physical/Mechanical IV-B1 Electromagnetic Radiation IV-B1a Ionizing IV-B1b Non-Ionizing IV-B1b1 Non-Visible IV-B1b2 Visible IV-B2 Sound IV-B3 Temperature; Heat/Cold IV-B4 Force/Pressure/Physical Trauma IV-C Other V PSYCHOSOCIAL/SOCIOECONOMIC V-A Psychological V-B Sociological V-C Economic VI GENETICS (Categories Only) VI-A Polymorphism/Genotypes/Haplotypes VI-B Mutations VI-C Linkages Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

VI-D Risk Alleles VI-E Genotoxicity VI-F Familial VI-G Congenital

2-7B. Effects/Impacts from AD Foundational Causes

Table 2-7B presents a taxonomy of effects/impacts from the AD foundational causes. Its members will be used to identify potential links to effects/impacts of the foundational causes identified in the final results taxonomy of Table 2-7C.

Table 2-7B - Taxonomy of Effects/Impacts from AD Foundational Causes

(adapted from reference [1])

CODE LEVEL CELLULAR LEVEL A1 increase neuroinflammation A2 increase neurotoxicity A3 increase neuronal death A4 increase neurodegeneration A5 induce DNA damage A6 damage mitochondria A7 increase neuronal oxidative stress BIOMARKER LEVEL B1 increase tau pathology/neurofibrillary tangles B2 increase Abeta generation B3 increase AGEs B4 increase insulin resistance B5 reduce brain volume B6 produce low tostesterone B7 produce tissue lesions B8 induce synaptic/neurotransmission dysfunction B9 induce hippocampal damage B10 induce olfactory dysfunction B11 impair glutamate uptake B12 compromise BBB integrity B13 impair glucose homeostasis B14 impair metal homeostasis PERFORMANCE LEVEL C1 increase memory loss C2 increase seizures C3 induce cognitive dysfunction DISEASE LEVEL D1 increase AD risk D2 increase diabetes risk D3 induce hypothyroidism D4 induce metabolic syndrome D5 increase obesity

These effects/impacts are divided into four categories:

Each lowest-level sub-category was obtained by inspecting visually many abstracts and titles of records that related cause to effect/impact, and extracting those effects mentioned multiple times.

The lowest-level sub-categories are not orthogonal; there is some partial overlap and redundancy. Much of this is due to the different less-than-precise language of the article authors themselves. For example, some authors may use neurotoxicity to refer to neural damage, others may use neurodegeneration or neuronal death or .....

The value of incorporating the members of the above table in the final results is that it conveys (to the research community, the medical clinician community, and the consumer community) how the research is linked either

1) directly to AD, or indirectly to AD through

2) strong disease precursors of AD (e.g., diabetes), or

3) strong behavioral precursors of AD (e.g., cognitive decline), or

4) strong biomarker precursors of AD (e.g., increase tau hyperphosphorylation), or

5) strong cellular precursors of AD (e.g., increase neuronal death).

Why is this important?

Consider two potential foundational causes of AD identified in the present study, high-fat diets and wireless radiation. High-fat-diets have been studied for a long time, and there appears to be good evidence that such diets are strong contributors to AD. The long-term data are sufficient to conclude there is a direct link between high-fat diets and AD.

Wireless radiation at cell phone radiofrequencies or WiFi frequencies has been in commercial/military use for perhaps thirty years, and in wide-scale use for perhaps ten+ years. It might take 50-60 years to identify impacts of this segment of the radiation spectrum on the development of AD. We have a choice. We can wait many decades for the types of conclusive evidence that would satisfy the statisticians, or we can start to take precautions based on the impact of wireless radiation on surrogate endpoints/biomarkers/AD characteristics already demonstrated. This is the Precautionary Principle, and the results contained in Table 2-7C provide a starting point for implementation of the Precautionary Principle for prevention and reversal of AD.

2-7C. Specific Foundational Causes of AD

Table 2-7C shows the AD potential foundational causes in this detailed taxonomic structure. There are four columns listed. The first column on the left (CAT) is the foundational cause category as shown in Table 2-7A. The next column is the foundational cause. To keep the volume of results manageable, in some cases only the cause in aggregate was shown, rather than listing all the members (e.g., vegetables). The third column is the effect(s) produced by the foundational cause, and the entry tags are those listed in Table 2-7B. The fourth column contains relevant references that confirm the foundational cause. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

In most cases, there were multiple papers linking each foundational cause listed either directly to AD or indirectly to one or more surrogate endpoints. Referencing every single relevant paper for every detailed foundational cause would have produced an overly voluminous unreadable table and write-up. In order to balance comprehensiveness with readability, multiple compromises were made.

First, one or two representative papers for each foundational cause were selected and referenced. Second, foundational causes that had relatively minor differences were aggregated. Some were listed separately under a categorical heading, and others were subsumed within the heading. Third, the effects/impacts of the foundational causes were extracted from at least the papers referenced, and sometimes from other relevant papers that were not selected for referencing. Thus, the effects/impacts shown for any potential cause should be viewed as a "floor" of all potential effects, not a "ceiling".

It should also be noted that all the effects/impacts were derived from papers whose central theme was AD/dementia, because of the criteria used to extract these records from Medline. So, a foundational cause that, e.g., "damaged mitochondria" (A6) did so within the overall context of relating to AD or dementia. If the four different levels shown, and the items contained in each level, are viewed as potential "pathways" to AD, then conventional wisdom implies that the more pathways impacted by a potential contributing factor, the greater likelihood that factor would be an important "cause" of AD. However, not only are the numbers of pathways impacted important, but the strength of the contributing factor's impact on each pathway is important. This strength of impact is not shown in the table, reflecting its ambiguity in the literature.

The foundational causes identified are at different levels of importance to AD, and are at different levels of verification/validation. In the Medline literature examined, some foundational causes were identified through:

1) in vitro cell or tissue tests;

2) animal experiments;

3) epidemiological studies;

4) individual case studies; and,

5) trials with large numbers of subjects.

Conventional wisdom implies that those foundational causes associated with large numbers of papers published and large numbers of test subjects would have greater credibility. However, as shown in [2-3], there may be (many) important foundational causes being withheld from the literature deliberately, so numbers of papers is not a definitive metric for credibility.

Table 2-7C - Foundational Causes of AD

(adapted from reference [1])

CAT CAUSE EFFECTS REF I LIFESTYLE

I-A DIET I-A1 EXCESSES High Fat Diet A2, B1, B2, C1, C3, [3-12] -saturated fat D1, D4, D5 -dairy fat -trans-unsaturated fat -hydrogenated fat -omega-6 PUFAs -n-6/n-3 ratio -maternal high fat diet Diabetogenic diet B2 [13] High calorie diet A1, B1, B12, C3, D1, [14-16] D5 High salt diet B2, C3, D1 [17] High carbohydrate diet A1, A3, A4, A7, B2, [18-25] -refined carbohydrates B4, B11, B12, B13, -sugars (fructose/sucrose/glucose/D-galactose) C1, C3, D1, D2 -gluten -high glycemic index diet High advanced glycation end products diet A6, A7, B1, B2, B3, [26-31] -high temperature food heating C1, C3, D1, D2 -food irradiation -high glucose -high nutrient-bound AGEs -animal foods high in fat and protein High cholesterol diet A1, A4 [32] High iron diet A1, C3, D1 [33-35] -high red meat -high processed meat High meat diet D1 [36] High arachidonic acid B1 [37] High methionine diet A1, A2, A7, B1, B8, [38-40] B2, C1, C3 High copper diet C3, D1 [35, 41] High zinc A3, A7, B1, B2 [42-43] High pickle diet D1 [44] High unfermented soy D1 [45] I-A2 DEFICIENCIES Vitamin B deficiency A3, A4, A6, A7, B1, [46-49] -myriad B-Vitamin deficiency B2, C1, C3 -B2/B6/B12 deficiency Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

-folate/folic acid deficiency -thiamine deficiency Vitamin C deficiency A7, C2 [50] Vitamin D deficiency A1, A4, A6, B1, B2, [51-52] B5, B8, C3, D1 Vitamin E deficiency D1 [53] Vitamin K deficiency C3 [54] -fluindone Potassium deficiency A1, A3, A7, B1, B2, [55-56] C3 Iron deficiency C3 [57] Zinc deficiency A3, C3, D1 [58] Magnesium deficiency C3 [59] Calcium deficiency A3, A7 [60] Selenium deficiency B2 [61] Starvation B2 [62] Dehydration B5, D1, D2, D5 [63] Malnutrition D1 [64] Early life nutrient restriction B2, D1 [65] Glucose deprivation A3, B1, B2 [66] Glutathione depletion A1, A2, A4 [67] Linoleic acid deficiency A4, D1 [68] Low docosahexaenoic acid A3 [53] Low tryptophan diet B2 [69] Nondrinkers C3, D1 [70] Low cocoa A1, A7, C3 [71] Low coffee C3, D1 [72] Low flavonoids/flavanols: A1, A7, B2, C3, D1 [71, 73-74] acacetin, aminogenistein, apigenin, kaempferol, 7,8-Dihydroxyflavone, anthocyanins, atriplex laciniata L, blueberries, Curcumin, cyanidin, datiscetin, delphinidin, EGCG, epicatechin, Epimedium brevicornum, fisetin, genistein, Ginkgo, glycitein, icariin, isoscutellarein 7-O- [6'''-O-acetyl-beta-D-allopyranosyl-(12)]-beta- D-glucopyranoside, isovitexin, morin, myricetin, Nobiletin, pelargonidin, phloridzin, rutin, salvigenin, Scutellaria baicalensis Georgi, Sideritis flavonoids, vitexin, xanthomicrol, luteolin, morin, PD98059, quercetin, taxifolin, β-naphthoflavone Low fruit: A7, B2, B3, B13, C1, [21, 75-76] low: blackberries, blueberries, strawberries, C3, D1 raspberries, cherries, oranges, plums, prunes, red grapes, pomegranates, date palm fruits Low vegetables A7, B13, C3, D1 [8] -cruciferous -dark and green leafy Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Low fatty fish B2, C3, D1 [77] I-A3 FOOD ADDITIVES/POLLUTANTS Industrialized/preserved food D1 [78] Monosodium glutamate A2, A3, B2, B9 [79] Menadione A3, A7 [80] Cysteine A7 [81] Diacetyl A2, B2 [82] I-B ACTIVITY I-B1 SEDENTARY LIFESTYLE Physical inactivity/low daily gardening, walking A6, A7, D1 [83-84] Chronic immobilization stress A4, B1, B2, B9, C3 [85] Cognitive inactivity D1 [86] Lack of exercise D1, D2 [23] Low cardiovascular fitness D1 [87] I-B2 SLEEP Sleep deprivation C3, D1 [20, 88] Circadian disruption C1, C3 [89-90] I-C SUBSTANCE ABUSE I-C1 RECREATIONAL DRUGS Amphetamine C3 [91] 3,4-Methylenedioxyamphetamine; MDMA; A2, A7, B1, C1, C3 [92] Ecstacy Cocaine/opiates A2, A4 [93-94] Phencyclidine C3 [95] I-C2 SMOKING Tobacco smoke A4 [96] Ethanol/excess alcohol A7, B9, C1, C3, D1 [97] II IATROGENIC II-A DRUGS II-A1 ANTI-NEOPLASTIC AGENTS Chemotherapy A2, A4, B9 [98] Chemical castration C3 [99] Camptothecin A2, A3 [100] Epoxomicin A3, A6 [101] Staurosporine/Etoposide A3, A4 [102-103] Methylmethane sulfonate A5 [104] Paclitaxel/Doxorubicin A3, A4, B1 [105] Doxycyclin B2 [106] Cyclophosphamide/cytophosphane A2, A7 [107] Letrozole B9, C1 [108] Methotrexate B9, C1, C3 [109] Choline mustard Az/Nitrogen mustard B9, C1 [110] Anastrozole B2, B9 [111] d,l-buthionine-S,R-sulfoximine/BSO A3, A6, A7, B14 [112] Fostriecin/Fos B1 [113] carbobenzoxy-Leu-Leu-leucinal/MG132 A2, A4 [114] Streptozocin B14, D1 [115] Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

II-A2 ANTI-INFECTIVE AGENTS Chloroquine(CQ); CQ; lysosomotropic agent B2 [116] Ionomycin A6, B2 [117] II-A3 ANTI-INFLAMMATORY AGENTS colchicine A1, A4, C1, D1 [118] II-A4 CARDIOVASCULAR AGENTS isoproterenol B1, C1 [119] atropine B2 [120] D-ribose A3, B1, B3 [121] Muscarinic receptor antagonists C1, C3 [122] II-A5 CENTRAL NERVOUS SYSTEM AGENTS II-A5a Analgesics and Pain Relievers Anesthetics/Opiods A2, A3, A4, A6, B1, [123-129] -acetaminophen B2, B9, C1, C3, D1 -barbital -barbitone -desflurane -dexmedetomidine -diethylbarbituric acid -diethylmalonyl urea -enflurane -halothane -isoflurane -ketamine -medinal -morphine -nitrous oxide -pentobarbital -propofol -psychotropic drugs -sevoflurane -sodium diethylbarbiturate -veronal

II-A5b Movement Stabilizers Anticholinergic medications A3, A7, B1, C3, D1 [130-132] -doxepin -chlorpheniramine -oxybutynin -trihexyphenidyl -propiverine -L-DOPA/dopamine II-A5C Depressants/Anti-Depressants and Stimulants selective serotonin re-uptake inhibitors D1 [133] benzodiazepine D1 [134] dizocilpine C1, C3 [135] 3-quinuclidinyl benzilate C3 [136] Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

II-A5d Mood Stabilizers -clozapine C1, C3 [137] -methyllycaconitine -dihydro-beta-erythrodine

anisomycin A7, B2 [138] II-A6 IMMUNE SYSTEM AGENTS II-A6a Immunosuppressive Agents/ Immunosuppression Cyclosporin B1, C1 [139] II-A6b Immunostimulation Agents polyinosinic:polycytidylic acid B2, C3 [140] II-A7 Hematologic Agents II-A7b Anti-Coagulants Sulfated glycosaminoglycans B1 [141] -heparin/heparan sulfate -dextran sulfate -pentosan polysulfate -chondroitin sulfate -dermatan sulfate II-A7c Other mitochondrial toxins A1, A3, A6, A7 [142] -1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine/MPTP II-A8 Steroids/Hormones Corticosteroids A1, A3, A4, B1, B5 [143-145] -methylprednisolone -dexamethasone Anabolic androgenic steroids B8, B9, C1, C3 [146] -nandrolone -stanozolol Corticosterone B1, B2, C3 [147] Wortmannin A7, B1 [148] 17beta-trenbolone A3, A4, B2 [149] Salmon calcitonin B2 [150] Human chorionic gonadotropin B2 [151-152] Corticotrophin releasing factor B2 [153] Sex steroid hormones B2 [154] -transient testosterone treatment -flutamide U18666A A3, A7, B2 [155] Allopregnanolone B9, C1, C3 [156] Medroxy-progesterone acetate C3, D1 [157] Androgen deprivation therapy D1 [158] Postmenopausal hormone therapy C3 [159] Testosterone depletion A1, D1, D2 [160] Leptin deficiency B1 [161] Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Prenatal sex hormone exposure D1 [162] II-A9 ANTI-HYPERTENSIVE AGENTS ACE inhibitor D1 [163] ICI 118,551/Selective beta2AR antagonist B1, B2, C3 [164] Telmisartan/Olmesartan B2 [165] Mecamylamine C3 [166] II-A10 GASTROINTESTINAL AGENTS Thiorphan/Phosphoramidon B2 [167] Proton pump inhibitors B2, D1 [168-169] -omeprazole -pantoprazole -lansoprazole -esomeprazole -rabeprazole II-A13 ANTI-BONE-LOSS AGENTS PGE2 B2 [170] II-A14 ANTI-DIABETIC AGENTS Intralipid and insulin B2 [171] Metformin B2 [172] II-A16 ANTI-ALLERGIC AGENTS Anticholinergics D1 [173] -first-generation antihistamines -tricyclic antidepressants -bladder antimuscarinics II-A18 ANTI-THYROID AGENTS Propythiouracyl A1, B1, B2, B5, B8, [174] C1 II-A19 Other Carbachol B8, B14 [175] MDL72974/Mofegiline A3, A7 [176] Pilocarpine A3, B1, B2 [177] Clenbuterol hydrochloride B2 [178] Semagacestat C3 [179] II-B RADIOTHERAPY Head radiotherapy C3, D1 [180-181] II-C SURGERY/ INVASIVE TREATMENTS II-C1 TRANSPLANTATION Liver transplant B2, C3 [182] II-C2 CARDIOVASCULAR Cardiac surgery/bypass A1, B1, B2, C3 [183-185] II-C5 KIDNEY/UROLOGIC Dialysis C1, C3 [186-187] Gonadectomy B2 [188] II-C7 DENTAL/ORAL/NOSE/EAR Olfactory bulbectomy A4, A6, A7, B2, C1 [189-190] Occlusal disharmony B2 [191] II-C8 GYNECOLOGIC Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Hysterectomy/oophorectomy C3 [192] Premature surgical menopause/Premature C3 [193] ovarian failure II-C17 OTHER Axotomy A3, A7 [194] Cerebral artery occlusion A3, A4, A7, B8, C1, [195-198] C3 Intermittent hypoxia/ischemia A3, A4, A7, B2, B12, [199-202] C1, C3 Brain embolism A4, B1, B2, C1, C3 [203-204] Aortic coarctation A1, B2 [205] Forebrain lesions C1, C3 [206-207] Adrenalectomy B2 [208] Pituitary hormone injections with Abeta B2 [209] Abdominal surgery B2, C3 [210] III BIOTOXIC AGENTS III-A MYCOTOXINS Mycotoxins A2, A3, A4, A7, B1, [211-214] -ochratoxin A/OTA C1, C3, D1 -Fumonisin B1/FB1 -macrocyclic trichothecenes 3-nitropropionic acid A6 [215] III-B EXOTOXINS Excitotoxins A1, A2, A3, A4, B9, [216-220] -kainic acid/ kainate C1, C2, C3, -quisqualic acid -ibotenic acid -domoic acid -quinolinic acid/quinolinate Phosphatase inhibitor B1 [221] -okadaic acid Excitatory amino acids D1 [222] Malonate B9 [223] Annonaceaeous acetogenins A2, D1 [224] Cyanobacteria A2, B1, B2, B14 [225-228] -beta-N-methylamino-L-alanine/BMAA -saxitoxin -anatoxin-a -blue-green algae -microcystin Diphtheria toxin B2 [229] Pseudomonas aeruginosa exotoxin Y B1, B12 [230] Saporin B1, B2, B13, C3 [231-233] -192 IgG-saporin -p75-saporin Cycad plant A2, A4, A5 [234] -cycasin/methylazoxymethanol Glutamate/Glutamine synthetase A2, A3, A4, A6, B2 [235-237] Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Mitochondrial inhibitors A6 [238] -rotenone -3-NPA -antimycin -KCN -oligomycin III-C BACTERIA/FUNGI/PARASITES Bacteria/bacterial infections A1, A4, A7, B1, B2, [239-253] -bacterial endotoxins B3, C3, D1 -bacterial lipopolysaccharide -gram-negative bacterium -spirochetes -Chlamydophyla pneumoniae -Helicobacter pylori -Escherichia coli -Treponema pallidum -Tannerella forsythia -Treponema denticola -T. socranskii -T. pectinovorum -T. medium -T. amylovorum -T. maltophilum -Fusobacterium nucleatum -Prevotella intermedia -Chlamydia pneumoniae -Porphyromonas gingivalis -propionibacterium acnes -Treponemas -T. lecithinolyticum -Borrelia burgdorferi Fungi/fungal infection -Cryptococcus -Coccidioides -Aspergillus -Histoplasma -Blastomyces -C. famata -C. parapsilosis -C. glabrata -C. krusei -Candida albicans -Candida ortholopsis -Candida tropicalis -Cladosporium -Malassezia globosa -Malassezia restricta -Neosartorya hiratsukae -Phoma Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

-Sacharomyces cerevisae -Sclerotinia borealis Parasites -Trypanosoma brucei rhodesiense -Trypanosoma brucei gambiense -Acanthamoeba -Balamuthia mandrillaris -Toxoplasma gondii -Taenia solium -Toxocara canis -T. cati -Toxocara ova -Leishmania amazonensis III-D VIRUSES Viruses/Viral infections/Virulence factors A1, A3, A4, B1, B2, [254-260] Bornaviridae C3, D1 -Mammalian 1 bornavirus Bunyaviridae -Hantavirus -La Crosse encephalitis virus Coronaviridae -Human coronavirus OC43 -Murine hepatitis virus Flaviviridae -Hepatitis C virus -Japanese encephalitis virus -Murray Valley encephalitis virus -St. Louis encephalitis virus -West Nile virus Hepadnaviridae -Hepatitis B virus Herpesviridae -Cytomegalovirus -Epstein-Barr virus -Herpes simplex virus 1 -Human herpesvirus 6 Orthomyxoviridae -Influenza A virus (H1N1) -Influenza A virus (H3N2) -Influenza A virus (H5N1) Paramyxoviridae -Hendra virus -Measles virus Picornaviridae -Enterovirus 71 -Theiler's murine encephalomyelitis virus Polyomaviridae -Simian 40 virus large T antigen Retroviridae Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

-Human immunodeficiency virus 1 -Human T-cell leukemia virus -Moloney murine leukemia virus Rhabdoviridae -Chandipura virus Togaviridae -Chikungunya virus -Eastern equine encephalitis virus -Venezuelan equine encephalitis virus III-E OTHER Abeta A1, A2, A3, A4, A6, [261-271] -amyloid precursor protein B2, B8, B14, C1, C3 -C31 -CT105 -Curli fibrils Homocysteine/3-Mercaptopropionic Acid B8, B12, C1 [272-273] Lipopolysaccharide A7, B3, C1 [274] Prions/Prion protein fragment A2, A3, B14 [275-277] Cytokines A1, A2, A3, A4, B1, [278-288] -CXCL10 B2, B9, C1, C3 -IL-1 beta -IL-10 -interferon-alpha -interferon-gamma -interleukin-6 -interleukin-18 -interleukin-8 -TNF-alpha Lipoperoxydation proteins A1, A2, A3 [289-290] -advanced lipoperoxydation products -oxidized low density lipoprotein Trophic factor withdrawal A3, A4, B2 [291-293] Amylin A1, A2, A4, A6, A7 [294] Lysophosphatidic acid B2 [295] S100B A1, B1, B2 [296] 3-hydroxykynurenine/3-hydroxyanthranilic acid A4, A7, B2 [297] Abscisic acid A1 [298] Phorbol myristate acetate A1 [298] Acid phosphatase D1 [299] 2-deoxy-D-glucose B2 [300] 3-methylindole/Skatole B10 [301] alpha-amino-3-hydrozy-5-methyl-4-isoxazole A2 [302] propionic acid/AMPA Asymmetric dimethylarginine A2, A7, B2, C3 [303-304] Dolichyl phosphate B12 [305] N-(2-chloroethyl)-N-ethyl-bromo- A1, A3, A4, B2, B13, [306] benzylamine/dsp4 C1 Galanin C1, C3 [307] Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

GW4869/hydrochloride hydrate B2 [308] Cottonseed B1, B2 [309] Homocysteic acid/Homocysteate A3, A7 [310] Isoprostane B2 [311] Lysophosphatidylcholine A2, A3, A7, B2 [312] Saturated non-esterified fatty acids B2 [313] Palmitic acid A3, C3 [314] Oncostatin M A2, B11 [315] S100A9 A1, B2, C3 [316] Salsolinol A2, A3 [317] Sulfatide A3 [318] Brefeldin A A3, A6, A7 [319] Thapsigargin A3, A6, A7 [319] GF-109203X B1 [320] Isopropyl-1-beta-D-thiogalactopyranoside A3, A6, B1 [321] C2-ceramide A3, A7 [322] dl-threo-1-phenyl-2-decanoylamino-3- B2 [323] morpholino-1-propanol/PDMP (1S,2R-d-erythro-2-N-myristoylamino)-1- B2 [323] phenyl-1-propanol/DMAPP alpha7 nAChR subunit alpha7(1-208) A1, B2, C3 [324] Adenosine triphosphate/ATP B1 [325] Recombinant BiP/GRP78 B2 [326] Bradykinin B1, B14 [327] CD40/CD40L B2 [328] Collagen B2 [329] Cyclic dipeptides A3 [330] D-serine A7 [331] Elastase A7, B1 [332] 4-Hydroxyhexenal/HHE A3, B11, B13 [333] High-mobility group box-1/HMGB1 C3 [334] Exogenous amyloidogenic proteins B2 [335] -casein -fibroin -sericin -actin -islet amyloid polypeptide Leukotrienes A1, B2, C1 [336-337] -Leukotriene B4/LTB4 -Leukotriene D4/LTD4 Myostatin precursor protein B2 [338] N-acetylcholinesterase A3, B1 [339] Secreted phospholipase A2-IIA/sPLA2-IIA A1 [340] Spermine A2 [341] Xanthine oxidase A3, A7 [342] 3-hydroxykynurenine/3-HK A2, A3, A6 [343] Mitochondrial lysates A1 [344] Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Phytohemagglutinin A3, B14 [345] Angiotensin II B1, B2, C3 [346] 3beta-hydroxy-5-oxo-5,6-secocholestan-6-al/ A2, A3, A7, B2 [347] ChSeco Cholesterol oxidation products/oxysterols A1, A2, A7 [348-349] -27-hydroxycholesterol/27-OHC -24-OH -7beta-hydroxycholesterol -7-ketocholesterol -5,6-alpha cholesterol epoxide -5,6-beta cholesterol epoxide -cholesterol triol -lathosterol -beta cholesterol epoxide -cholesterol triol Calyculin A A2, A7, B1 [350] Chromogranin A A1 [351] Forskolin B1 [352] N-methyl-D-aspartate A3, B9 [353] PGJ2 A1, A3, B1 [354-355] Quisqualate A3, B9, C2 [356] Tunicamycin A3, B14 [357] 2-chloro-2'-deoxyadenosine/2-CDA/ cladribine B2, C3 [358] N-acetylglucosamine A2, B8, B9 [359]

Cholinesterase B2 [360] -acetylcholinesterase -butyrylcholinesterase Glycogen synthase kinase 3-beta/GSK3beta B1 [361] HMG-CoA reductase D1 [362] Pam(3)CSK(4) A1 [363] Superoxide dismutase deficiency A1, A7, B1, B2, B3, [364] C1 IV OCCUPATIONAL/ENVIRONMENTAL EXPOSURES IV-A CHEMICALS/MATERIALS IV-A1 INDUSTRIAL/HOUSEHOLD CHEMICALS/MATERIALS IV-A1a Hydrocarbons 20-methylcholanthrene/methylcholanthrene A1 [365] IV-A1b Solvents Petroleum-based solvents D1 [366] -Mineral turpentine -Diesel fuel -Fuel oil -Kerosene Chlorinated solvents C3 [367] -Trichloroethylene Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

-Perchlorethylene -Trichloroethane -Dichloromethane -Benzene Dimethyl sulfoxide/DMSO B1 [368] Organic solvents D1 [369-370] -Benzene -Toluene -Phenols -Alcohols -Ketones -Methylmethacrylate IV-A1c Chemical Compounds Neurotoxins A3, A7 [371-372] -6-hydroxydopamine/6-OHDA -5,6-dihydroxytryptamine/5,6-DHT -5,7-dihydroxytryptamine/5,7-DHT Type-2 Alkenes/Reactive aldehydes A2, A3, A4, A7, B1, [373-378] -Acrolein B2, B3, B8 -4-Hydroxynonenal/HNE -Acrylamide -Methyl glyoxal Nitrosamine/N-nitrosodiethylamine A3, A4, B4, C3 [379]

Adenosine, 3', 5'-cyclic monophosphate/ cAMP B2 [380] Carbon tetrachloride A1, A4, A7, B4, B13 [381] Chemical warfare agents/nerve agents C1, C3 [382] -organophosphates -soman -sarin -ethyl S-2-di-isopropylaminoethyl- phosphonothiolate -VX -tabun Cyanide A3, A7 [383-385] -Potassium cyanide -Sodium cyanide Formaldehyde B1, C1 [386] Hydrogen Peroxide/H2O2 A2, A3, A6, A7 [387] Lipophilic chemicals C3, D1 [388] -persistent organic pollutants -bisphenol A -phthalates -low molecular weight hydrocarbons -polynuclear aromatic hydrocarbons -endocrine disruptors Sulfur dioxide/ SO2 A2, B8, C3 [389] Phthalates B1, B4, B14, C3 [390] Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

-Di-(2-ethylhexyl)-phthalate/DEHP -mono-2-ethylhexyl phthalate/MEHP -DEHP metabolites Brominated flame retardants A2, A3, A6, A7, B2 [391-392] -hexabromocyclo-dodecane/HBCD -tetrabromobisphenol-Al/TBBPA -decabromodiphenyl ether/DBDE -polybrominated diphenyl ethers/PBDEs Ammonia A1, B2, B8 [393-394] Hypochlorous acid/HOCl A2, A6, B13 [395-396] Methanol A3, B1, C1 [397] Peroxynitrite B1 [398] Sodium azide A3, B1, B2 [399] Acetaldehyde A3, A7 [400] 3-Bromopyruvate B13, C3 [401] Vehicular emission oxides C3, D1 [402] -nitrogen dioxide/NO2 -carbon monoxide/CO Sodium fluoride C1, C3 [403 Membrane-mimicking detergents B2 [404-405] -sodium dodecyl sulfate -lithium dodecyl sulfate Nitric oxide donors B1 [406-407] -sodium nitroprusside -DETA NONOate Amorphous aluminosilicates B2 [408] Sodium nitrite A3, A4, B1, B2, B9, [409] B11, C1 Tert-butyl hydroperoxide/t-BHP A3, A7 [410] Alloxan B1, B2 [411] Ammonium chloride A4, A6 [412] Anionic dyes B1 [413] -Congo Red -Thiazine Red -Thioflavin S Aroclor 1254 A3 [414] Cobalt chloride A2, A3, A6, A7, C1, [415] C3 Magnesium chloride B2 [416] 2,2'-azobis(2-methylpropionamidine) A7 [417] dihydrochloride/AAPH Methylglyoxal/Glyoxal A1, A2, A7, B12 [378, 418] Disuccinimidyl suberate B2 [419] Naphthazarin/5,8-dihydroxy-1,4- A7 [420] naphthoquinone/5,8-dihydroxy-1,4- naphthalenedione Pyrithiamine B1, B2, C1 [421] Pyrogallol A3, A7 [422] Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Glyceraldehyde-3-phosphate/GAPDH A3, A6, B2 [423] IV-A1d Other Ethylcholine mustard aziridinium ion/ AF64A B8, C1 [424] 1-methyl-4-phenylpyridinium ion A2, A3, A6, A7 [425] 2,2'-dithiodipyridine B14 [426] Aftin-4 A7, B2, B8, C3 [427] Kaolin B2 [428] Ozone A3, A7, C1, C3 [429] 2;3;7;8-tetrachlorodibenzo-p-dioxin A2, D1 [430-431] IV-A2 AGRICULTURAL CHEMICALS Pesticides/Insecticides/Herbicides/Fungicides A1, A2, A3, A5, A6, [391, 431- -Organochlorine Pesticides A7, B1, B2, B11, B14, 443] -Organophosphate Pesticides C1, C3, D1, -2,4,5-trichlorophenoxyacetic acid -2,4-Dichlorophenoxyacetic Acid -Agent Orange -Aldrin -Alkylphenolpolyethoxylates -APEOs -Arsenic -Beta-hexachlorocyclohexane/beta-HCH -Bipyridyles -Carbamates -Carbofuran -Chlorfenvinphos -Chlorpyrifos/CPF -Cycloheximide -Cypermethrin -Deltamethrin -Dichlorodiphenyldichloroethylene/DDE -Dichlorodiphenyltrichloroethane/DDT -Dichlorodiphenyldichloroethane/DDD -Dieldrin -Dimethyl parathion -Endosulfan -Famoxadone -Fenamidone -Glyphosate -Hexachlorobenzene -Hexachlorocyclohexane/HCH -Imidacloprid -Lindane -Maneb -Methamidophos -Methyl parathion -Neonicotinoids -Nonylphenol -Octylphenol Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

-Paraquat -Parathion -Pyraclostrobin -Pyrethroids -Trans-nonachlor -Trichlorfon/TCF -Trifloxystrobin IV-A3 MATERIALS IV-A3a Heavy Metals Heavy Metals A1, A2, A3, A4, A6, [391, 444- -aluminum A7, B1, B2, B14, D1 455] -arsenic -cadmium -calcium/Ca2/CaCl -calcium ionophore/A-23187/calcimycin -cobalt -copper -iron -lead -manganese -mercury -methylmercury -selenium -tin -zinc IV-A3b Particulates Air pollution A1, A4, A7, B1, B2, [456-458] -fine/ultrafine particles D1 -inhalable dust -surgical smoke IV-A3c Nanotechnology Nanoparticles A1, A2, A3, A4, A7, [459-462] -iron B2, B8, B12; B14 -titanium dioxide -CdSe quantum dots -diesel exhaust -alumina -manganese oxide -copper -silica/silicon dioxide -zinc oxide -silver -nickel IV-B Physical/Mechanical IV-B1 Electromagnetic Radiation IV-B1a Ionizing Gamma radiation A3, B1 [463-464] -dental X-ray Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

-gamma rays Particle radiation B2, B8, B9, B12, C3 [465-466] -56Fe-particle radiation -cosmic radiation -HZE particle radiation Radionuclide pollutants A7, C1, C3, D1 [467-468] -uranium -cesium -cobalt -radon IV-B1b Non-Ionizing IV-B1b1 Non-Visible Electromagnetic fields B1, B2, B8, B9, C1, 469-473] -extremely low frequency/ELF-EMF C3, D1 -900 MHz/RFEMR -electromagnetic pulse/EMP -electroconvulsive shock/ECS -UV irradiation IV-B1b2 Visible photolysis of 1-(2-nitrophenyl)ethyl sulfate B2 [474] IV-B2 SOUND Noise A1, A4, B2, B3, D1 [475-477] -chronic noise exposure -short-lasting impulse noise -ultrasound sonication IV-B3 TEMPERATURE; HEAT/COLD Heat stress A6, A7, B1, B2 [478-481] -heat shock -heating -hyperthermia Cold stress A3, B1, B2, C1, C3 [482] -cold water stress -cold water hypothermia IV-B4 Force/ Pressure/ Physical Trauma Traumatic brain injury A4, B2, B9, C1, C3, [483-486] D1 Head trauma A1, B1, B8, B9, C1, [487-490] -history of head trauma C3, D1 -closed head injury -axonal injury

Spinal cord injury A1, A4, C3 [491] Mechanical stress A1, A3, B1, B2, D1 [492-493] -Valsalva maneuver -repetitive heavy lifting -repetitive strong cough -accumulated mechanical stress IV-C OTHER Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Oxygen alterations A1, A3, A4, A7, B2, [494-495] -hyperoxia C3 -hypoxia V PSYCHOSOCIAL/SOCIOECONOMIC V-A PSYCHOLOGICAL Chronic stress A4, A6, A7, B1, B2, [496-503] -repeated stress B9, C1, C3, D1 -chronic mild stress -chronic psychological stress -multiple chronic stresses -behavioral stress -childhood trauma -bereavement -chronic restraint stress -high job stress -low level of job control

Low mental activity B5, C3, D1 [504-507] -low cognitively engaging activity -low purposeful activities -low leisure activities/low hobbies --low music/drawing/meditation/reading/arts/ crafts V-B SOCIOLOGICAL Social isolation A3, B1, B2, B8, C1, [508-513] -isolation C3, D1 -loneliness -living alone -unmarried -maternal separation -low social activity index -low social support at work -constricted life space

Low education D1 [514-516] -illiteracy V-C ECONOMIC Early life socioeconomic circumstances C3 [517]

2-7C1. Analysis of Results in Table 2-7C

(adapted from reference [1])

The findings in the Lifestyle, Iatrogenic, Biotoxic Agents, Occupational/ Environmental Exposures, and Psychosocial/Socioeconomic categories will now be examined by sub-category. The sub- category alphanumerical headings correspond to those in Table 2-7C. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

I. Lifestyle

Lifestyle includes choices mainly under individual control, and is divided arbitrarily into Diet, Activity, Substance Abuse, Other.

I-A. Diet

Poor diet reflects the adverse effects of excesses and deficiencies of dietary components. It has been used to induce myriad diseases in test animals, and it was a critical disease factor from many epidemiological and case studies.

I-A1. Dietary Excesses

Dietary excesses include: high-fat; diabetogenic diet; high-calorie; high-salt; high-carbohydrate; high advanced glycation end products (AGEs); high-cholesterol; high-iron; high-meat; high arachidonic acid; high methionine; high copper; high zinc; high pickle diet; high unfermented soy; and high- temperature cooking that results in harmful products (e.g., AGEs, nitrosamines, polycyclic aromatic hydrocarbons, and acrylamides).

As Table 2-7C shows, high-fat diet (from the specific types of fat listed in the table) had impacts at the cellular, biomarker, performance, and disease categories listed in Table 2-7B. These high-fat diets were 1) directly related to AD, 2) indirectly related to AD through their direct impact on other diseases directly related to AD (e.g., metabolic syndrome, diabetes), and 3) indirectly related to AD through their direct impact on the pre-disease surrogate endpoints directly related to AD. High-fats were also a key component of the diabetogenic diet listed in the table.

High-calorie and high-salt diets had both direct and indirect relationships to AD. High- carbohydrate diet, especially refined carbohydrates/sugars, also had full spectrum impacts. They also contributed to the diabetogenic diet.

High-AGEs, high-cholesterol, high-iron, and high-meat diets are intertwined, to a large extent. Meat tends to be high-cholesterol, high-iron, and, especially when cooked at high temperatures, associated with production of high AGEs. Most of the articles related to meat consumption and AD emphasized adverse effects. Unfortunately, in most of these meat studies, especially epidemiological studies on humans, there was no separation of confounding effects.

Most meat available to the American public comes from CAFO (confined animal feeding operations). These animals are raised confined in very close quarters. To reduce infections from such close confinement, animals are given antibiotics, and to increase growth more rapidly, animals are given synthetic growth hormones. Their feed is grain-based, not the grass they would have if pasture-raised. Would the dementia-related diseases associated with meat consumption in the articles be as copious and serious for pasture/grass-fed animals not raised under confined conditions, and not given antibiotics and synthetic growth hormones? Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

Most meat eaten is cooked, much of it at high temperatures, usually in the presence of endogenous and exogenous additional fats. High-temperature cooking, especially of animal foods that are high in protein and fat, results in substantial production of AGEs and other harmful substances (e.g., nitrosamines, polycyclic aromatic hydrocarbons, and acrylamides). How are the harmful effects of the cooking separated from the harmful effects of the meat? Separation was not evident in any papers examined. The bulk of the biomedical literature has not demonstrated that meat from 'organic' pasture- raised grass-fed animals not fed antibiotics and growth hormones and not cooked at high temperatures is equally harmful to CAFO meat consumed by the vast majority of the American public, and there is some evidence that a moderate amount of high-quality meat may be beneficial.

Finally, diets high in arachidonic acid, methionine, copper, zinc, pickles, and unfermented soy contribute directly or indirectly to the development of AD.

1A2. Dietary Deficiencies

Many deficiencies listed in the literature may be symptoms of metabolic problems, not foundational causes in the present sense. Thus, a Vitamin A deficiency may be caused by 1) insufficient Vitamin A intake (foundational cause), or 2) some metabolic problem that results in reduced Vitamin A levels (symptom). Dietary deficiencies include low: vitamins, especially Vitamins B (B2, B6, B12, folate/folic acid, thiamine), C, D, E; minerals, especially potassium, iron, zinc, magnesium, calcium, selenium; calories (starvation, malnutrition, early life nutrient restriction); water (dehydration); glucose; glutathione; linoleic acid; docosahexaenoic acid; tryptophan; alcohol (nondrinkers); flavonoids/flavanols (cocoa, coffee, acacetin, aminogenistein, apigenin, kaempferol, 7,8-Dihydroxyflavone, anthocyanins, atriplex laciniata L, curcumin, cyanidin, datiscetin, delphinidin, EGCG, epicatechin, Epimedium brevicornum, fisetin, genistein, ginkgo, glycitein, icariin, isoscutellarein 7-O-[6'''-O-acetyl-beta-D- allopyranosyl-(12)]-beta-D-glucopyranoside, isovitexin, morin, myricetin, nobiletin, pelargonidin, phloridzin, rutin, salvigenin, Scutellaria baicalensis Georgi, Sideritis flavonoids, vitexin, xanthomicrol, luteolin, morin, PD98059, quercetin, taxifolin, β-naphthoflavone); fruit (blackberries, blueberries, strawberries, raspberries, cherries, oranges, plums, prunes, red grapes, pomegranates, date palm fruits); vegetables, especially cruciferous, dark and green leafy; fatty fish.

A very clear message about the dietary contribution to AD can be extracted from the above picture of dietary excesses and deficiencies. From the macro perspective, the amounts of fat, salt, sugar, refined carbohydrates, calories, and meat need to be reduced strongly, along with high temperature cooking, and the amounts of vitamin and mineral-laden fruits, vegetables, and fatty fish need to be increased substantially to reduce the risk of AD and perhaps contribute to reversal of AD.

I-A3. Food Additives

Many food additives are accompanied by adverse effects, and these effects may be under- diagnosed and under-researched. Many of the excesses and deficiencies mentioned above are the result of substances being added to, or removed from, the fresh whole food.

Additives include preservatives, monosodium glutamate, menadione, cysteine, diacetylcysteine, and diacetyl. Depending on how one defines "food additives", those additives with the widest impacts Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

tend to include the major items listed under excesses above, such as fat, sugar, and salt. These components are typically added to foods for taste enhancement, not nutritional improvement. The effects of these additives appear to be at the cellular and biomarker levels.

I-B. Activity

The main sub-categories of Activity are exercise, sedentary lifestyle, and sleep.

I-B1. Sedentary Lifestyle/Lack of Exercise

The sedentary lifestyle, including low exercise, low physical activity, low daily gardening, low walking, and chronic immobilization, was mentioned quite often, and cognitive inactivity also received some mention. The resultant low cardiovascular fitness was also emphasized.

Sleep

Circadian disruption and poor sleep/sleep deprivation were also mentioned, although the main foundational components of poor sleep would be 1) choosing to sleep less or 2) not practicing good sleep- preparation habits. Other contributing factors to poor sleep, such as excessive pain, anxiety, etc, may be less under one's control, and are not regarded as foundational under the definition in the present monograph.

I-C. Substance Abuse

Substance abuse includes "recreational" drugs of all types (cocaine, methamphetamine, etc), other substances such as laxatives, common household products not usually identified as recreational drugs (such as mothballs), and especially excessive cigarette smoking and alcohol. The main substance abuse contributing factors to AD for the present study were 1) recreational drugs (especially cocaine, amphetamines/3,4-Methylenedioxyamphetamine (MDMA - Ecstacy), phencyclidine, opioids) and 2) excessive smoking and alcohol. The bulk of the studies showed the recreational drugs' contributions to AD surrogate endpoints, such as neurodegeneration markers and cognitive dysfunction.

Potential Synergies

The individual AD foundational causes identified with Lifestyle are usually studied in isolation, and synergistic effects are typically not identified. Given the number of Lifestyle component combinations that could potentially be synergistic, and adding in

1) the foundational causes from the remaining categories (identified in Table 2-7C) to the potential combinations, and

2) potential foundational causes that surface only when operating in synergy but which have not yet been identified in Table 2-7C as individual foundational causes, it is clear that only the tip of AD foundational causes iceberg is being identified in this study.

II. Iatrogenic

Iatrogenic reflects diseases, symptoms, and injuries resulting from medical treatment, and is divided into four sub-categories: Drugs; Radiotherapy; Surgeries/ Invasive Procedures; Diagnostic Agents/Procedures. Iatrogenic is a substantial category, due mainly to the large numbers of drugs and surgeries that have side-effects and complications. The main categories, along with detailed drugs and surgeries, are presented in Table 2-7C.

II-A. Drugs

While the drug categories have some overlap, each drug is listed in one category only in Table 2- 7C for purposes of brevity when generating the drug categories. The more frequently a drug is used, or the more frequently surgery or invasive treatments are employed, the more opportunity for side-effects and complications, and the more opportunity for publications describing these side-effects and complications. This study does not provide an indication of how often such side-effects and complications would occur as a percentage of use.

There were eighteen major drug categories identified in Table 2-7C, but only those with substantial entries will be discussed in this narrative. These include anti-neoplastic agents, cardiovascular agents, the massive category of central nervous system agents, hematologic agents, steroids/hormones, antihypertensive agents, and gastrointestinal agents.

What the table does not show is the effect of drug-drug combinations, or drug-other agent combinations. The effects of these combinations could be important, but might not surface in some types of studies. A study on drug-drug combinations concluded that, of approximately 11,000 drug products on the US market, trillions of clinical trials would be required to provide an evidentiary basis of safety for all combinations of ten drugs [518]. Even for all combinations of three drugs, the number of clinical trials required to evaluate safety, or lack thereof, would be astronomical.

Thus, there are many ways that 1) a drug that has been shown to contribute to AD in isolation, when combined with two other drugs that have not been shown to contribute to AD in isolation, could in aggregate have a much stronger contribution to AD, and/or 2) three drugs that have been shown to have a modest contribution to AD in isolation, when combined, could in aggregate have a much stronger contribution to AD, and/or 3) three drugs that have been shown to have negligible contribution to AD in isolation, when combined, could in aggregate have a strong contribution to AD. Even if there are small numbers for any one combination of three drugs, when they are aggregated over the total number of potential combinations, this could add up to a large number of strong contributions. This effect might not surface in any epidemiological study because 1) it would fall beneath the statistical radar screen, 2) temporal variation in the combinations would be difficult to assess, and 3) the numbers of clinical trials required to assess the impact of drug combinations are astronomical and would be impractical. For combinations of drugs larger than three, which increase for people as they age [518], the numbers of combinations and clinical trials to demonstrate safety increase rapidly.

This is a powerful class of drugs, and they tend to exert toxic/destructive effects on cancer cells. It is therefore unsurprising that these drugs would result in surrogate endpoint effects such as neurotoxicity/neurodegeneration/apoptoses on some healthy cells as well. The types of impacts in Table 2-7C bear this out. Neurotoxic-type effects are seen for many of the agents, as well as the accompanying memory degradation, but direct links to AD are not reported as frequently. The old dictum "absence of evidence is not evidence of absence" should be a warning flag on drawing hard conclusions about direct links.

II-A4. Cardiovascular Agents

The impacts of the four agents/agent classes (isoproterenol, atropine, D-ribose, muscarinic receptor antagonists) presented in Table 2-7C concentrate on the surrogate endpoints, with emphasis on the biomarkers (increase tau, Abeta) and performance (decrease memory, cognition).

II-A5. Central Nervous System Agents

This was by far the largest category of potential contributors to AD. This should not be surprising, since the members of this category act on the central nervous system (and some on the peripheral nervous system as well), and the brain is an integral part of the central nervous system. The impacts of the myriad contributing factors in this category differ somewhat by sub-category.

The analgesics and pain relievers (anesthetics/opiods) sub-category, consisting of acetaminophen, barbital, barbitone, desflurane, dexmedetomidine, diethylbarbituric acid, diethylmalonyl urea, enflurane, halothane, isoflurane, ketamine, medinal, morphine, nitrous oxide, pentobarbital, propofol, psychotropic drugs, sevoflurane, sodium diethylbarbiturate, veronal, affected all four impact areas. There was a substantial literature on the AD-related impacts of these sub-category members. One analytic problem deriving from this observation is that the relationship between the types of surgery to AD is conflated with the relationship between the anesthetic to AD, and it is difficult to separate the two, since anesthetics are used almost universally in surgery, especially major surgery.

The movement stabilizer sub-category, consisting of the anticholinergic medications doxepin, chlorpheniramine, oxybutynin, trihexyphenidyl, propiverine, L-DOPA/dopamine, was less numerous in terms of publications than the anesthetic sub-category, but covered the four impact classes as well.

The depressant/antidepressant sub-category, consisting of selective serotonin re-uptake inhibitors, benzodiazepine, dizocilpine, and 3-quinuclidinyl benzilate, had impact on performance and AD in the references shown. The absence of impact at the cellular and biomarker levels could mean that these classes of impacts were not the objectives of the research that was conducted, or they were reported in other papers not presented here.

The mood stabilizer sub-category, consisting of clozapine, methyllycaconitine, dihydro-beta- erythrodine, and anisomycin, impacted across the surrogate endpoints.

The main component of this category is the anti-coagulant sub-category, consisting mainly of the sulfated glycosaminoglycans heparin/heparan sulfate, dextran sulfate, pentosan polysulfate, chondroitin sulfate, dermatan sulfate, and fluindione.

II-A8. Steroids/Hormones

The substances in this category include corticosteroids (methylprednisolone, dexamethasone), anabolic androgenic steroids (nandrolone, stanozolol), corticosterone, Wortmannin, 17beta-trenbolone, salmon calcitonin, human chorionic gonadotropin, corticotrophin releasing factor, sex steroid hormones (transient testosterone treatment, flutamide), U18666A, allopregnanolone, medroxy-progesterone acetate, androgen deprivation therapy, postmenopausal hormone therapy, testosterone depletion, human chorionic gonadotropin, prenatal sex hormone exposure, and the deficiency of leptin. This class of pharmaceuticals (especially the corticosteroids) is used for a wide spectrum of medical conditions, and the broad scope of potential impacts is concerning. While some of the drugs in the larger Iatrogenic category have rather narrow applications, the long-term effects on neurodegenerative diseases of widely used drugs such as anesthetics and steroids should be cause for serious concern.

II-A9. Antihypertensive Agents

These agents include ACE inhibitors, ICI 118,551/Selective beta2AR antagonists, telmisartan/olmesartan, and Mecamylamine. Some of the anti-hypertensive agents listed are widely used because of the prevalence of hypertension, and their long-term effects need to be examined more closely. The main impacts listed are those on the surrogate endpoints, although the ACE inhibitors are linked to AD. The referenced papers don't report impacts at the cellular level, although, again, that does not imply the absence of such impacts.

II-A10. Gastrointestinal Agents

These agents include thiorphan/phosphoramidon, and the large class of proton pump inhibitors (omeprazole, pantoprazole, lansoprazole, esomeprazole, and rabeprazole). Again, this is disturbing for the long-term, because of the almost common-place used of this family of drugs for digestive problems.

II-B. Radiotherapy

Radiotherapy that involves the head region impacts cognition and AD.

II-C. Surgery/Invasive Treatments

The following categorization is not unique. Some procedures could be assigned to multiple categories. Surgeries/invasive procedures that contribute to AD tend to involve vessel occlusion, cerebral ischemia, broader cardiac surgery, estrogen depletion, and myriad forms of dialysis.

One interesting observation is that the surgery impacts are all on AD surrogate endpoints, not on AD directly, for the references selected. This may be due to personal choice of the authors. Some authors identified a number of surrogate endpoints that were impacted, and referred to the aggregate as Alzheimer's-like. Other authors would refer to the aggregate as Alzheimer's Disease. Since inhalation anesthesia seems to be a strong contributing factor, almost any major surgery employing this type of Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

anesthesia would have to involve some potential risk for AD, either through the surrogate endpoints, or directly.

III. Biotoxic Agents

Biotoxic Agents reflect mainly the biological substances to which we are exposed naturally, but sometimes accidentally, and sometimes by design. This category is divided into five sub-categories: Mycotoxins; Exotoxins; Bacteria/ Fungi/ Parasites; Viruses; Other. Biotoxins contributing to AD include some mycotoxins, but mainly exotoxins, bacteria, and viruses.

III-A. Mycotoxins

Only a few mycotoxins were identified, including ochratoxin A, fumonisin B1, and macrocyclic trichothecenes. Their impacts cover all four levels.

III-B. Exotoxins

Many exotoxins were identified, including excitotoxins (kainic acid/kainate, quisqualic acid, ibotenic acid, domoic acid, quinolinic acid/quinolinate), phosphatase inhibitors (okadaic acid), excitatory amino acids, malonate, annonaceaeous acetogenins, cyanobacteria (beta-N-methylamino-L- alanine/BMAA, saxitoxin, anatoxin-a, blue-green algae, microcystin), diphtheria toxin, pseudomonas aeruginosa exotoxin Y, saporins (192 IgG-saporin, p75-saporin), cycad plant (cycasin/methylazoxymethanol), glutamate/glutamine synthetase, mitochondrial inhibitors (rotenone, 3- NPA, antimycin, KCN, oligomycin). Some substances in the Other category could have been assigned to the Exotoxin category. The impacts were heavily weighted toward the cellular and biomarker levels, less so toward the performance level, and even less toward the disease level.

III-C. Bacteria/Fungi/Parasites

Myriad bacteria, fungi, and parasites (shown in Table 8-3) are dominant in sub-category III-C. The bacteria/bacterial infections include bacterial endotoxins, bacterial lipopolysaccharide, gram-negative bacterium, spirochetes, Chlamydophyla pneumoniae, Helicobacter pylori, Escherichia coli, Treponema pallidum, Tannerella forsythia, Treponema denticola, T. socranskii, T. pectinovorum, T. medium, T. amylovorum, T. maltophilum, Fusobacterium nucleatum, Prevotella intermedia, Chlamydia pneumoniae, Porphyromonas gingivalis, propionibacterium acnes, Treponemas, T. lecithinolyticum, and Borrelia burgdorferi. Bacteria are somewhat ubiquitous, so the flexibility of cause removal for items in this sub- category is much less than for items in the Lifestyle and Iatrogenic categories.

The fungi/fungal infections include Cryptococcus, Coccidioides, Aspergillus, Histoplasma, Blastomyces, C. famata, C. parapsilosis, C. glabrata, C. krusei, Candida albicans, Candida ortholopsis, Candida tropicalis, Cladosporium, Malassezia globosa, Malassezia restricta, Neosartorya hiratsukae, Phoma, Sacharomyces cerevisae, and Sclerotinia borealis. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

The parasites include Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, Acanthamoeba, Balamuthia mandrillaris, Toxoplasma gondii, Taenia solium, Toxocara canis, T. cati, Toxocara ova, and Leishmania amazonensis.

III-D. Viruses

Myriad viruses (shown in Table 2-7C) are dominant in sub-category III-D. These viruses include Bornaviridae (Mammalian 1 bornavirus), Bunyaviridae (Hantavirus, La Crosse encephalitis virus), Coronaviridae (Human coronavirus OC43, Murine hepatitis virus), Flaviviridae (Hepatitis C virus, Japanese encephalitis virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, West Nile virus), Hepadnaviridae (Hepatitis B virus), Herpesviridae (Cytomegalovirus, Epstein-Barr virus, Herpes simplex virus 1, Human herpesvirus 6), Orthomyxoviridae (Influenza A virus (H1N1), Influenza A virus (H3N2), Influenza A virus (H5N1)), Paramyxoviridae (Hendra virus, Measles virus), Picornaviridae (Enterovirus 71, Theiler's murine encephalomyelitis virus), Polyomaviridae (Simian 40 virus large T antigen), Retroviridae (Human immunodeficiency virus 1, Human T-cell leukemia virus, Moloney murine leukemia virus), Rhabdoviridae (Chandipura virus), Togaviridae (Chikungunya virus, Eastern equine encephalitis virus, Venezuelan equine encephalitis virus).

Based on the volume of records examined in the bacteria/fungi/viruses categories, linkages to tau and Abeta pathologies were mentioned often, as were direct linkages to AD. Neuroinflammation induced by bacterial and viral infections appeared to be responsible for some of the tau pathology.

III-E. Other

The category named Other contains myriad substances, which are listed in Table 2-7C. It includes some plant-based contributing factors (e.g., 12-myristate 13-acetate, Forskolin, arecoline hydrobromide, quisqualate, etc), and a very substantial number of endogenous substances that were administered exogenously (e.g., 27-hydroxycholesterol, acetylcholinesterase, Bradykinin, CD40, etc).

Ordinarily, endogenous substances are not foundational causes, but intermediate causes, since their harmful effects typically are driven by other foundational causes. However, for consistency, if an endogenous substance was administered exogenously for purposes of experimentation or trial, it was considered as an exotoxin or other foundational cause for the purposes of this monograph. Thus, amyloid beta, an endogenous substance, could be viewed as an endotoxin when internal processes are being discussed, but also as an exotoxin when administered in laboratory experiments.

Because of the heterogeneity of the myriad substances in this class, specific impact statements need to be tailored to the specific members of this class. However, from an overall perspective, the majority of impacts are at the cellular and biomarker levels, much fewer impacts at the performance level, and very few impacts at the disease level. It should be cautioned again that the absence of impacts reported should not be interpreted as their non-existence. They may not exist, they may exist and were not an objective of the research, or they may exist and were not reported.

IV-A. Chemicals/Materials

IV-A1. Industrial and Household Chemicals/Materials

This sub-category is very broad. There is overlap among the next level taxonomy elements; for example, some of the solvents are hydrocarbons and some of the chemical compounds are hydrocarbons.

This sub-category includes hydrocarbons, solvents, chemical compounds, and Other.

The hydrocarbons sub-category includes, e.g., methylcholanthrene, polycyclic aromatic hydrocarbons, diesel fuel, kerosene, etc.

The solvents sub-category includes, e.g., petroleum-based solvents (mineral turpentine, diesel fuel, fuel oil, kerosene, etc), chlorinated solvents (trichloroethylene, perchlorethylene, trichloroethane, dichloromethane, benzene), organic solvents (benzene, toluene, phenols, alcohols, ketones, methylmethacrylate), dimethyl sulfoxide/ DMSO, etc. The impacts from the members of this sub- category, as reported in the references selected, tended to focus on performance and disease. This was due to a number of epidemiology studies of occupational impacts, which tend to focus on higher level impacts.

The chemical compounds/Other sub-categories include a full spectrum of chemical compounds, especially chlorine, bromine, nitrogen, sodium, sulfur, and carbon compounds. Members of these sub- categories include, e.g., Neurotoxins (6-hydroxydopamine/6-OHDA, 5,6-dihydroxytryptamine/ 5,6-DHT, -5,7-dihydroxytryptamine/5,7-DHT, Type-2 Alkenes/Reactive aldehydes (Acrolein, 4- Hydroxynonenal/HNE, Acrylamide, Methyl glyoxal), Nitrosamine/ N-nitrosodiethylamine, Adenosine, 3', 5'-cyclic monophosphate/cAMP, Carbon tetrachloride, Chemical warfare agents/ nerve agents (organophosphates, soman, sarin, ethyl S-2-di-isopropylaminoethyl-phosphonothiolate, VX, tabun), Cyanide (Potassium cyanide, Sodium cyanide), Formaldehyde, Hydrogen Peroxide/H2O2, Lipophilic chemicals (persistent organic pollutants, bisphenol A, phthalates, low molecular weight hydrocarbons, polynuclear aromatic hydrocarbons, endocrine disruptors), Sulfur dioxide/SO2, Phthalates (Di-(2- ethylhexyl)-phthalate/DEHP, mono-2-ethylhexyl phthalate/MEHP, DEHP metabolites), Brominated flame retardants (hexabromocyclo-dodecane/HBCD, tetrabromobisphenol-Al/TBBPA, decabromodiphenyl ether/DBDE, polybrominated diphenyl ethers/PBDEs), Ammonia, Hypochlorous acid/HOCl, Methanol, Peroxynitrite, Sodium azide, Acetaldehyde, 3-Bromopyruvate, Vehicular emission oxides (nitrogen dioxide/NO2, carbon monoxide/CO), Sodium fluoride, Membrane-mimicking detergents (sodium dodecyl sulfate, lithium dodecyl sulfate), Nitric oxide donors (sodium nitroprusside, DETA NONOate), Amorphous aluminosilicates, Sodium nitrite, Tert-butyl hydroperoxide/t-BHP, Alloxan, Ammonium chloride, Anionic dyes (Congo Red, Thiazine Red, Thioflavin S), Aroclor 1254, Cobalt chloride, Magnesium chloride, 2,2'-azobis(2-methylpropionamidine) dihydrochloride/AAPH, Methylglyoxal/ Glyoxal, Disuccinimidyl suberate, Naphthazarin/5,8-dihydroxy-1,4-naphthoquinone/ 5,8- dihydroxy-1,4-naphthalenedione, Pyrithiamine, Pyrogallol, Glyceraldehyde-3-phosphate/GAPDH, Ethylcholine mustard aziridinium ion/AF64A, 1-methyl-4-phenylpyridinium ion, 2,2'-dithiodipyridine, Aftin-4, Kaolin, Ozone, 2;3;7;8-tetrachlorodibenzo-p-dioxin. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

The largest sub-category, by far, is the chemical compounds. This sub-category is associated with roughly even impacts at the cellular, biomarker, and performance levels. There is much less reported direct association at the disease level, for the selected references.

IV-A2. Agricultural Chemicals

This sub-category emphasizes pesticides, herbicides, insecticides, and fungicides, and includes, e.g., Organochlorine pesticides, Organophosphate pesticides, 2,4,5-trichlorophenoxyacetic acid, 2,4- dichlorophenoxyacetic acid, Agent Orange, Aldrin, Alkylphenolpolyethoxylates, APEOs, Arsenic, Beta- hexachlorocyclohexane/beta-HCH, Bipyridyles, Carbamates, Carbofuran, Chlorfenvinphos, Chlorpyrifos/ CPF, Cycloheximide, Cypermethrin, Deltamethrin, Dichlorodiphenyldichloroethylene/DDE, Dichlorodiphenyltrichloroethane/DDT, Dichlorodiphenyldichloroethane/DDD, Dieldrin, Dimethyl parathion, Endosulfan, Famoxadone, Fenamidone, Glyphosate, Hexachlorobenzene, Hexachlorocyclohexane/HCH, Imidacloprid, Lindane, Maneb, Methamidophos, Methyl parathion, Neonicotinoids, Nonylphenol, Octylphenol, Paraquat, Parathion, Pyraclostrobin, Pyrethroids, Trans- nonachlor, Trichlorfon/TCF, Trifloxystrobin, etc.

Adverse impacts span the cellular, biomarker, performance, and disease levels. These chemicals impact the larger population through the food supply, and have devastating effects on the agricultural workforce. Given the ubiquitous nature of agricultural chemicals and industrial/household chemicals in daily life, eliminating them will be challenging.

IV-A3. Materials

The materials/particulates that constitute this category are broadly-based, and in many cases have become part of the average lifestyle. Some examples include:

-heavy metals (e.g., aluminum, arsenic, cadmium, calcium/Ca2/CaCl, calcium ionophore/A- 23187/calcimycin , cobalt, copper, iron, lead, manganese, mercury , methylmercury, selenium, tin, zinc, etc)

-particulates (e.g., air pollution, surgical smoke, dust, etc)

-nanoparticles (e.g., iron nanoparticles, titanium dioxide nanoparticles, CdSe quantum dots, diesel exhaust nanoparticles, alumina nanoparticles, manganese oxide nanoparticles, copper nanoparticles, silicon dioxide nanoparticles, zinc oxide nanoparticles, silver nanoparticles, nickel nanoparticles, etc)

Impacts of these materials through diverse ingestion pathways cover the full spectrum of levels. Both metals and small sized particles have adverse effects. When the two are combined, the synergy becomes problematical. Metallic particles within the nanoparticle range (<100 nm) are able to cross many internal protective barriers, including the blood-brain-barrier (BBB), and cause myriad problems. While penetration of the BBB by nanoparticles is sometimes used for drug delivery, unwanted penetration (as reflected in the present study's references) can be quite harmful.

This sub-category includes ionizing radiation, non-ionizing non-visible radiation, non-ionizing visible radiation, sound radiation, temperature fields, and force fields.

The ionizing radiation component includes, e.g., gamma radiation (dental X-rays, gamma rays, etc), particle radiation (56Fe-particle radiation, cosmic radiation, HZE particle radiation), radionuclide pollutants (uranium, cesium, cobalt, radon). The main impacts focus on the biomarker and performance levels, with some at the cellular levels and much less at the disease level.

The non-ionizing non-visible radiation component includes, e.g., electromagnetic fields at myriad frequencies, such as extremely low frequency/ELF-EMF, 900 MHz radiofrequency (RF), electromagnetic pulse/EMP, electroconvulsive shock/ECS, UV irradiation, etc. The references selected emphasize biomarker level impact, then performance level impacts, and some links to AD.

The non-ionizing visible radiation component includes e.g., UV irradiation, photolysis of 1-(2- nitrophenyl)ethyl sulfate, with impacts emphasizing Abeta production.

The sound radiation component includes, e.g., short-lasting impulse noise, chronic noise exposure, night-time aircraft noise, ultrasound sonication, etc. While impacts are identified at the cellular, biomarker, and disease levels, Abeta generation and exacerbation are emphasized.

The thermal component includes, e.g., cold water hypothermia, cold water stress, heat shock, heat stress, heating, hyperthermia, etc, and impacts the cellular, biomarker, and performance levels.

The physical force component includes, e.g., blasts, blast traumatic brain injury, hippocampal injury, accumulated mechanical stress, spinal cord injury, frequent strong Valsalva maneuvers, long hours of repetitive heavy lifting, sequences of blows during the playing of a wind instrument, forceful and repetitive cough, bearing-down efforts during parturition, history of head trauma, etc. The impacts cover all four levels, with perhaps added emphasis on AD.

The main components of this sub-category, the different types of physical fields with which we interact (electromagnetic, sound, temperature, pressure, force) are ubiquitous. Avoiding exposure to these emissions/interactions would require a major change in lifestyle (and probably location) for most people. The 'Other' category is small, and contains adverse effects from over- and under-exposure to oxygen.

V. Psychosocial/Socioeconomic

Psychosocial/Socioeconomic are those foundational causes that reflect personal problems, social interactions, larger societal interactions, and economic relationships. Psychological and sociological stress were major causative factors; economic types of stress seemed to play less of a direct role.

V-A. Psychological

This sub-category includes, e.g., chronic stress (repeated stress, chronic mild stress, chronic psychological stress, multiple chronic stresses, behavioral stress, childhood trauma, bereavement, chronic restraint stress, high job stress), low mental activity (low cognitively engaging activity, low purposeful Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

activities, low leisure activities/low hobbies, low music/drawing/meditation/reading/arts/crafts), etc. Impacts seemed to spread out over all four levels.

V-B. Sociological

This sub-category includes, e.g., social isolation (isolation, loneliness, living alone, unmarried, maternal separation, low social activity index, low social support at work, constricted life space), low education (illiteracy), etc. Impacts cover all four levels, with emphasis on the biomarker, performance, and disease levels.

V-C. Economic

This sub-category includes, e.g., economic stress (childhood socioeconomic circumstance), etc. In this small sub-category, impact focused on cognitive deficits.

Table 2-8

AD Causes

(Reduced)

# RECORDS AD CAUSE 1057 HEAVY METALS 1054 HEAD TRAUMA 547 SMOKING 531 H2O2 446 EXCESS ALCOHOL 401 EXCITOTOXINS 397 HIGH AGEs DIET 360 VIRUSES 314 REACTIVE ALDEHYDES 249 CHRONIC STRESS 205 ANESTHETICS 184 VIT B DEFICIEN 153 CHEMOTHERAPY 135 OVARIECTOMY 129 PESTICIDES 124 MPTP 117 HIGH FAT DIET 111 SEDENTARY 78 OHDA/DHT 76 RECREAT DRUGS 72 HIGH CHOLESTEROL DIET 58 THAPSIGARGIN 55 IONIZING RADIATION 43 VIT D DEFICIEN 41 AIR POLLUTION 41 BYPASS SURGERY 41 NON-IONIZING RADIATION 40 CYANOBACTERIA 40 NERVE AGENTS 40 ROTENONE 37 FORMALDEHYDE 31 ORG SOLVENTS 29 IRON DEFICIEN 26 BULBECTOMY 24 ZINC DEFICIEN 22 HIGH CALORIE DIET 22 HIGH REFIN CARBO DIET 20 CYANIDE 15 NANOPARTICLES 14 HIGH MEAT DIET Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

14 VIT E DEFICIEN 10 CHLORIN SOLVENTS/PCBs 10 LIPOPHILIC CHEMICALS 6 MAGNESIUM DEFICIEN 5 DIOXIN 5 MSG 4 BROMIN FLAME RETARD 4 HIGH SALT DIET 4 MYCOTOXINS 3 VIT C DEFICIEN

Table 3-1

AD Characteristics

(reduced)

ACETYLCHOLINE ADAM10 AGEs Akt ALPHA-SECRETASE ALUMINUM AMMONIA APOPTOSIS ARSENIC ATP B12 B6 BACE-1 Bax Bcl-2 BDNF CADMIUM CALCIUM HOMEOSTASIS c-AMP CASPASE CEREB BLOOD FLOW CHOLESTEROL CHOLINESTERASE CHROMIUM c-myc COPPER CREB CRP DENDRITIC SPINE DHA DNA METHYLATION ESTROGEN FOLATE GLP-1 GLUCOSE METABOLISM GLUTAMATE GLUTAMINYL CYCLASE GLUTATHIONE GPX GSK-3 HDAC/HISTONE DEACETYLASE HDL HEAVY METAL Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

HISTONE ACETYL HMGCoAr HOMOCYSTEINE HYPERPHOSPHORYLATION IDE IL-1 IL-6 IRON LDL LEAD MALONDIALDEHYDE/MDA MAO MELATONIN MERCURY MRI NEPRILYSIN/NEP NF-KappaB NMDA Nrf2 PET SCAN PRION PROTEINS REACTIVE OXYGEN SPECIES SEROTONIN TAU AGGREGATES/TAU AGGREGATION ANDROGENS TNF-alpha VITAMIN E ZINC

Table 3-2

AD Hypotheses/Factor Matrix Categories

AMINOPEPTIDASE AMMONIA AMYLOID BRAIN ATROPHY CALCIUM/DELETERIOUS NETWORK CELL CYCLE CHOLINERGIC DYSLIPIDEMIA EPIGENETIC EXCITOTOXICITY HORMONE DYSREGULATION INFLAMMATION INSULIN SIGNALING METABOLIC METAL MITOCHONDRIAL NEUROGENESIS NEUROTRANSMITTER DYSFUNCTION OXIDATIVE STRESS PROTEIN CANCER TAU VASCULAR

Figure 2-3

AD Treatment Taxonomy - CLUTO Clustering

(number of records in parenthesis - Second Level)

TOP FIRST LEVEL SECOND LEVEL (#RECORDS) LEVEL

PREVENT OR REVERSE (1068) - GAMMA-SECRETASE INHIBITORS; BACE-1 ABETA AND TAU BUILDUP INHIBITORS; APP PROCESSING REGULATORS; REDUCE PRODUCTION OF ABETA (3672) - IMMUNOTHERAPY: PREVENTION OR REVERSAL OF PATHOLOGICAL ABETA/TAU BUILDUP ACETYLCHOLINESTERASE (1367) - ACETYLCHOLINESTERASE INHIBITION; OXIDATIVE INHIBITOR/ABETA STRESS AND (4504) - OXIDATIVE

LABORATORY AND AND LABORATORY NEUROINFLAMMATION STRESS/NEUROINFLAMMATION CLINICAL RESEARCH CLINICAL REDUCTION TREATMENTS/RATS PATIENT DEMENTIA (4395) - PATIENTS; FDA-APPROVED DRUG PREVENTION AND TREATMENTS TREATMENT (1967) - REDUCE DEMENTIA RISK: VITAMINS; EXERCISE; STATINS; HORMONES; DIET PATIENT CARETAKING (2059) - AD CARETAKING THERAPIES: DRUG AND NON-DRUG PSYCHOTROPIC DRUGS; NOOTROPIC DRUGS; THERAPIES COGNITIVE STIMULATION; SENSORY STIMULATION; MUSIC; MASSAGE; SOCIAL INTERACTION; GROUP THERAPY (2212) - PATIENT SYMPTOM ALLEVIATION THERAPIES: ANTI-PSYCHOTICS; ANTI-

PATIENT MANAGEMENT PATIENT DEPRESSANTS; ANTI-DELIRIUM; ANTI-INSOMNIA; ANTI-AGGRESSION; ANTI-ANXIETY

7B. Use of Concordance software for identifying existing AD characteristics and treatments

Concordance software allows linking terms to be viewed in their larger context surrounded by treatments and characteristics, or causes and characteristics. If the software has sufficient flexibility, the window in which the linking term appears can be adjusted in size to accomodate whatever analysis is desired.

The present study did not use Concordance software. It used a fixed window of four words to identify AD treatments and AD characteristics with the text linking term approach. To illustrate how disease treatments and characteristics could be identified more efficiently with the use of Concordance software, some sample runs were made using Laurence Anthony's free Concordance software [4].

In the following examples, four linking terms were used for illustrative purposes: ameliorated, attenuated, restored, increased. The treatments database was imported into the Concordance software, each of the four terms was entered in the search window, and hundreds of lines of text centered around the linking terms were retrieved. The first few lines of text retrieved for each linking term are shown below.

Each paragraph below reflects the text contained in the window surrounding the linking term. The leftmost word, bolded and CAPITALIZED, is the linking term. It is also bolded in the center of the text. A few of the paragraphs for each linking term had the treatment words and characteristics words colored, for illustrative purposes. For those few paragraphs, the words in green are the AD treatments, and the words in red are some of the characteristics impacted by the treatment. The AD characteristic related to other linking terms in the text were not highlighted, although they would certainly be selected when identifying AD characteristics.

As the results show, some linking terms are more efficient at identifying AD treatments and AD characteristics than others. The linking term 'increase' was particularly inefficient. However, we found 'increase' or 'decrease' to be useful when a treatment was known, and it was desired to identify all the AD characteristics impacted by that treatment.

Also, as the results show, some AD treatments and characteristics are in close proximity to the linking term, while others are beyond the range of this relatively sizeable window. This has implications on selecting proximity parameters when the linking terms are used as a search query for record retrieval from Pubmed or Thompson Medline.

Some of the paragraphs may appear almost redundant to those following or preceding them. This reflects how the Concordance algorithm selects windows of text. The algorithm examines the text file that is input (mainly title and abstract), and selects each instance where the linking term appears. Thus, if the title and abstract both contain the linking term, and the title is similar to the abstract conclusion that contains the linking term, then two (or more) adjacent windows of text will appear very similar.

7C1. Linking term AMELIORATED

AMELIORATED beta (Abeta) aggregates and attenuate Abeta cytotoxicity in vitro. Additionally, CNI-1493 and C1213 ameliorated Abeta-induced behavioral deficits in nematodes. Finally, C1213 reduced Abeta plaque burden and

AMELIORATED dose-dependently increased the cell viability. In Abeta1-42-treated mice, DL0410 administration significantly ameliorated learning and memory deficits in MWM test and passive avoidance test. Furthermore, DL0410

AMELIORATED 347-8648 (Electronic) IS - 1347-8613 (Linking) VI - 132 IP - 1 DP - 2016 Sep TI - Dipotassium N-stearoyltyrosinate ameliorated pathological injuries in triple-transgenic mouse model of Alzheimer's disease. PG - 92-99 LID -

AMELIORATED ttest. Following 30 days of consecutive treatment, memory in the AD mouse model was ameliorated in the 10 mg/kg ginsenoside Rg1 treatment group. As demonstrated by biochemical experiments,

AMELIORATED from fission toward fusion. After 6 weeks, AP39 administration to APP/PS1 mice significantly ameliorated their spatial memory deficits in the Morris water maze and NORT and reduced

AMELIORATED the degradation of amyloid precursor protein (APP). Further, oral administration of Onjisaponin B ameliorated Abeta pathology and behavioral defects in APP/PS1 mice. Taken together, our results

AMELIORATED in C57BL/6 mice, and Exendin-4 given by nasal cavity or hippocampal administration ameliorated Abeta31-35-induced circadian rhythm disturbance of locomotor activity and impairment of learning and

AMELIORATED : The impaired cognitive function and increased hippocampal Abeta deposition in AD mice were ameliorated by G-Rg1 and G-Rg2. In addition, a total of 11 potential biomarkers

AMELIORATED ed Abeta1-42 in an LDLR-dependent manner, reduced Abeta deposition, attenuated neuroinflammatory responses, ameliorated neurologic changes and reversed behavioral deficits in AD model mice. These findings justified

AMELIORATED Tg2576 mice for 4 months significantly reduced both soluble and insoluble Abeta42 levels and ameliorated cognitive impairments, even after drug withdrawal for 10 days following oral administration for 2 mont

AMELIORATED DL0410 on mice behaviours. All the behavioural experimental results showed that DL0410 significantly ameliorated memory deficits. Meanwhile, DL0410 attenuated neural cell damage and reduced senile plaques sign

AMELIORATED in glutamate release in the tau-P301L model, both of which are ameliorated with riluzole treatment. The authors' findings have implications for our understanding of synapt Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

AMELIORATED -induced cell toxicity better than GM1-rHDL in vitro and reduced Abeta deposition, ameliorated neurologic changes, and rescued memory loss more efficiently than both alphaNAP solution and

AMELIORATED , pretreatment of PC12 cell with noopept significantly attenuated tau hyperphosphorylation at Ser396 and ameliorated the alterations of neurite outgrowth evoked by capital A, Cyrillicbeta25-35. CONCLUSIONS: Taken

AMELIORATED of 6-shogaol significantly reduced microgliosis and astrogliosis in intrahippocampal AbetaO-injected mice, ameliorated AbetaO and scopolamine-induced memory impairment, and elevated NGF levels and pre- and

AMELIORATED antioxidant levels, energy metabolism, neurotransmitter levels, and neuronal apoptosis. RESULTS: Bajijiasu ameliorated Abeta-induced learning and memory dysfunction, enhanced antioxidative activity and energy metabolism,

AMELIORATED recruitment, retention, and implementation. (2) Clinical impact: previously undocumented problems identified and ameliorated, as recorded in participants' records before and after introduction of the profile, and

AMELIORATED problems for all participants (mean 12.7 (SD 4.7)). One month later, some problems had been ameliorated (mean 4.9 (3.6)). Clinical gains included new prescriptions to manage pain (2 participants), psoriasi

AMELIORATED . Amyloid plaque load and synaptic loss as well as cognitive impairment had been ameliorated in AD models, and dopaminergic loss of transmission and motor function was reversed

AMELIORATED 0170220 IS - 1472-6882 (Electronic) IS - 1472-6882 (Linking) VI - 14 DP - 2014 Jan 14 TI - Compound danshen tablet ameliorated abeta25-35-induced spatial memory impairment in mice via rescuing imbalance between cytokines and

AMELIORATED -related toxicity was observed after 28-day treatment at 100 mg/kg. Further, AS2715348 significantly ameliorated cognitive deficits in APP-transgenic Tg2576 mice. Finally, AS2715348 significantly reduced brain Abeta

AMELIORATED on brain iron regulation. HupA treatment reduced insoluble and soluble beta amyloid levels, ameliorated amyloid plaques formation, and hyperphosphorylated tau in the cortex and hippocampus of APPswe/

AMELIORATED addition, oAbeta42 treatment significantly facilitated long-term depression (LTD). Treatment with T-817MA ameliorated the LTP reduction; however, T-817MA treatment did not inhibit the facilitation of

AMELIORATED mean follow-up period was 691 days. RESULTS: Decrease in MMSE score was significantly ameliorated by administration of cilostazol. Subgroup analysis revealed that cilostazol significantly improved MMS Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

AMELIORATED -3beta, a major tau kinase, in type 2 diabetic rats. Liraglutide treatment not only ameliorated hyperglycemia and peripheral insulin resistance, but also reversed these brain abnormalities in a

AMELIORATED of arctigenin in mice highly decreased Abeta formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD

AMELIORATED associated with normal aging and AD in mouse models. Pretraining administration of levetiracetam ameliorated memory impairments of aged C57BL/6 mice (17-20months of age) in the contextual

AMELIORATED assessed in a mouse mTBI model. In neuronal cultures in this study, Ex-4 ameliorated H2O2-induced oxidative stress and glutamate toxicity. To evaluate in vivo translation,

AMELIORATED or mTBI (30 g weight drop under anesthesia). Ex-4 proved well-tolerated and fully ameliorated mTBI-induced deficits in novel object recognition 7 and 30 days post-trauma. Less mTBI-

AMELIORATED 80 decreased the deposition of insoluble amyloid-beta(42). In senescence- accelerated mice (SAMP8), Am80 ameliorated the decrease of cortical acetylcholine, as well as reducing anxiety in behavioral tests

AMELIORATED outgrowth in DRG neurones. Treatment studies confirmed that APP induced- damage can be ameliorated by beta- and gamma-secretase inhibitors (providing protection to 60-100% of control levels), cli

AMELIORATED a spatial memory deficit, apoptosis, and caspase-9 activation in hippocampal neurons. Puerarin treatment ameliorated Abeta(1-42)-induced cognitive impairment and reversed the increase of apoptosis in the hippocampus.

AMELIORATED of mice caused by muscarinic receptor antagonists and intracranially injected toxic Abetas was ameliorated by Humanin therapy. Multiple studies have indicated the existence of a putative specific

AMELIORATED may be due to changes in the dopaminergic system as they could be ameliorated by levodopa treatment, that might also have a therapeutic significance for AD. FAU -

AMELIORATED therapy, it exhibits the expected adverse effects of dopamine excess, which can be ameliorated by reducing the L-dopa dosage. CYP1A2 inhibitors slow the elimination of

AMELIORATED istry and real time polymerase chain reaction (PCR). Intragastric administration of berberine significantly ameliorated the spatial memory impairment and increased the expression of IL- 1beta, iNOS in

AMELIORATED when fasted overnight. We further showed that both of these defects can be ameliorated by rosiglitazone administration. Here, we report that during behavioral testing which involves r Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

AMELIORATED in OB animals in the Open-field test, however, these changes were not ameliorated by either drug treatment. The ability for tacrine but not physostigmine to attenuate

AMELIORATED effective in reducing both brain A beta 40 and A beta 42. In addition, bryostatin ameliorated the rate of premature death and improved behavioral outcomes. Collectively, these data corrobor

AMELIORATED of conditioned responses (CRs) in young adult rabbits, and the nicotinic agonist, GTS-21 ameliorated conditioning deficits in older rabbits. Galantamine induces allosteric modulation of nicotinic choline

AMELIORATED studies indicated that rivastigmine has central nervous system selectivity over peripheral inhibition. It ameliorated memory impairment in rats with forebrain lesions. The drug is rapidly absorbed orally,

AMELIORATED and a water supply. The post-NMS relapse of his abnormal behavior was ameliorated by a kind of herbal medicine "Ohren-Gedoku-Toh". We attempted to grasp

AMELIORATED of intranasal treatment with telmisartan (a brain penetrating ARB) reduced brain inflammation and ameliorated amyloid burden (a component of Alzheimer's plaques) in AD transgenic mouse model.

AMELIORATED calcium levels (Ca(++)). Treatment with vanillin in different doses and donepezil have significantly ameliorated i.c.v. STZ and AlCl3+d-galactose induced reduction in executive function,

AMELIORATED -1 (Nrf2 in mammals) were required for the extract-mediated delayed paralysis. The extract ameliorated oxidative stress by reducing the level of H2O2, which appeared to account

AMELIORATED significant decrease in the rate of progression to dementia. Significantly, use of CCBs ameliorated the negative effects of the presence of APOE-4 alleles on cognitive decline. To

AMELIORATED chotosan (CTS), a Kampo formula consisting of Uncaria and other 10 different crude drugs, ameliorated cognitive deficits in several animal models of dementia including type 2 diabetic db/db

AMELIORATED not hexachlorophene, stabilized diffuse amyloid plaques, reduced the levels of Abeta42 oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril

AMELIORATED of microglia and astrocytes, consequently prevented neuron loss, reduced amyloid plaque formation, and ameliorated impaired cognition. Neuronal pheochromocytoma (PC12) cells induced with amyloid-beta peptide 1-42 and

AMELIORATED the few drugs used for treatment of AD. Another compound used in nanobiotechnology ameliorated as a nanocarrier the beneficial effects of some of these potential pharmaceutical agents. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

AMELIORATED treatment in order to determine which elements of the pathological features might be ameliorated. We compared the effects of the NSAIDs ibuprofen and celecoxib on immunohistological and

AMELIORATED in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim

AMELIORATED -SOD), and glutathione peroxidase (GSH-Px) activities. A concomitant treatment with lipoic acid ameliorated cognitive dysfunction and neurodegeneration in the hippocampus, and also reduced peripheral oxidative

AMELIORATED -amnesic agent in mice. Aqueous extract of dried whole plant of O. sanctum ameliorated the amnesic effect of scopolamine (0.4 mg/kg), diazepam (1 mg/kg) and aging induced

AMELIORATED cascade. Neuropsychiatric symptoms are also common in Alzheimer's disease and may be ameliorated by conventional psychotropic agents. Clinicians can currently offer substantial help to Alzheimer's

AMELIORATED -lesioned and aged rats, but not in intact young rats. These drugs also ameliorated the behavioral deficits in habituation, water maze, and passive avoidance tasks in these

AMELIORATED animals. These results suggest that these drugs stimulated NGF synthesis in vivo and ameliorated the behavioral deficits which were accompanied with the reduced choline acetyltransferase activity in

AMELIORATED old). FR121196[N-(4-acetyl-1-piperazinyl)-4-fluorobenzenesulfonamide+ ++], a newly introduced cognitive enhancer, ameliorated the failure in memory retention with bell-shaped dose- response curves in doses

AMELIORATED (0.5 mg/kg) or by lesions of the medial septum or fimbria-fornix. FR121196 ameliorated the scopolamine-induced memory deficit with a bell-shaped dose-response curve, whereas

AMELIORATED memory deficits brought about by medial septum or fimbria-fornix lesioning, whereas physostigmine ameliorated these deficits in scopolamine-treated and medial septum-lesioned rats, but not in

AMELIORATED of these drugs were estimated through clinical observations, the recording of the first ameliorated state and the maximum one, psychological check-up by using Hamilton's scale

AMELIORATED - 20160917 IS - 1476-3524 (Electronic) IS - 1029-8428 (Linking) VI - 30 IP - 3 DP - 2016 Oct TI - DADS Analogues Ameliorated the Cognitive Impairments of Alzheimer-Like Rat Model Induced by Scopolamine. PG - 407-26 LID - 10.1 Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

AMELIORATED roup presented with spatial learning and memory impairments. CDS and donepezil administration significantly ameliorated the Abeta25-35 peptide-induced memory impairment in both Morris water maze (P < 0.05) and

AMELIORATED ion corresponding to central anticholinergic activity. Additionally, donepezil, a cholinesterase inhibitor, ameliorated tau pathology and neurodegeneration in the same mouse model. These results indicate the

AMELIORATED 0.5% huperzine A; H. serrata extract inhibited AChE, but not BuChE. H. serrata extract ameliorated cognitive function in mice. These results indicate that Japanese H. serrata extract ameliorates

AMELIORATED 's acetylcholine and dopamine. Daily administration of CT extract throughout Abeta 1-42 infusion periods ameliorated the cognitive deficits, decreased amyloid deposition and reversed cholinergic and hippocampal do

AMELIORATED tion and reversed cholinergic and hippocampal dopaminergic dysfunction caused by Abeta 1-42. Donepezil also ameliorated the cognitive dysfunction, but only blocked the amyloid deposition and cholinergic dysfunction caused

AMELIORATED by Abeta 1-42. CONCLUSIONS: We suggest that CT extract, containing enough echinacoside and acteoside, ameliorated the cognitive dysfunction caused by Abeta 1-42 via blocking amyloid deposition, reversing choli

AMELIORATED in the two-platform task of a water maze in aged rats were ameliorated by RS-1259 as well as donepezil. Both RS-1259 and donepezil increased the awake

AMELIORATED causes of behaviour change. Concomitant medical illness should be treated and sensory impairment ameliorated. Nonpharmacological approaches should be instituted prior to medication use. These interventions

AMELIORATED baselines at 6 weeks after treatment (all p<0.05). Meanwhile, MoCA scores were also obviously ameliorated in the mild AD patients with rTMS. Besides, subgroup analysis showed that the

AMELIORATED from behavioral test batteries clearly revealed that dietary supplementation of Nutra II effectively ameliorated the motor deficiency and cognitive impairment of 5XFAD mice. In addition, Nutra II

AMELIORATED significant antioxidant capacity, reduced the levels of total tau and hyperphosphorylated tau and ameliorated cognitive deficits in younger triple transgenic AD (3xTg-AD) mice. Whether Se-Met

AMELIORATED evaluated by Western blot analysis. The results showed that walnut peptides supplementation effectively ameliorated the cognitive deficits and memory impairment of mice. Meanwhile, our study also revealed Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

AMELIORATED 2576 mice to various degrees depending on the age and the sex. Mt1 overexpression ameliorated the effects of hAbetaPP on exploration in young females, and potentiated those on

AMELIORATED choline acetylase (ChAT) activities were assayed by commercial kits. We found that edaravone ameliorated spatial learning and memory deficits in the rats. 4-HNE level in the hippocampus

AMELIORATED oral treatment with M30 (3x/week), initiated 8 days after STZ-icv administration dosedependently ameliorated already developed cognitive deficits in MWM test (reduced number of mistakes 3 months after

AMELIORATED reduced the expression of Abeta-42 in APP/PS1 transgenic (Tg) mice. Training also ameliorated mitochondrial respiratory function by increasing the complexes I, and IV and ATP synthase

AMELIORATED gyrus and neuronal damage in the CA1 of the ipsilateral hippocampus. Moreover, CHD ameliorated cognitive impairment induced by Abeta oligomer1-42 toxicity. These results demonstrate the neuro

AMELIORATED brain. Intranasal administration with a lentiviral vector encoding human NRF2 increased CD36 expression, ameliorated the weak antioxidant response triggered by hypoxia, diminished Abeta deposition, and improved spatial

AMELIORATED multiple pathways. Ligand activation of RAR and RXR in APP/PS1 transgenic mice ameliorated the symptoms of AD and reduced amyloid accumulation and tau hyperphosphorylation. Retinoids also

AMELIORATED in estrogen-deficient mice, but supplementation with 17beta-estradiol or alpha- Zearalanol efficaciously ameliorated this situation. CONCLUSION: These results demonstrate that alpha-Zearalanol is potentially beneficial

AMELIORATED was detected by immunohistochemistry and Western blot analysis. Our results showed that EGCG ameliorated the impaired learning and memory in APP/PS1 mice. Notably, we found a

AMELIORATED pathway and facilitate several other cytoprotective mechanisms. In this study, administration of SFN ameliorated cognitive function of Abeta-induced AD acute mouse models in Y- maze and

AMELIORATED < 0.05) increase in transfer latency in passive avoidance test. Similarly, the extracts (200 mg/kg) ameliorated memory deficit as a result of significant (p < 0.001) decrease in escape latency and

AMELIORATED neurotoxicity in primary neuron-microglia co-cultures. In vivo, intracerebroventricular administration of IL-34 ameliorated impairment of associative learning and reduced oAbeta levels through up-regulation of insulin-

AMELIORATED in males but other changes were similar or higher in females. Exercise treatment ameliorated cognitive deterioration and BPSD-like behaviors such as anxiety and the startle response. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

AMELIORATED s C activated microglia to promote neuroprotection. Moreover, intracerebroventricular administration of CpG ameliorated both the cognitive impairments induced by oAbeta1-42 and the impairment of associative learning

AMELIORATED acetyltransferase (ChAT) in hippocampus were observed in ICV-STZ rats. Se supplementation significantly ameliorated all alterations induced by ICV-STZ in rats. Our study reveals that Se,

AMELIORATED dysfunction, that is due to poor binding of substrates and coenzymes may be ameliorated by supplementing adequate levels of substrates or coenzyme precursors. Such supplementation with

AMELIORATED ovarian steroid deprivation resulted in spatial memory impairment, while melatonin and E2 significantly ameliorated spatial memory deficits in OVX rats. The latency to find the hidden platform

AMELIORATED indices. However, pretreatment of synaptosomes and primary neuronal cell culture with X-34 greatly ameliorated lipid peroxidation induced by these free radicals and Abeta(1-42). Protein oxidation was not

AMELIORATED 1-42 induced 31% decrease in acetylcholine level in the cortex, which was tended to be ameliorated by ferulic acid. 4. In addition, A beta 1-42 increased immunoreactivities of the astrocyte mark

AMELIORATED against the EA-CG treatment in the Tg mice. Furthermore, EA-CG significantly ameliorated the level of soluble Abeta42 and Abeta40. Similarly, we observed that the fibril

AMELIORATED -maze test and Morris water maze test). Golgi staining results revealed that XSE ameliorated dendritic spine density deficits in CA1 pyramidal neurons in the hippocampus. Western blot

7C2. Linking term ATTENUATED

ATTENUATED 7573 (Electronic) IS - 0378-8741 (Linking) VI - 194 DP - 2016 Dec 24 TI - Tannoid principles of Emblica officinalis attenuated aluminum chloride induced apoptosis by suppressing oxidative stress and tau pathology via Akt/

ATTENUATED 9 transgenic mice, we found that HE-My and its ethanol extracts (HE-Et) attenuated cerebral Abeta plaque burden. It's worth noting that the attenuated portion of

ATTENUATED out. Results illustrated that oral treatment of MERM (200 and 400 mg/kg bw) significantly attenuated Abeta (25-35) induced memory impairment as evaluated by behavioral tests. In addition treatment with

ATTENUATED the cognitive function by significantly inhibiting AChE, BuChE and MAO-B. Furthermore, MERM attenuated lipid peroxidation, protein oxidation, restored the antioxidant status and inhibited neuronal apo Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

ATTENUATED stress in the absence of any familial AD mutation, oral administration of NMZ attenuated hallmark AD pathology and restored biomarkers of synaptic and neuronal function. CONCLUSIONS: The

ATTENUATED acid. Intragastric pretreatment of mice with KMS4001 (30mg/kg/day) for 5 days significantly attenuated the Ass1-42 (i.c.v.)-induced memory impairment both in passive avoidance test

ATTENUATED found that Gas improved learning and memory abilities of Tg2576 transgenic mice and attenuated intracellular oxidative stress in hippocampi of Tg2576 mice. We discovered that the expression

ATTENUATED group. Immunohistochemical analysis revealed that treatment with the CTS/PL/beta- CD microspheres attenuated the expression of protein kinase C-delta and inhibited the activation of microglias.

ATTENUATED clearance of (125)I-radiolabeled Abeta1-42 in an LDLR-dependent manner, reduced Abeta deposition, attenuated neuroinflammatory responses, ameliorated neurologic changes and reversed behavioral deficits in AD

ATTENUATED , multimorbidity, and body mass index (BMI). Additional adjustment for apolipoprotein (apoE) epsilon4 genotype attenuated the association to nonsignificant in women but not in men in DP1 (beta = 0.13,

ATTENUATED , rescued protein phosphatase-2A activity by decreasing its demethylation at Leu309 selectively and attenuated Alzheimer's disease-like pathology and cognitive impairment in adeno- associated virus vector-1-

ATTENUATED ioural experimental results showed that DL0410 significantly ameliorated memory deficits. Meanwhile, DL0410 attenuated neural cell damage and reduced senile plaques significantly in the hippocampus of APP/

ATTENUATED and Celastrus angulatus. The beta-dihydroagarofuran-type sesquiterpenoids 58, 59, 61, and 63 significantly attenuated scopolamine-induced prolonged escape latency and increased number of errors compared with the

ATTENUATED , cornu ammonis 3 (CA3), and cornu ammonis 1 (CA1) regions of the hippocampus. Riluzole also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter 1, which packages glutama

ATTENUATED -beta-sheet structure, characteristics of amyloid aggregation, and toxicity of Abeta1- 42 were strongly attenuated by this chemical modification. CI - Copyright (c) 2015. Published by Elsevier Ltd. FAU - Kino,

ATTENUATED 2A cells exhibited the Alzheimer's disease (AD) related pathological markers which are attenuated with co-treatment of donepezil. Findings of the study suggested the potent use Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

ATTENUATED elevated the activities of superoxide dismutase, and reduced the levels of malondialdehyde. CEGI attenuated neuronal damage in the hippocampus of APP/PS1 mice and upregulated protein and

ATTENUATED , were treated with triptolide for 8 weeks. We observed enhanced spatial learning performances, and attenuated Abeta production and deposition in the brain. Triptolide also inhibited the processing of

ATTENUATED was studied using a proteomics approach and western blotting. RESULTS: Baicalein treatment significantly attenuated Abeta1-40-induced abnormalities in cognitive function. Additionally, the expression levels of 24 protei

ATTENUATED concentration in films on DNP in vitro permeation across pig skin was assessed. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) measurements were carried out to examine

ATTENUATED the mitochondrial membrane potential. In addition, pretreatment of PC12 cell with noopept significantly attenuated tau hyperphosphorylation at Ser396 and ameliorated the alterations of neurite outgrowth evoked by

ATTENUATED preserved the integrity of neurites and the expression of presynaptic proteins. It also attenuated Abeta-induced impairment of synaptic exocytosis. By using letrozole as an aromatase antagonist,

ATTENUATED Abeta-induced learning and memory dysfunction, enhanced antioxidative activity and energy metabolism, and attenuated cholinergic system damage. Our findings suggest that bajijiasu can enhance antioxidant capacity and

ATTENUATED A (CA) impaired the axonal transport in neuroblastoma-2a (N2a) cells. Berberine attenuated tau hyperphosphorylation and cytotoxicity induced by CA. Our study aimed at investigating the

ATTENUATED increased hippocampal protein expression of nitrotyrosine, a protein marker of oxidative stress, were attenuated in the AD mice. These results suggest that quetiapine can attenuate object recognition

ATTENUATED in brain of APP/PS1 mice in an autophagy-dependent manner. Meanwhile, temsirolimus attenuated cellular apoptosis in hippocampus of APP/PS1 mice, which was accompanied by an

ATTENUATED enhanced the phosphorylation of JAK2/STAT3 pathway and inhibition of JAK2 by AG 490 attenuated the anti-inflammatory effects of HSYA. Overall, our findings suggested that HSYA inhibited

ATTENUATED mice and decreased apoptosis of SH-SY5Y (APPwt/swe) cells. FLZ markedly attenuated Abeta accumulation and tau phosphorylation both in vivo and in vitro. Mechanistic study Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

ATTENUATED not only reduced Abeta production via inhibition amyloidogenic APP processing pathway, but also attenuated tau hyperphosphoylation mediated by Akt/GSK3beta. FAU - Bao, Xiu-Qi AU - Bao

ATTENUATED lower plasma C-reactive protein, homocysteine and asymmetric dimethy-larginine levels. RS significantly attenuated acetylcholinesterase (AChE) activity, whereas Na(+)/K(+)-adenosine triphosphatase (ATPase) activity was

ATTENUATED with EVP-0015962 was well tolerated in mice and lowered the production of Abeta42, attenuated memory deficits, and reduced Abeta plaque formation and inflammation in Tg2576 transgenic animals.

ATTENUATED by amyloid beta (Abeta)1-42 in AD models. Our results show that IndOH-LNCs attenuated Abeta-induced cell death and were able to block the neuroinflammation triggered by

ATTENUATED -LNCs (1 mg/kg, intraperitoneally) for 14 days. Only the treatment with IndOH- LNCs significantly attenuated the impairment of this behavior triggered by intracerebroventricular injection of Abeta1-42. Further,

ATTENUATED continuous quetiapine administration, memory deficit was reversed and brain Abeta plaque pathology was attenuated in the AD mice. Quetiapine also decreased the soluble Abeta peptide levels in

ATTENUATED decreased the soluble Abeta peptide levels in brain and cerebrospinal fluid (CSF), and attenuated the decreased synaptic protein levels in the AD mice. Furthermore, quetiapine normalized the

ATTENUATED distinct but overlapping therapeutic time windows of early stage pathology development. MW-151 treatment attenuated the increase in microglial and astrocyte activation and proinflammatory cytokine production in th

ATTENUATED positive allosteric modulator, PQCA, improves cognitive performance and cerebral blood flow. RESULTS: PQCA attenuated a scopolamine-induced deficit in novel object recognition in rat, self-ordered spatial

ATTENUATED primary murine microglia via a tyrosine kinase pathway involving Src kinase that was attenuated by dasatinib. Dasatinib administration to APP/PS1 mice decreased protein phosphotyrosine, active Src,

ATTENUATED that systemic treatment of APP/PS1 Tg mice with M30 for 9 months, significantly attenuated cognitive impairments in a variety of tasks of spatial learning and memory retention,

ATTENUATED chelating/radical scavenging compound, M30, effectively reduced Abeta accumulation and tau phosphorylation, and attenuated memory deficits. CONCLUSIONS: These findings suggest that M30 is a potential therapeutic agent Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

ATTENUATED mild-to-moderate AD. Acute and subchronic treatment with solanezumab of transgenic mice attenuated or reversed memory deficits with no effects on incidence or severity of cerebral

ATTENUATED villi abundance. On the other hand, HF-induced enterocytic perinuclear Abeta was significantly attenuated by Probucol. No significant changes in Abeta were observed within the lacteals. The

ATTENUATED fluoxetine reduce AD risk, whereas other drug classes promote risk. Risk may be attenuated by antipsychotics and lithium (down-regulate TNF), atypical antipsychotics (down-regulate TF), risperid

ATTENUATED , the elevated level of thiobarbituric acid reactive substances (TBARS) in STZ group was attenuated significantly in SAC pre-treated group when compared with STZ lesioned group. Apoptotic

ATTENUATED , TBARS, and decreased GSH levels), and brain acetylcholinesterase activity. Treatment of sodium butyrate attenuated diabetes induced impairment of learning, memory, endothelial function, and various biochemical paramete

ATTENUATED 30 enhanced the levels of phospho-AKT (Ser473) and phospho- GSK-3beta (Ser9) and attenuated Tau phosphorylation. M30 was also shown to protect cultured cortical neurons against Abeta(25-35)

ATTENUATED activation. Further, FA modulated the expression of Peroxiredoxin, an anti-oxidative protein, and attenuated phosphorylation of ERK1/2 activated by Abeta oligomers. FAU - Picone, Pasquale AU - Picone P

ATTENUATED in the AD brain increases beta-amyloid neurotoxicity. Caprospinol treatment of diseased rats attenuated memory impairment, as assessed using Morris watermaze tests. This recovery of cognitive function

ATTENUATED of AD. Electrophysiological assessment showed that i.c.v. administration of Abeta1- 40 significantly attenuated hippocampal long-term potentiation. Treatment with galantamine, a drug currently in clinical use

ATTENUATED of GSK3beta may be associated with alpha7 nAChR-induced signaling leading to attenuated tau hyperphosphorylation, raising the intriguing possibility that alpha7 nAChR agonism may have disease

ATTENUATED medium frequencies (6,7-10,2 Hz), the changes of beta-rhythm were augmented in frontal and attenuated in occipital areas. The analysis of frequency and spatial structure of EEG changes

ATTENUATED documented in clinical studies with atypical antipsychotics, although this effect tends to be attenuated with advancing age and in elderly patients with dementia. Antipsychotics, both conventional and Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

ATTENUATED -terminal fragment following cleavage by beta-secretase) in the transgenic mice. Furthermore, quetiapine attenuated anxiety-like behavior, up-regulated cerebral Bcl-2 protein, and decreased cerebral nitrotyrosine

ATTENUATED HMW extracellular oligomeric Abeta peptides in the brain. Most importantly, valsartan administration also attenuated the development of Abeta-mediated cognitive deterioration, even when delivered at a dose

ATTENUATED production in the hippocampus back towards normal in the animal model. Animals with attenuated cytokine production had reductions in synaptic dysfunction and hippocampus-dependent behavioral deficit

ATTENUATED endoproteolytic cleavage is sufficient to elevate the Abeta42/Abeta40 ratio and that the attenuated response to sulindac sulfide results partially from the deficiency in endoproteolysis. Importantly, a

ATTENUATED 1/2 (MRP1/2) inhibitor (e.g. probenecid and MK-571) in both luminal and abluminal sides attenuated the polarized transport. In a bilateral in situ brain perfusion model, the uptake

ATTENUATED , as did other NMDA-R antagonists. Memantine and the anti-NR1 antibody also attenuated a rapid ADDL-induced increase in intraneuronal calcium, which was essential for stimulated

ATTENUATED negative membrane potentials and the block of both types of NMDA receptors was attenuated with depolarization. However, galantamine potentiation of the NMDA receptors was not voltage depe

ATTENUATED similar to those of rosiglitazone-treated mice. We further report here that rosiglitazone attenuated reductions in insulin-degrading enzyme (IDE) mRNA and activity, and reduced amyloid beta-

ATTENUATED toxicity was assessed after 24 h. Micromolar concentrations of nicergoline or its metabolite, MDL, attenuated betaAP(25-35)-induced neuronal death, whereas MMDL (another metabolite of nicergoline), the alpha

ATTENUATED the OB surgery was associated with spatial working memory disturbances that were effectively attenuated with both doses of tacrine, but not physostigmine. Increased hyperactivity and defecation was

ATTENUATED of activated astrocytes surrounding beta-amyloid deposits. In vitro, the drug dose- dependently attenuated the toxic effect of beta-amyloid on neuronal cells. Enoxaparin dose-dependently reduced

ATTENUATED of this neurotransmitter after administration of CHF2819. At 1.5 mg/kg p.o. CHF2819 attenuated scopolamine-induced amnesia in a passive avoidance task. Furthermore, it decreased dopamine (DA) Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

ATTENUATED channel antagonists. Moreover, direct radical-scavengers, such as vitamin E or vitamin C, attenuated A beta toxicity with high efficacy. Interestingly, combined drug treatments did not necessarily

ATTENUATED . Differences in tardive dyskinesia rates between diagnostic groups found in univariate analyses were attenuated when the authors controlled for these variables. CONCLUSIONS: Tardive dyskinesia rates for patients

ATTENUATED on the magnitude of LTP in the mossy fiber-CA3 pathway, but significantly attenuated its enhancement by FK960 (10-7 M). In hippocampal slices from animals treated with cysteamine (20

ATTENUATED effect, but it remains possible that various sources of measurement error may have attenuated an effect of clinical significance from either type of drug. Conclusive evidence can

ATTENUATED AGE-mediated crosslinking. Formation of the AGE-crosslinked amyloid peptide aggregates could be attenuated by the AGE-inhibitors Tenilsetam, aminoguanidine and carnosine. These experimental data, and clinical

ATTENUATED and ibotenic acid induced marked retention deficit of active avoidance learning that was attenuated in a dose-dependent manner by Trasina after 14 and 21 days of treatment. Frontal

ATTENUATED acetylcholine levels in the central nervous system. Single doses of velnacrine (100 or 150mg) attenuated cognitive impairment induced by central cholinergic blockade in healthy volunteers, and memory improved

ATTENUATED Vmax (maximal cytotoxic potential) and Km of NK cell-mediated cytolysis are also attenuated. Single cell assays using agarose matrix reveal that THA moderately interferes with tumor

ATTENUATED in parietal and temporal regions. MID patients exhibited markedly augmented delta/theta and attenuated alpha and beta activity and a slowing of the DF and C. These

ATTENUATED changes were associated with subjective sedation as measured by analogue rating scales. Physostigmine attenuated the impairment in verbal learning and reduced subjective sedation. In the biochemical study

ATTENUATED APP/Psen1 mice was reduced by methysticin treatment. Most importantly, methysticin treatment significantly attenuated the long-term memory decline of APP/Psen1 mice. CONCLUSION: In summary, these

ATTENUATED AD. Nonsteroidal anti-inflammatory drugs delayed the onset and progression of AD and attenuated cognitive dysfunction. Based upon epidemiological evidence and animal studies, antioxidants emerged as

ATTENUATED , a selective agonist of TRPV1 and donepezil, a potent acetylcholine esterase inhibitor have attenuated i.c.v. STZ and AlCl3+d-galactose induced experimental AD. Hence, pharmacological Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

ATTENUATED - 20160822 LR - 20160215 IS - 1471-4159 (Electronic) IS - 0022-3042 (Linking) VI - 136 IP - 5 DP - 2016 Mar TI - Attenuated presenilin-1 endoproteolysis enhances store-operated calcium currents in neuronal cells. PG - 1085-95

ATTENUATED familial Alzheimer's disease PS1 mutations. This study deals with the effect of attenuated endoproteolysis of PS1 on store-operated calcium (SOC) entry in neuronal cells and

ATTENUATED the burden of Abeta plaque in the brain. Treatment with 1-phenylisatin and donepezil attenuated i.c.v. STZ as well as AlCl3+d-galactose induced impairment of

ATTENUATED . We found that the chronic treatment improved spatial learning, enhanced AKT signaling, and attenuated tau hyperphosphorylation and neuroinflammation. These findings shed new light on the possible mechanism

ATTENUATED spike activity, prevented the loss of spines, synaptophysin immunoreactivity, and neurons, and thus attenuated the deficits in synaptic plasticity and learning and memory in APP and presenilin 1 (

ATTENUATED TH loss. DHA or DHA/ALA restored phosphorylated and total GSK3beta and attenuated hyperactivation of the tau C-Jun N-terminal kinases (JNKs) while increasing MAP1

ATTENUATED . Propranolol, at a lower dose than that used as antihypertensive (5 mg/kg, 6 wk), attenuated cognitive impairments shown by Tg2576 mice aged 9 months in the novel object recognition

ATTENUATED , assessment of spatial learning and memory functions revealed that treatment with tolfenamic acid attenuated long-term memory and working memory deficits, determined using Morris water maze and

ATTENUATED found that mPGES-1 deletion reduced the accumulation of microglia around senile plaques and attenuated learning impairments in Tg2576 mice. These results indicated that mPGES-1 is induced in

ATTENUATED parkinsonian tremor. In the final experiment, the adenosine A(2A) antagonist MSX-3 significantly attenuated the tremulous jaw movements induced by the 3.0mg/kg dose of galantamine, which

ATTENUATED elevated levels of acetylcholinesterase and monoamine oxidase enzymes in amnesia induced mice were attenuated by treatment with EAG. The generation of free radicals was decreased due increased

ATTENUATED neurons exposed to diazoxide. Diazoxide hyperpolarized neurons, reduced the frequency of action potentials, attenuated Ca2+ influx through NMDA receptor channels, and reduced oxidative stress. 3xTgAD mice treated Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

ATTENUATED cerebrovascular dysfunction and cognitive impairment. Oral administration of a low dose of olmesartan attenuated cerebrovascular dysfunction in young Alzheimer disease-model transgenic mice (APP23 mouse), with

ATTENUATED low dose of olmesartan completely prevented beta-amyloid-induced vascular dysregulation and partially attenuated the impairment of hippocampal synaptic plasticity. These findings suggest the possibility that ameliora

ATTENUATED -Hispanic Blacks (PR=0.75, 95% CI=0.57, 0.99) and non-Hispanic others (PR=0.50, 95% CI=0.26, 0.96) but were attenuated for Hispanics (PR=0.84, 95% CI=0.59, 1.20). DISCUSSION: Results provide evidence that racial/ethnic dis

7C3. Linking term RESTORED

RESTORED inhibiting AChE, BuChE and MAO-B. Furthermore, MERM attenuated lipid peroxidation, protein oxidation, restored the antioxidant status and inhibited neuronal apoptosis by down-regulating the level of

RESTORED AD and one model of sporadic AD. In 3 x Tg hippocampal slices, NMZ restored LTP. In vivo, memory was improved with NMZ in all animal models with

RESTORED any familial AD mutation, oral administration of NMZ attenuated hallmark AD pathology and restored biomarkers of synaptic and neuronal function. CONCLUSIONS: The multifunctional approach, embodied by NMZ,

RESTORED proteins were upregulated following ginsenoside Rg1 application. Correspondingly, longterm potentiation (LTP) was restored following ginsenoside Rg1 application in the AD mice model. Taken together, ginsenoside Rg1

RESTORED whereas lipid peroxidation and acetylcholine esterase were increased significantly (P<0.01). These changes were restored significantly (P<0.01) by CN-SLNs (5mg/kg and 10mg/kg) and (P<0.05) by

RESTORED of the hippocampal region showed the extent of neuronal loss which was thereby restored back on treatment with CN-SLNs and free CN. Our findings demonstrate that

RESTORED were identified in the brains of AD mice and their levels were partly restored after treatment with G-Rg1 and G-Rg2. G-Rg1 and G-Rg2

RESTORED over-excitation is primarily mediated by dysfunctional GABA signaling and can possibly be restored by rectifying anomalous metabolism observed in the GABAergic neurons during AD. Additionally, neurogenesi

RESTORED potentiating actions of CMZ in vitro and sedative activity in vivo. Importantly, NMZ restored LTP in hippocampal slices from AD transgenic mice, whereas CMZ was without effect. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

RESTORED brain TNF-alpha and IL-1beta levels. Chronic treatment with naringin dose dependently restored cognitive deficits in ICV-STZ rat along with mitigation of mitochondrial dysfunction mediated

RESTORED brain abnormalities of the mice biochemically and immunohistochemically. We found that intranasal insulin restored insulin signaling, increased the levels of synaptic proteins, and reduced Abeta40 level and

RESTORED the microtubule stabilizing drug taxol, tau Ser(262) phosphorylation decreased and synaptophysin level was restored. Our data demonstrate that overexpression of 14-3-3z accelerates proteosomal turnover of synaptop

RESTORED -NMR), we showed that MB administration after the onset of amyloid pathology significantly restored the concentration of two metabolites related to mitochondrial metabolism, namely alanine and lactate.

RESTORED efflux, to restore axonal trafficking, and to enhance long-term potentiation (LTP) and restored LTP following treatment with Abeta oligomers. We have also synthesized a new class

RESTORED induces unexpected changes in both cortical excitability (increased) and central cholinergic transmission (restored) of AD patients. These unexpected effects might depend on the dopamine D(2)-like

RESTORED . SAHA dose-dependently increased GRN mRNA and protein levels in cultured cells and restored near-normal GRN expression in haploinsufficient cells from human subjects. Although elevation of

RESTORED mouse AD model (5xFAD). Amyloid beta(1-42)-induced atrophies of axons and dendrites were restored by post-treatment with icariin in rat cortical neurons. Administration of icariin for 8

RESTORED ections of sodium valproate, sodium butyrate, or vorinostat (suberoylanilide hydroxamic acid; Zolinza) completely restored contextual memory in these mutant mice. Further behavioral testing of the HDACi-treated

RESTORED cell viability. FA treatment, in particular if loaded into SLNs, decreased ROS generation, restored mitochondrial membrane potential (Deltapsi(m)) and reduced cytochrome c release and intrinsic pathw

RESTORED y reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA restored brain histone acetylation levels and, as a most likely consequence, activated the transcription

RESTORED not 0.3 mg/kg) improved aged mice performance. CONCLUSION: This preclinical demonstration that S 24795 restored specific age-related memory deficits with as much efficacy as donepezil adds to Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

RESTORED recognize this sector, while bulbectomized animals treated with noopept (0.01 mg/kg for 21 days) restored this predominance, thus demonstrating the improvement of the spatial memory. These animals also

RESTORED pine (32 microg/kg). Similarly, physostigmine (3.2, 10 or 32 microg/kg) significantly and dose-dependently restored the visual recognition memory deficits produced by scopolamine (10 microg/kg) but not those

RESTORED action potential due to these compounds. Doses of tacrine ranging from 1 to 4 microM restored the AP configuration close to control values. Tacrine also antagonized the binding of 1-

RESTORED areas involved in the processing of emotion and cognition, which are only partially restored after the biochemical remission of the disease. Therefore, periodical neuropsychiatric evaluations are re

RESTORED synaptosomes was found. Treatment with a mixture of n - 3/n - 6 of fatty acids restored the unwanted effect. The beneficial effects of fatty acids are mediated via the

RESTORED alpha-lipoic acid (ALA), which also prevented TH loss. DHA or DHA/ALA restored phosphorylated and total GSK3beta and attenuated hyperactivation of the tau C-Jun

RESTORED that chronic reduction of TOR activity by rapamycin treatment started after disease onset restored cerebral blood flow (CBF) and brain vascular density, reduced cerebral amyloid angiopathy and

RESTORED starting from the OKA injection improved performance in memory tests and also significantly restored GSH, MDA, nitrite levels, ROS generation and [Ca(2+)](i) level. This study demonstrates

RESTORED 4 days after Abeta(25-35) treatment, axonal and dendritic outgrowths in cultured cortical neurons were restored as demonstrated by extended lengths of phosphorylated neurofilament-H (P-NF- H) and

RESTORED cell death. In several animal models mimicking different aspects of AD, these drugs restored cognitive impairments, and in select cases induced a decrease in brain Abeta elevation,

RESTORED mice with small hippocampi, unlike rivastigmine and nicotine, AF150(S) and AF267B restored cognitive impairments also on escape latency in a Morris water maze paradigm, in

RESTORED filaments [PHF]; and loss of cholinergic function conducive to cognitive impairments.) These drugs restored cognitive impairments in several animal models for AD, mimicking different aspects of AD,

RESTORED mice with small hippocampi, unlike rivastigmine and nicotine, AF150(S) and AF267B restored cognitive impairments also on escape latency in a Morris water maze paradigm in Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

RESTORED model that mimics AD pathology and cognitive impairments), prolonged treatment with AF150(S) restored cognitive and behavioral impairments and decreased tau hyperphosphorylation, PHF and astrogliosis

RESTORED of phosphatases, respectively. Prolonged administration of AF150(S) in apolipoprotein E- knockout mice restored cognitive impairments, cholinergic hypofunction, and tau hyperphosphorylation, and unveiled a high-

RESTORED is not processed in the furin-deficient LoVo cell line; however, processing is restored upon furin transfection. Finally, in vitro digestion of recombinant soluble BACE with recombinant

RESTORED rats was slightly impaired during the first training day and tetrahydroaminoacridine 3 mg/kg restored the performance of combined-lesioned rats. Combined-lesioned rats performed as well as

RESTORED (ADMET) and less toxicity than Donepezil. Memory deficits in scopolamine-lesioned animals were restored by MTDL-3.MTDL-3 particularly emerged as a ligand showing remarkable potential benefits for

RESTORED that the PCC hypoperfusion is a result of cholinergic dysfunction and can be restored by cholinergic enhancement. This present longitudinal study aimed to detect the restoration of

RESTORED significantly correlated with rCBF changes in the PCC of responders. CONCLUSIONS: Cholinergic enhancement restored PCC rCBF under the three conditions of mild AD, responders and short follow-

RESTORED and memory. Moreover, the structure of the neurons of the treated groups was restored and the expression of synaptophysin increased in both the hippocampus and cortex. In

RESTORED abnormal inflammatory response is associated with AD. Treatment by VE, ALC and LA restored the above mentioned parameters to about normal levels comparable to those of donepezil,

RESTORED by 40% of that in sham-operated animals. The reduced ChAT positive neurons were restored by donepezil treatments. Consistent with these observations, the cognitive deficits observed in OBX

RESTORED and lower resting flow velocity levels (40 +/- 13 cm/s; p = 0.06 vs. control), which were restored in a dose-dependent manner under AChEI (0.4 +/- 0.2; 44 +/- 11 cm/s). CONCLUSIONS: AD is associated

RESTORED unstable and declined in magnitude over the experimental period. Increasing the delay interval restored this deficit. Donepezil, at doses that robustly attenuated a scopolamine (0.06 mg/kg s.

RESTORED miniature inhibitory postsynaptic currents, and decreased extrasynaptic tonic inhibitory current, while DHM restored these GABAAR-mediated currents in TG-SwDI. We found that gephyrin, a postsynaptic Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

RESTORED of GABAergic synapses, decreased in hippocampus and cortex in TG-SwDI. DHM treatment restored gephyrin levels. These results suggest that DHM treatment not only improves symptoms, but

RESTORED ved antioxidative enzyme activity of superoxide dismutase and glutathione peroxidase. In addition, apigenin restored neurotrophic ERK/CREB/BDNF pathway in the cerebral cortex. In conclusion, apigenin may

RESTORED problem falls. It was indicated that make a decrease a fall risk for restored cognitive function with executive function in the elderly peoples. Thus, improve the quality

RESTORED disorder improved sufficiently for the forensic evaluators to opine that they had been restored to competency after involuntary treatment with antipsychotic medication. These results are similar to

RESTORED -labeling assay. Liquiritin at doses of 50-100 mg/kg significantly improved the cognitive ability, restored the abnormal activities of glutathione peroxidase and superoxide dismutase, and decreased the levels

RESTORED of BAY 73-6691 improved learning and memory in the Morris water maze test, and restored several hippocampal memory-associated proteins. Our study identified a neuroprotective role for BAY 73-66

RESTORED significant elevation in HO-1 activity and attenuated STZ-induced oxidative stress. Moreover, hemin restored acetylcholinesterase activity and cognitive functions in STZ infused rats. Pre- administration of Sn

RESTORED number of mistakes 3 months after the STZ-icv treatment - 59%; p b 0.05) and fully restored them in PA test (+314%; p b 0.05). Chronic M30 treatment fully restored (-47%/PHF1;- 65%/AT8;

RESTORED 0.05) and fully restored them in PA test (+314%; p b 0.05). Chronic M30 treatment fully restored (-47%/PHF1;-65%/AT8; p b 0.05) STZ-induced hyperphosphorylation of tau protein and normalized decreased

RESTORED impaired mitochondrial antioxidant enzymes and mitochondrial OGG1 activities seen in Tg mice were restored with training. Acetylation level of mitochondrial OGG1 and MnSOD was markedly suppressed in

RESTORED . However, administration of alpha-lipoic acid (50mg/kg, i.p.) for 28 days significantly restored cognitive deficits induced by BCCAO. Biochemical determination revealed that alpha-lipoic acid markedly

RESTORED with alpha-lipoic acid significantly improved behavioral alterations, protected against oxidative stress, and restored central cholinergic system in the rat model of vascular dementia induced by BCCAO. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

RESTORED a novel object, indicating the reversal of STZ-induced memory impairment. LCZE also restored STZ-induced alteration in AChE activity and oxidative stress parameters in both brain

RESTORED ultraPEALut significantly reduced inducible nitric oxide synthase and glial fibrillary acidic protein expression, restored neuronal nitric oxide synthase and brainderived neurotrophic factor and reduced the apoptosis. Tak

RESTORED (+) K(+) ATPase and acetylcholinesterase (AChE)) in AD Tg mice brain regions and was restored by figs treatment. Further, figs supplementation might be able to decrease the plasma

RESTORED - (Abeta-) mediated Alzheimer's disease. In Morris water maze model, the extract significantly restored the defected memory of amyloid-beta injected mice (P < 0.01). The reduced levels of

RESTORED enzymes such as glutathione peroxidase, glutathione reductase, catalase, and superoxide dismutase were also restored significantly to similar levels as seen in normal control mice (P < 0.01). The levels

RESTORED damage were reversed by administration of pioglitazone (15 and 30 mg/kg). Pioglitazone also significantly restored the BDNF level and attenuated the actions of inflammatory markers in ICV betaA-

RESTORED -small ka, CyrillicB pathways, 7 days after Abeta injection. These antioxidant and inflammatory pathways restored to the vehicle level within 20 days. Taken together, our findings reinforce and extend

RESTORED impairment and decreased lipid peroxidation, reactive oxygen species, and reactive gliosis. It also restored the eNOS and nNOS expression to normal levels. In conclusion the aminoestrogen prolame

RESTORED and impairment of post-tetanic potentiation in mossy fiber-CA3 synapses were fully restored when brain slices obtained from Tg2576 were pretreated with antioxidant, suggesting that mitochondrial

RESTORED plus Maze and Passive Shock Avoidance exteroceptive behavioural models. Pre- treatment with Mangiferin restored increased whole brain acetylcholinestrease, lipid peroxidation and reduced glutathione due to scop

RESTORED Abeta(4)(0), a typical indicator of AD progression. Furthermore, the intake of vitamin C restored the declined synaptophysin and the phosphorylation of tau at Ser396. On the other

RESTORED from aged mice. In APP-expressing neuroblastoma cells in culture, mitochondrial function was restored by melatonin or by the structurally related compounds indole-3-propionic acid or N(1)-

RESTORED of H(2)O(2) on the adhesive behavior of the cells was almost totally restored by each of the derivatives. In addition, each of the derivatives except compounds 20 Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

RESTORED cortex. Pre- and post-treatment of curcumin in STZ (ICV) treated rats significantly restored the memory deficit and IR protein level in both the regions. Furthermore, STZ (

RESTORED Tg19959 mice compared to wild-type littermates, but memory and synaptophysin levels were restored to wild-type levels in Tg19959-MnSOD littermates. These benefits occurred without changes

RESTORED Abeta25-35-induced apoptosis of PC12 cells. Preincubation of the cell with puerarin also restored the ROS and mitochondrial membrane potential levels that had been altered as a

RESTORED cell-permeant antioxidant and GSH precursor, alleviated oxidative damage and cognitive decline, and restored glutathione synthase and GSH levels in ApoE-deficient mice deprived of folate to

RESTORED flammation possibly contributed to astrocytic dysfunction. Lastly, HOEC which exhibited anti-inflammatory effects restored the capacity of injured or aged astrocytes to clear Abeta. In conclusion, astrocytes

RESTORED -associated virus expressing CD200 into the hippocampus and sacrificed at 12 months. CD200 expression restored neural progenitor cell proliferation and differentiation in the subgranular and granular cell layers

RESTORED (-1) ), which was orally administered once a day (6 days per week) for 8 weeks, significantly restored age-reduced spontaneous alternation to 95.2% of that seen in young rats (P < 0.05). C29

RESTORED quadrant, which was shortened in the aged control rats. Oral administration of C29 restored age-reduced doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) expression and cAMP

RESTORED . Moreover, synaptic function, indicated by the expression of pre-synaptic protein synapsin-1, was restored and the secretion of anti-inflammatory and neurotrophic factors were increased, such as

RESTORED Alzheimer's disease. After a relatively short-term treatment of 10 days, hesperidin significantly restored deficits in non-cognitive nesting ability and social interaction. Further immunohistochemical analy

RESTORED amyloid plaques in cortex and hippocampus of transgenic mice 5 months of age, and restored impaired nesting ability. Our results suggest that Icariin might be considered a promising

RESTORED 24 h. The cell viability was decreased in Abeta(25-35) treated cells which was significantly restored by Cin pretreatment. Cin successfully reduced the mitochondrial membrane potential, ROS and NO

RESTORED were found to be up-regulated in transgenic placebo mice, while minocycline treatment restored these levels to normality. The anti-inflammatory and beta-secretase 1 effects could be Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

RESTORED assess how it influenced cognitive decline and development of pathology. 4 months of treatment restored cognition to non-transgenic performance. Inflammatory profiling revealed a marked decrease in GFAP,

RESTORED the disease but not after plaques deposition. Conversely, the NMDA receptor antagonist memantine restored LTP selectively in DG at later stages of the disease. Both these effects

RESTORED equivalent to those used in humans. After the treatment, memantine-treated mice had restored cognition and significantly reduced the levels of insoluble amyloid-beta (Abeta), Abeta dodecamers (

RESTORED diseases. PG - 218-22 AB - In in vitro experiments, amiridine in concentration of 100, 200, and 300 microM restored disturbed structure of microtubules assembled from tubulin and microtubule-associated proteins isolated f

RESTORED experiments under low magnesium conditions. In this case as well, impaired LTP was restored in the presence of therapeutically relevant concentrations of memantine (1 microM). In vivo, doses

RESTORED 'improved' Mg(2+) (voltage-dependency, kinetics, affinity)-attenuated this deficit. Synaptic plasticity was restored by therapeutically-relevant concentrations of memantine (1 microM). Moreover, doses leading to similar

RESTORED memory-related behaviors, long-term potentiation in the hippocampal CA1 region was markedly restored by rivastigmine treatments. In immunoblotting analyses, the reductions of calcium/calmodulin-dependent pr

RESTORED kinase IV (CaMKIV) phosphorylation in the CA1 region in OBX mice were significantly restored by rivastigmine treatments. In addition, phosphorylation of AMPAR subunit glutamate receptor 1 (GluA1) (S

RESTORED targets of CaMKII and CaMKIV, respectively, in the CA1 region was also significantly restored by chronic rivastigmine treatments. Finally, we confirmed that rivastigmine-induced improvements of

RESTORED . PG - 189-202 AB - The M1 muscarinic agonists AF102B, AF150(S) & AF267B--i) restored cognitive impairments in several animal models for AD with an excellent safety margin;

RESTORED impairments in mice with small hippocampi. In apolipoprotein E-knockout mice, AF150(S) restored cognitive impairments and cholinergic hypofunction and decreased tau hyperphosphorylation. In aged

7C4. Linking term INCREASED

INCREASED homozygous for the epsilon4 allele of apolipoprotein E4 (APOE4/4 homozygotes), who carry an increased risk for the disease. Therefore, to build on this important efficacy attribute and Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED maze. More importantly, the number of neurons in the hippocampal DG was significantly increased by FLX. Additionally, FLX reduced the deposition of beta amyloid, inhibited GSK-3beta

INCREASED . Additionally, FLX reduced the deposition of beta amyloid, inhibited GSK-3beta activity and increased the level of beta-catenin in middle-aged APP/PS1 mice. Collectively, the

INCREASED 's disease involves multiple pathways that, at the macrolevel, include decreased proliferation plus increased loss affecting neurons, astrocytes, and capillaries and, at the subcellular level, involve several

INCREASED mary hippocampal neurons: berbernine treatment decreased the levels of extracellular and intracellular Abeta1-42, increased the protein levels of LC3-II, beclin-1, hVps34, and Cathepsin-D, and decreased

INCREASED : A total of 10,754 patients were included. During the periods with IAs, hospitalization rates increased by 0.36/year compared with 0.23/year in the periods without for the same patient,

INCREASED , while the protein expression of Bcl-2 and the ratio of Bcl-2/Bax were increased by LSS. We demonstrate that LSS significantly improves cognitive function and prevent neuronal

INCREASED the blood-brain barrier, reduced Abeta plaque deposition and the malondialdehyde level, and increased the percentage of normal neurons and cholinergic activity in the hippocampus of AD

INCREASED a preclinical transgenic mouse model for Alzheimer's disease (APPSDL mice). DMSO treatment increased spine density in a region-specific manner in the hippocampus of APPSDL mice

INCREASED prescribed memantine. Advanced age reduced the likelihood of AChEI consumption. Mild dementia severity increased the use of AChEIs, and moderate-advanced dementia increased the likelihood of memantine

INCREASED consumption. Mild dementia severity increased the use of AChEIs, and moderate- advanced dementia increased the likelihood of memantine consumption. After diagnosis, the likelihood of AChEI consumption decreased

INCREASED , whereas the likelihood of memantine consumption, either alone or in combination with AChEIs, increased. CONCLUSIONS: Antidementia drug use in this study showed the initial use of AChEIs

INCREASED the activation of MAPK cascades in the hippocampus were determined. RESULTS: Enhanced memory, increased neuronal density, decreased AChE activity and decreased oxidative stress status together with activated

INCREASED : Alzheimer's disease (AD), the most common disease causing dementia, is linked to increased mortality. However, the effect of antipsychotic use on specific causes of mortality has Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED related deaths, and 28 intentional self-harm related deaths are presented. Current antipsychotic exposure increased mortality rate with HR between 1.92 and 2.31 for cardiovascular, cancer, and infection related death.

INCREASED , cancer, and infection related death. Cumulative antipsychotic dosages were most commonly associated with increased rates of mortality for cardiovascular and infection as cause of death, whereas the

INCREASED -harm as cause of death. CONCLUSIONS: We showed that cumulative antipsychotic drug dosages increased mortality rates for cardiovascular and infection as cause of death. These findings highlight

INCREASED be very low i.e. 4.79 and 6.10 nM for 12 and 36 microg, respectively, whereas it increased exponentially by increasing the units of BuChE. The mode of inhibition and kinetic

INCREASED , psychotropic medication use, and risk for a dementia diagnosis. RESULTS: PTSD diagnosis significantly increased the risk for dementia diagnosis (HR = 1.35; [95% CI = 1.27-1.43]). However, there were significant inter

INCREASED medication receipt. BZAs or SNRIs use at baseline was associated with a significantly increased risk for dementia diagnosis independent of a PTSD diagnosis. CONCLUSION: PTSD diagnosis is

INCREASED diagnosis independent of a PTSD diagnosis. CONCLUSION: PTSD diagnosis is associated with an increased risk for dementia diagnosis that varied with receipt of psychotropic medications. Further research

INCREASED by several proteases. Several lines of evidence suggest that accumulation of Abeta by increased production or decreased degradation induces the tau-mediated neuronal toxicity and symptomatic ma

INCREASED basis of AD pathogenesis. Partial loss of gamma-secretase activity leads to the increased generation of toxic Abeta isoforms, indicating that activation of gamma-secretase would provide

INCREASED localization of ADAM10, BACE1, and PS1 thereby promoting Abeta generation, whereas high isoprenoids increased both maturation as well as amyloidogenic-cleavage of AbetaPP, which was evident through

INCREASED the BBB and to target the place of treatment. With this approach an increased drug bioavailability has been achieved in the CNS using intravenous administration in place

INCREASED without antipsychotics with Cox proportional hazard models. Antipsychotic use was associated with an increased risk of mortality (adjusted hazard ratio [aHR] 1.61; 95% Confidence Interval [CI] 1.53-1.70). The absolu Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED mortality rate was 4.58 (95% CI 4.53-4.63) deaths per 100 person-years. The risk of mortality was increased from the first days of use and attenuated gradually but remained increased even

INCREASED was increased from the first days of use and attenuated gradually but remained increased even after two years of use (aHR 1.30; 95% CI 1.16-1.46). Compared with nonuse, antipsychotic polypharma

INCREASED 1.46). Compared with nonuse, antipsychotic polypharmacy (aHR 2.88; 95% CI 2.38- 3.49) was associated with an increased risk of mortality than monotherapy (aHR 1.57; 95% CI 1.49- 1.66). Haloperidol was associated with higher

INCREASED immunohistochemistry and western blotting. Suppressing autophagy induced pyramidal cell death without affecting increased pro-survival signalling induced by nimodipine. Nimodipine protected the brain from chronic cerebral

INCREASED Case-Control Study. PG - 119-128 LID - 10.3233/JAD-160956 [doi] AB - BACKGROUND: Risk of pneumonia is increased in persons with Alzheimer's disease (AD). In some studies, anticholinergic drugs (AC)

INCREASED disease (AD). In some studies, anticholinergic drugs (AC) have been associated with an increased pneumonia risk. OBJECTIVE: We analyzed the risk of pneumonia associated with ACs in

INCREASED significant interactions between BChE-K genotype and the duration of donepezil treatment, with increased changes in MMSE and CDR-SB scores compared to the common allele in

INCREASED suggested that the use of benzodiazepines in the elderly is associated with an increased risk of dementia. However, this association might be due to confounding by indication

INCREASED Adverse Reaction Online Database (ROR: 1.88, 95% CI: 1.83-1.94; IC: 0.85, 95% CI: 0.80-0.89). ROR and IC values increased with the duration of action of benzodiazepines. In the PSSA, a significant association

INCREASED -term use of benzodiazepines and long-acting benzodiazepines are strongly associated with an increased risk of dementia. FAU - Takada, Mitsutaka AU - Takada M AD - Division of Clinical

INCREASED are common clinical problems in dementia, and are associated with significant caregiver distress, increased healthcare costs, and institutionalisation. Drug treatment is often sought to alleviate these problems,

INCREASED cells, pretreatment with DL0410 (1, 3, and 10 mumol/L) decreased the phosphorylation of JNK and increased the phosphorylation of Akt, markedly decreased copper-stimulated Abeta1-42 production, reversed t

INCREASED timulated Abeta1-42 production, reversed the loss of mitochondrial membrane potential, and dose-dependently increased the cell viability. In Abeta1-42-treated mice, DL0410 administration significantly ameliorated learning Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED confirmed that memantine antagonizes memory impairment in Alzheimer's model APP23 mice. Memantine increased CaMKII activity in the APP23 mouse hippocampus, and memantine- induced enhancement of hippocampal

INCREASED 2004 warnings, the use of atypical APs decreased, whereas the use of conventional APs increased, in Italy and the UK until 2009. However, the trend for APs individually showed

INCREASED showed that the use of risperidone/olanzapine decreased, whereas the use of quetiapine increased in both countries. After the 2009 warnings (until 2012), the use of atypical and conventional

INCREASED APs decreased in the UK (from 11 to 9 and 5 to 3 %, respectively), but such use increased in Italy (from 11 to 18 and 9 to 14 %, respectively). CONCLUSION: The 2004 warnings led to a

INCREASED 2004 warnings led to a reduction in the use of olanzapine and risperidone and increased the use of quetiapine/conventional APs in both

INCREASED -induced anxiolytic effects as evidenced in the EPM and in the LDT and increased locomotor activity in the OFT. Additionally, it was observed that dopamine (DA) and

INCREASED the OFT. Additionally, it was observed that dopamine (DA) and serotonin (5-HT) levels increased while 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio in the hippocampus decreased. Our results in

INCREASED -induced SH-SY5Y neuronal cell injury were also evaluated. Treatment with 12b increased cell viability in SH-SY5Y cells pretreated with 250 muM NMDA, with significant

INCREASED the female AD mice, and VPA treatment thickened the postsynaptic density and markedly increased the number and density of presynaptic vesicles in both male and female AD

INCREASED at NHP, but not with age or cognitive and instrumental ADL capacities. CONCLUSIONS: Increased community-based care did not reduce the survival time in NHs among individuals

INCREASED of cytokines/chemokines and microgliosis in damaged regions. Cytokines have been associated with increased tau phosphorylation and decreased levels of synaptophysin, establishing their roles in the cytoskeletal

INCREASED function. In contrast, curcumin enhanced mitochondrial fusion activity and reduced fission machinery, and increased biogenesis and synaptic proteins. Mitochondrial function and cell viability were elevated in curcumin

INCREASED cognitive impairments. A behavioral test suggested that POP significantly decreased escape latency and increased crossing parameters of platform quadrant in a Morris water maze test. Furthermore, POP Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED quadrant in a Morris water maze test. Furthermore, POP decreased error numbers and increased passive avoidance latency in a step-down test. Biochemical examinations revealed that POP

INCREASED - and short-term memory of the rats. Moreover, the brain antioxidant activity was increased by elevating the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxida

INCREASED n-derived neurotrophic factor (BDNF) expression. It robustly inhibits tau abnormal hyperphosphorylation via increased BDNF mediated decrease in glycogen synthase kinase-3beta (GSK- 3beta, major tau kinase)

INCREASED the safety and efficacy of gamma-secretase inhibitors only. RESULTS: There was an increased risk of adverse events (Odds Ratio (OR) 1.38, 95% CI 1.09-1.73; p = 0.01), serious adverse events (OR 1.

INCREASED CI 1.22-1.84; p < 0.001), and skin cancers (OR 4.77, 95% CI 2.83-8.06; p < 0.001). There was significantly increased risk of infections (OR 1.36, 95% CI 1.13-1.63; p < 0.001) in the subgroup analysis excluding tarenflurbi

INCREASED CDR-sb. CONCLUSION: The use of gamma-secretase inhibitors is associated with significantly increased risk of serious adverse events including skin cancers, and worsening in cognitive indicators.

INCREASED . The increasing prevalence of AD and the low efficacy of current therapies have increased the amount of research on unraveling of disease pathways and development of treatment

INCREASED treat diseases and regenerate tissues. Recently, manufacturing of nano-sized delivery systems has increased the efficacy and delivery potential of biomaterials. In this article, we review the

INCREASED primary outcomes MMSE and episodic memory with Bushen capsule treatment. FMRI results showed increased connectivity in the right precuneus and the global connectivity indexed with goodness of

INCREASED diminished, the ratio of nerve growth factor (NGF) to NGF precursor (proNGF) was increased and hippocampal neurogenesis was promoted after these administrations. All the mentioned benefits of

INCREASED epsilon4 contributes to AD pathogenesis through multiple pathways including facilitated amyloid-beta deposition, increased tangle formation, synaptic dysfunction, exacerbated neuroinflammation, and cerebrovascular defects

INCREASED attention during recent years in drug design studies. The deregulation of GSK-3beta increased the loss of hippocampal neurons by triggering apoptosis-mediating production of neurofibrillary tangles Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED brain tissues in the pathogenesis of Alzheimer's disease (AD) cause energy deficiency, increased generation of reactive oxygen species (ROS), and premature neuronal death. However, the causal

INCREASED developed major behavioral and biochemical features of AD neurodegeneration, including spatial memory loss, increased brain levels of Abeta, and energy deficiency. Mitochondria isolated from the neocortex and

INCREASED that correlated with high levels of soluble Abeta1-40. Mitochondria from OBX mice showed increased contents of lipid peroxidation products, indicative of the development of oxidative stress. We

INCREASED Alzheimer's disease (AD) that may favour a T helper 2 phenotype leading to increased naturally occurring auto-antibodies (NAb) against beta-amyloid (Abeta). We hypothesized the involv

INCREASED assay. Plasma samples were also obtained for Abeta and NAb determination. RESULTS: Donepezil increased in vitro the expression of the transcription factor GATA binding protein 3 (GATA3) through

INCREASED by the specific antagonist methyllycaconitine. Ex vivo PBMC alpha7nAChR mRNA expression was increased in both AD groups, while GATA3 expression was not. A significant increase in

INCREASED . CONCLUSIONS: Donepezil might modulate a T helper 2 bias via alpha7nAChR leading to increased expression of NAb. Further studies on the role of the modulation of the

INCREASED tional group [odds ratio (OR) 1.34, 95 % confidence interval (CI) 0.5-3.58; p = 0.56]. However, compared with the increased function CYP2D6 alleles group, the normal function group had a better response

INCREASED pain, pain behavior, and/or treatment efficacy in people with dementia? CONCLUSION: Despite increased use of analgesics, pain is still prevalent in people with dementia. Validated pain

INCREASED ) in mild-to-moderate Alzheimer's disease patients. RESULTS: Cerebrolysin, but not donepezil, increased serum brain derived neurotrophic factor at week 16, while the combination therapy enhanced it

INCREASED against the occurrence of dementia (RR, 0.94; 95% CI, 0.91-0.97); on the contrary, peripheral ACEIs (PACEIs) increased the risk of dementia (RR, 1.20; 95% CI, 1.00-1.43). In an analysis of cognitive decline, CACEIs

INCREASED effect of beta-asarone against Alzheimer's disease: regulation of synaptic plasticity by increased expression of SYP and GluR1. PG - 1461-9 LID - 10.2147/DDDT.S93559 [doi] AB - AIM: beta-

INCREASED in vivo, improved the learning and memory ability of APP/PS1 mice, and increased the expression of SYP and GluR1 both in vivo and in vitro. Thus, Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED of immune nanoparticles with a controlled delivery of the peptide iAbeta5 was substantially increased compared to the nanoparticles (NPs) without monoclonal antibody functionalization. CI - Copyright (c) 2

INCREASED 50% of treated patients over a short period of several months. In addition, an increased rate of dementia in young patients has been noted over the longer term,

INCREASED revalence of people prescribed antidepressant drugs remained unchanged while antidementia drug prescription increased from 17.9 to 21.5 %. When controlled for demographic changes, 36 out of 39 behavioral and psychological

INCREASED AP39 (a newly synthesized mitochondrially targeted H2S donor) on mitochondrial function. AP39 increased intracellular H2S levels, mainly in mitochondrial regions. AP39 exerted dose- dependent effects

INCREASED . AP39 exerted dose-dependent effects on mitochondrial activity in APP/PS1 neurons, including increased cellular bioenergy metabolism and cell viability at low concentrations (25-100 nM) and decreased energy

INCREASED energy production and cell viability at a high concentration (250 nM). Furthermore, AP39 (100 nM) increased ATP levels, protected mitochondrial DNA, and decreased ROS generation. AP39 regulated mitochondrial dyna

INCREASED (P<0.01) in the Abeta25-35 injected group, whereas lipid peroxidation and acetylcholine esterase were increased significantly (P<0.01). These changes were restored significantly (P<0.01) by CN-SLNs (5mg/kg

INCREASED could be attained at lower dose and also its oral bioavailability could be increased by encapsulating CN in SLNs. Thus the results suggest that CN-SLNs could

INCREASED orepinephrine reuptake inhibitors (SSNRIs) compared to tricyclic antidepressants. There was a significantly increased risk of treatment discontinuation for older patients and patients treated in NP practice.

INCREASED - S0306-4522(16)00247-5 [pii] AB - The expression of beta-site APP-cleaving enzyme 1 (BACE1) is increased in the brain of late-onset sporadic Alzheimer's disease (AD) and oxidative

INCREASED Network View. PG - 152-68 LID - 10.1089/omi.2015.0172 [doi] AB - The prevalence of acquired hyperlipidemia has increased due to sedentary life style and lipid-rich diet. In this work, a

INCREASED to treat behavioural and psychological symptoms of dementia, despite significant safety concerns regarding increased risk of stroke and mortality. The numbers of patients with dementia and related

INCREASED of strong pathological associations between type 2 diabetes and Alzheimer's disease (AD) has increased in recent years. Contrary to suggestions that anti-diabetes drugs may have potential Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED , we demonstrate here that the insulin sensitizing anti-diabetes drug metformin (Glucophage(R)) increased the generation of amyloid-beta (Abeta), one of the major pathological hallmarks of

INCREASED generation. Together, these data suggest that metformin-induced accumulation of autophagosomes resulted in increased gamma-secretase activity and Abeta generation. Additional experiments indicated that metformin inc

INCREASED in increased gamma-secretase activity and Abeta generation. Additional experiments indicated that metformin increased phosphorylation of AMP-activated protein kinase, which activates autophagy by suppressing mammalian targ

INCREASED the older 5XFAD group, which exhibited more profound memory deficits concomitant with highly increased concentrations of Abeta as compared with those of the younger 5XFAD group. Since

INCREASED reactivity. Finally, incubation of primary astrocytes with genistein results in a PPARgamma-mediated increased release of ApoE. Our results strongly suggest that controlled clinical trials should be

INCREASED with mild-to-moderate AD. It was independently correlated with impaired autonomy and increased caregiver burden but did not significantly influence treatment outcomes. FAU - Godefroy, Olivier AU -

INCREASED receiving regular PPI medication (n = 2950; mean [SD] age, 83.8 [5.4] years; 77.9% female) had a significantly increased risk of incident dementia compared with the patients not receiving PPI medication (n = 70,729;

INCREASED and is in line with mouse models in which the use of PPIs increased the levels of beta- amyloid in the brains of mice. Randomized, prospective clinical

INCREASED were characterized using a texture analyzer indicating that these systems can have an increased residence time in the site of absorption. Donepezil-free base was incorporated in

INCREASED rris water maze (MWM) and immunohistochemistry, respectively. RESULTS: The impaired cognitive function and increased hippocampal Abeta deposition in AD mice were ameliorated by G-Rg1 and G-

INCREASED the adult hippocampus, we evaluated whether ANDRO stimulates this process. Treatment with ANDRO increased neural progenitor cell proliferation and the number of immature neurons in the hippocampus

INCREASED /PS1DeltaE9 transgenic mouse model of Alzheimer's disease. In these mice, ANDRO increased cell proliferation and the density of immature neurons in the dentate gyrus. Concomitantly

INCREASED in the hippocampus of wild-type and APPswe/PS1DeltaE9 mice determined by increased levels of beta-catenin, the inactive form of GSK-3beta, and NeuroD1, a Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED (P < 0.05 or P < 0.01); ChAT and SOD activities as well as BCL-2 content were increased significantly (P < 0.05 or P < 0.01) the formation of senile plaque was decreased and brain

INCREASED 95% CI 2.23-2.91), this is corresponding to a 65% increase from 34.9 to 57.6%. The paracetamol prescription increased by 113%, from 22.7% in 2000 to 48.4% in 2011. Strong opioids (fentanyl, buprenorphine, morphine, oxycod

INCREASED ased by 113%, from 22.7% in 2000 to 48.4% in 2011. Strong opioids (fentanyl, buprenorphine, morphine, oxycodone) increased from 1.9% in 2000 to 17.9% in 2011 (P < 0.001), whereas non-steroidal anti-inflammatory drug presc

INCREASED drug use between the groups were found in 2011. CONCLUSIONS: the analgesic drug prescription increased significantly from 2000 to 2011, especially the use of paracetamol and strong opioids. We also

INCREASED as Beers Criteria. One trial reported reduced drug-related readmissions and another reported increased adverse drug reactions. CONCLUSION: multi-disciplinary teams involving pharmacists may improve pre

INCREASED impact of disclosure on several key psychological factors. RESULTS: Four of 11 subjects demonstrated increased amyloid aggregation and reported that they were not surprised, particularly given their family

INCREASED with significant emotional impact, irrespective of actual amyloid burden status. Those subjects with increased amyloid burden were more likely than those without significant amyloidosis to make positive

INCREASED regression model, the following variables were linked to a significant extent with an increased risk of dementia: diabetes (OR: 1.17; 95% CI: 1.10-1.24), lipid metabolism (1.07; 1.00-1.14), stro

INCREASED to develop effective drug treatments. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional single-target approaches. In amyotrophic lateral sclerosis, we have

INCREASED differentiate into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro.

INCREASED dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro. We also demonstrate that HK532-IGF-I cells survive

INCREASED a "drug repositioning" or "repurposing" approach with potential disease-modifying compounds has been increased. The new generation antipsychotics are commonly used in AD and other dementias for Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED ) and Notch-sparing GSIs have shown reduced amyloid-beta (Abeta) peptide levels but increased Notch-related and -unrelated adverse effects. In this study, we examined the effects

INCREASED -related and -unrelated adverse effects. Compound-1 reduced Abeta40 and Abeta42 levels but inversely increased Abeta37 in Neuro2a cells, leading to no net changes in total Abeta

INCREASED (100mg/kg), the GSI LY450139 decreased HES1 mRNA expression in thymus tissues and increased the intensity of periodic acid-Schiff (PAS)-positive areas in the intestine. Moreover,

INCREASED 3) were -0.13 +/- 0.29 and -2.69 +/- 23.7, respectively. In the intervention group, ADL scores were significantly increased by 14.0 +/- 11.1 6 months after reduced benzodiazepine use. CONCLUSIONS: QOL was maintained with

INCREASED . CONCLUSIONS: QOL was maintained with reduced drug use, while ADL score was slightly increased. In addition, the reduction of benzodiazepine use significantly increased ADL. In order to

INCREASED ADL score was slightly increased. In addition, the reduction of benzodiazepine use significantly increased ADL. In order to reduce polypharmacy among community-dwelling elderly patients, it is

INCREASED ADT use and Alzheimer's disease risk. We also observed a statistically significant increased risk of Alzheimer's disease with increasing duration of ADT (P = .016). CONCLUSION: Our

INCREASED between the use of ADT in the treatment of prostate cancer and an increased risk of Alzheimer's disease in a general population cohort. This study demonstrates

INCREASED -1beta and TRAF6 to levels similar to gx-50 inhibition; moreover, overexpression of TLR4 increased the expression of MyD88 and TRAF6, which was significantly reduced by gx-50. These

INCREASED [1]. AD is caused by an imbalance between Abeta production and clearance, resulting in increased amount of Abeta in various forms [2]. Reduction of Abeta production and increasing clearance

INCREASED to induce Parkinsonism, tardive dyskinesia and their long-term use was associated with increased risk of hip fractures and impaired cognitive function and even death. METHODS: The

INCREASED Discontinuation rates varied substantially and ranged between 0% and 49% with a median of 18%. Significantly increased discontinuation rates were found for galantamine and rivastigmine as compared to placebo in

INCREASED of tyrosine receptor kinase B (TrkB) by 7, 8-dihydroxyflavone (7, 8-DHF), the selective TrkB agonist, increased surface alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPARs) AMPA r

INCREASED the hippocampus of Tg2576 mice. A key feature of 7, 8-DHF action was the increased expression of both GluA1 and GluA2 at synapses. Interestingly, 7, 8-DHF had no effect Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED used time-series analysis to assess trends over time. RESULTS: The study sample increased by 21% over the 10-year study period, from 49,251 patients to 59,785 patients. The majority of

INCREASED (9% increase) antidepressants. The proportion of patients dispensed two or more psychotropic drug classes increased from 42% in 2004 to 50% in 2013. CONCLUSIONS: Utilization patterns of psychotropic drugs in institution

INCREASED a high rate. A decline in the use of benzodiazepines along with an increased use of sedative and non-sedative antidepressants suggests that the latter class of

INCREASED .23 [0.81-1.87]). INTERPRETATION: Withdrawal of donepezil in patients with moderate-to-severe Alzheimer's disease increased the risk of nursing home placement during 12 months of treatment, but made no

INCREASED to minimise the duration of concomitant use and to find safer alternatives without increased bleeding risk. FAU - Taipale, Heidi AU - Taipale H AD - Kuopio Research Centre of

INCREASED expression of APP, NMDAR1B and the phosphorylation level of NMDAR2B, and increased the phosphorylation level of CAMKII and the expression of PSD-95. In this study,

INCREASED precursor protein (APP) cleavage via beta-Site amyloid precursor protein cleaving enzyme 1 (BACE1). Increased levels of brain Abeta have been implicated in the pathogenesis of Alzheimer's

INCREASED peptide also modulated beta-amyloid and tau pathologies in APPswe mice, and it increased the amount of M receptor with modulation of acetylcholinesterase in scopolamine-induced rats.

INCREASED site. RESULTS: Five of 10 sites and 43 of 49 service users approached participated. Profile administration increased the number of problems addressed from a mean of 6.02 [SD 2.92] to 9.86 [4.48], effect size 3.84, 9

INCREASED dementia, but the evidence for effect is limited. Antipsychotics have been associated with increased risk of adverse events and mortality in patients with dementia, leading to safety

INCREASED were significant across almost all age groups. Treatment intensity among patients using antipsychotics increased as the annual median number of defined daily doses (DDD) increased from 33.3 to 42.0

INCREASED using antipsychotics increased as the annual median number of defined daily doses (DDD) increased from 33.3 to 42.0 DDD. CONCLUSIONS: The changing patterns of psychotropic drug use may be

INCREASED follow-up period. The use of memantine and cholinesterase inhibitor-memantine combination treatment increased with disease severity. After adjustment for confounding, a one-point increase in the Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED one-point increase in the disease severity scale (CDR-SOB) was associated with 15.6% increased odds of memantine use. A one-point decrease in CERAD Neuropsychological battery (CERAD-

INCREASED -point decrease in CERAD Neuropsychological battery (CERAD-NB) total score was associated with 2.4% increased odds of memantine use. The overall unadjusted rate of switching between anti-dementia

INCREASED activity compared to those who were not. Low overall ADS scores due to increased awareness of adverse effects of medications and brevity of follow-up are potential

INCREASED chronic inflammation patients and their matched controls, respectively. Systemic vasculitis was associated with increased hazard ratios of dementia (1.75, 95% confidence interval (CI) 1.35-2.27, p < 0.001). The analyses reveal

INCREASED reased hazard ratios of dementia (1.75, 95% confidence interval (CI) 1.35-2.27, p < 0.001). The analyses revealed increased risk of dementia for systemic vasculitis (1.64, 95% CI 1.24- 2.18), Crohn's diseases (2.08, 95% CI

INCREASED - and beta-secretase-cleaved soluble amyloid-beta protein precursor (sAbetaPP) levels had significantly increased and rCMRglc had stabilized. Levels of CSF Abeta40 and sAbetaPP correlated positively with

INCREASED negatively with rCMRglc and cognition. In summary, long-term phenserine treatment resulted in increased levels of CSF Abeta40, sAbetaPPalpha, and sAbetaPPbeta, which positively correlated with improveme

INCREASED had a lower risk of death. Antidementive drug treatment was correlated with an increased risk of LTC (considerable LTC: RR = 1.66, p = 0.000, severe LTC: RR = 1.50, p = 0.000, extreme LTC:

INCREASED the treatment of dementia patients is associated with a reduced LTC dependence and increased survival of dementia patients. Antidementive drug treatments appear to extend live years with

INCREASED correlated in AD PBMCs at 12 months post-inclusion. In addition, Beclin-1 and p62 increased in the low inflammatory environment induced by C16. Only LC3-I levels were

INCREASED 87466 [doi] AB - The use of multi drug regimens among the elderly population has increased tremendously over the last decade although the benefits of medications are always accompanied

INCREASED , even when prescribed at recommended doses. The elderly populations are particularly at an increased risk of adverse drug reactions considering comorbidity, poly-therapy, physiological changes affecting Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED . PG - 743-54 LID - 10.1007/s40266-015-0295-4 [doi] AB - OBJECTIVE: Heart failure (HF) is associated with an increased risk of dementia, and studies show that dyslipidemia may be involved in the

INCREASED reduction of pro-inflammatory cytokines and the generation of protective factors had been increased ultimately. In conclusion, Rd had a neuroprotective effect on APP Tg mice, and

INCREASED the elderly dosages. The proportion of patients who did not take anticholinergic drugs increased from 30% to 60% (P

INCREASED - 20160826 LR - 20151121 IS - 1873-7862 (Electronic) IS - 0924-977X (Linking) VI - 25 IP - 11 DP - 2015 Nov TI - Increased all-cause mortality with use of psychotropic medication in dementia patients and controls:

INCREASED in patients with dementia as compared to control subjects. Mortality hazard ratios were increased for subjects prescribed serotonergic antidepressant drugs (respectively, HR=1.355 (SD=0.023), P=0.001 in

INCREASED in dementia patients. We found that use of psychotropic drugs is associated with increased all-cause mortality in both patients with dementia and control subjects. Thus, the

INCREASED mortality in both patients with dementia and control subjects. Thus, the frequently reported increased mortality with antipsychotic drugs in dementia is not restricted to subjects with impaired

INCREASED Patients. PG - 1057-67 LID - 10.1248/yakushi.15-00109 [doi] AB - In Japan the prevalence of dementia has increased considerably, and pharmacists are involved in addressing these patients' medication-related problems. He

INCREASED state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single to multiple dose. The memantine patch

INCREASED development to aging. ERbeta genetic polymorphisms have been associated with cognitive impairment and increased risk for AD predominantly in women. The role of ERbeta in the intervention

INCREASED ype sesquiterpenoids 58, 59, 61, and 63 significantly attenuated scopolamine-induced prolonged escape latency and increased number of errors compared with the control group. At 10 muM, 21 of the 62 tested

INCREASED -type sesquiterpenoids rescued Abeta25-35-induced SH-SY5Y cells from viability reduction, which increased the cell viability from 64.6% for the model to more than 74.0%. The majority of

INCREASED with previous data. In contrast, other studies reported that Psen1 methylation may be increased or decreased in AD patients, suggesting that additional studies are required. In conclusion, Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED 2576 mice but not in those receiving drugs, and this was accompanied by an increased number of Doublecortin- (DCX-) positive cells in the dentate gyrus, a surrogate marker

INCREASED the identification of some solvent-exposed residues that are absolutely critical to achieve increased solubility and to avoid precipitation of the enzyme in inclusion bodies when expressed

INCREASED of medium-to-high potency first-generation antipsychotic drugs was associated with an increased risk of seizures (adjusted odds ratio 2.51 [95 % CI 1.51-4.18]) compared with non-use, while use

INCREASED otency first-generation antipsychotic drugs (adjusted odds ratio 2.24 [95 % CI 1.05- 4.81]) was associated with an increased risk of seizures compared with non-use, but current use of amisulpride, aripiprazole,

INCREASED medium-to-high potency first-generation antipsychotic drugs was associated with a 2.5- fold increased risk of seizures compared with non-use of antipsychotic drugs in patients with

INCREASED chotic drug subclasses, except amisulpride, aripiprazole, risperidone, or sulpiride, was associated with an increased risk of seizures. FAU - Bloechliger, Marlene AU - Bloechliger M AD - Basel Pharmacoepidemiology Unit,

INCREASED not statistically significant. CONCLUSIONS: Our findings suggest that IDU is associated with an increased risk of hospitalization in older persons and in persons with dementia. IDU is

INCREASED reduced levels of acetylcholine (ACh), epinephrine (E), norepinephrine (NE), and dopamine (DA), and increased activities of acetylcholine esterase (AChE) and monoamine oxidase (MAO). Treatment with B-extract 20

INCREASED 1, 2, 3, and greater than 3, respectively. Compared with the mildly progressive patients, the adjusted HRs increased as the aDCSI increased (2 y HRs: 1.30, 1.53, and 1.97; final HRs: 2.38, 6.95, and 24.0 with the c

INCREASED . Compared with the mildly progressive patients, the adjusted HRs increased as the aDCSI increased (2 y HRs: 1.30, 1.53, and 1.97; final HRs: 2.38, 6.95, and 24.0 with the change in the aDCSI score

INCREASED them into mature neurons. Patient iPSC-derived neurons demonstrated pronounced TAU pathology with increased fragmentation and phospho-TAU immunoreactivity, decreased neurite extension, and increased but re

INCREASED pathology with increased fragmentation and phospho-TAU immunoreactivity, decreased neurite extension, and increased but reversible oxidative stress response to inhibition of mitochondrial respiration. Furthermore, FTD ne

INCREASED , and superoxide dismutase (SOD) were measured. AlCl3 significantly impaired learning and memory and increased brain AChE, brain total protein, TBARS, and nitrate/nitrite and decreased brain GSH Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

INCREASED were used to calculate hazard ratios (HRs). RESULTS: Hypertension was associated with an increased risk for cognitive decline (HR 1.20; 95% confidence interval (CI) 1.04, 1.39; P = 0.02). Among wom

INCREASED savings were estimated at $18,355 and $20,947 per patient and quality-adjusted life- years (QALYs) increased by an average of 0.12 and 0.13 from a societal and healthcare payer perspective, respectively.

INCREASED that participants with a formal diagnosis and a physician in the network have increased rates of receiving antidementia drug treatments. These findings suggest that dementia networks focusing

References - Chapter 7

Chapter 8

CONCLUSIONS FROM APRIL 2017 MONOGRAPH

(adapted from reference [1])

8A. Contributing Factors Identified

Approximately 400-600 AD foundational causes are identified in the April 2017 monograph [1] (depending on how one aggregates). Given the myriad disincentives for reporting adverse medical events [2, 3], this number should be viewed as a 'floor'.

These foundational causes are divided into six traditional categories for clarity of presentation:

 Lifestyle,  Iatrogenic,  Biotoxic Agents,  Occupational/ Environmental Exposures,  Psychosocial/Socioeconomic,  Genetics.

The latter category, Genetics, was not addressed in the findings because the main focus of the April 2017 monograph is on foundational causes that are (by definition) somewhat actionable (action could, at least in theory, be taken to attenuate, neutralize, or eliminate them). It is difficult to modify a person's genetic endowment at the present time, although that may not be true in the future.

8A1. Latent Variables

To gain an understanding of the deeper commonality among these foundational causes, they can be re-categorized manually according to a few main latent variables [1]:

 Direct Technology,  Indirect Technology,  Inadequate Regulation,  Individual Choice,  Poverty.

Each of these five major themes (latent variables) will be discussed now.

8A1a. Direct Technology

Direct Technology (the degree of direct impact of technology on the foundational cause) plays a strong role in Lifestyle, Iatrogenic, and Occupational/ Environmental foundational causes. In addition, through its impact on the immune and other critical systems, modern technology may play a role in whether exposure to bacteria and viruses results in symptoms and diseases.

Modern technology impacts the growing, processing, and preparation of foods, and many of the adverse effects identified in the present study can be traced back to the use (mis-use) of technology in the food cycle. The Iatrogenic adverse effects of modern technology result mainly from the high-technology- based drugs, surgery, diagnostics, and therapy that characterize much of modern medicine today. The Occupational/Environmental adverse effects result mainly from the employment of modern technology in commerce, the environment, and the workplace.

8A1b. Indirect Technology

Indirect Technology reflects those adverse health-impacting behaviors enabled by Direct Technology. One example is reduced labor because of modern technology. This leads to today's highly damaging sedentary lifestyle that contributes to myriad diseases, including AD.

Another example is large numbers of people being able to live in inhospitable northern climates because of modern transportation, food logistics, clothing, and shelter. This results in less exposure to sunlight and less Vitamin D production, contributing to diseases (such as AD) related in part to Vitamin D deficiency.

8A1c. Inadequate Regulation

Inadequate Regulation is coupled strongly to the introduction of high technology in all aspects of life. Many of the problems with foods derive from relatively unregulated chemicals, materials, and other contaminants entering the food supply during agriculture and animal husbandry. Many of the Occupational/ Environmental exposures arise from relatively unregulated harmful substances entering the workplace and the environment, especially in less developed countries, but in more developed countries as well. Many of the Iatrogenic problems could be traced to drugs, diagnostics, therapies, and other procedures entering practice with insufficient front-end long-term testing, and inadequate evaluation of side-effects.

Two major aspects of Inadequate Regulation revolve around insufficient safety: inadequate safety data gathering, and inadequate safety testing. Much of the adverse impact data gathering tends to be from passive surveillance systems, where response rates can be an order of magnitude (or more) less than real- world incidence rates. Pre-market testing, in many cases, suffers from inadequate sample sizes, unrepresentative samples, insufficient long-term testing, and insufficient combination testing to identify potential synergistic effects. Insufficient long-term testing on humans is particularly troubling, since many serious diseases such as AD may have decadal latency periods from specific toxic stimuli. Transgenerational effects [3] could not be excluded without appropriate long-term testing.

Additionally, results from animal testing (which could be long-term from the perspective of many short-lived animals used in testing) do not necessarily translate to human outcomes. First, there is a species difference, and impacts on one species do not necessarily carry over to the same types of impacts on another species. Second, laboratory animals are raised in relatively pristine environments, and subjected to a very few toxic substances during studies on disease contributing factors. Conversely, humans experience/are exposed to many of the AD contributing factors identified in the present AD study, and the synergy from these combinations would not have been replicated in the laboratory animal testing.

8A1d. Individual Choice

Individual Choice reflects decisions by people to choose unhealthy diets, sedentary activities, recreational drugs, elective drugs and surgery, unhealthy occupations, unhealthy residential environments, unhealthy relationships, etc. There is the unwritten corollary assumption that people have adequate knowledge about the consequences of these choices, and there are no other major factors that limit their choices. For many people, this is a highly unrealistic assumption. They have very limited knowledge about the consequences of these choices, either through accurate information not being available, or apathy in searching out this information, or being provided incorrect information [2, 3].

8A1e. Poverty

Poverty limits individual choices about diet, occupations, and environment. Poverty plays a strong role in malnutrition and the diseases of deficiency resulting therefrom, directly and indirectly. By limiting access to modern medicine and modern technology, poverty avoids some of the adverse impacts ascribed to modern technology presented in this monograph, but at the same time, denies many of the benefits available from modern medicine and modern technology.

8B. Synergies/Combination Effects/Additional Contributing Factors

8B1. Under-Reporting of Combinations of Potential Contributing Factors

Many, if not most, people are exposed to at least tens of the ~400-600 potential foundational causes identified in this monograph, and perhaps tens more of the foundational causes that remain under- reported. Given the potential synergistic effects of these causes acting in concert, whereby the potential damage from the combinations exceeds the damage of the causes acting in isolation, the opportunity for developing AD is significant.

However, while ~400-600 potential foundational causes appears to be a large number, it may be the tip of the iceberg of the real number of potential foundational causes. If two or more substances do not show an adverse effect for AD when each is studied in isolation, then they would probably not be examined in combination in the lab or clinic, even though some could produce an adverse effect in combination. So, a large number of combinations would have to be examined, to cover both the case where each member of the combination showed no adverse effect when studied in isolation, and the case where each member of the combination would have a very slight effect on AD when studied in isolation, but the combination would produce a large effect. While some of these combinations would have been Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

reported in the present study, those reported would probably be a very small fraction of all potential combinations.

The targeted literature studies in particular tend to select substances of interest for the experiments, then look for biomarkers/characteristics of interest. Unless there is good reason to select a combination for study, it probably would not get chosen.

8B2. Numerical Estimates of Potential Combinations

The reason few combinations are selected for study derives from combinatorics. Consider the number of possible combinations of two and three items. For n variables, and possible combinations of a subset of n consisting of r variables, the number of combinations is: C(n,r)=n!/(r!*(n-r)!), where [!] denotes the factorial function. For large n, and r small compared to n, C(n,r)~=nr/r! For large n, C becomes a large number. How large? Consider the following.

It would be useful to identify those substances that, in isolation or in combination, could potentially impact AD or its surrogate endpoints, but have not been studied yet. There are many tens of thousands of items that could be potential candidates for study. Is there any way to narrow those down?

Reference [2] examined contributing factors to ~4,000 diseases, and identified factors that contributed to 1) any of these diseases and 2) a threshold number of diseases. In reference [2], on the order of 800 substances that contributed to at least a threshold number of the ~4,000 diseases were identified. These 800 pervasive causes constituted about ten percent of the total number of causes (90% of which impacted less than the threshold number of diseases) identified for the ~4,000 diseases. The total number of causes identified for all diseases (~8,000) might be a good starting point for identifying additional potential AD causes. Why is this a reasonable assumption?

The various systems in the body are inter-related. The immune system, neural system, endocrine system, circulatory system, etc, are linked. There are research disciplines devoted to study of these linked systems (e.g., neuroimmunology, neuroimmunoendocrinology, etc). Most of the ~8,000 causes identified in reference [2] impacted one or more of these inter-related systems. Many of the studies focused on the impact of the test substance on (typically) one system only. It would be reasonable to expect that a substance impacting one of the systems above would have some level of impact on the other systems above, with some impacts being more significant than others.

Thus, the ~8,000 potential causes identified in reference [2], minus those that were identified in the present AD study, would be candidates for evaluation as potential AD causes. Subtracting the ~500 AD causes identified in the present study from the ~8,000 causes leaves on the order of ~7,500 items to be examined in isolation. Assume there were another 500 items evaluated for potential impacts on AD in other studies but were shown not to have an effect (in isolation, although we may want to examine them as part of a combination). We are then left with on the order of

1) ~7,500 substances to study in combination, and

This would include the case where the ~500 identified contributing factors in isolation could have a stronger effect in combination, for those cases where the combinations have not been studied.

The numbers of combinations of two and three for 7,500 test items, C(7500,2), C(7500,3), are, according to the formula above for small r:

C(7500,2)=~28 million

C(7500,3)=~70 billion

These numbers are astronomical in any of the cases shown. Research on each of these combinations is a major resource and time effort, in the lab and/or in the field/clinic. There's no way all the combinations, or even the most relevant ones, can be run. Unfortunately, the myriad combinations of potentially toxic stimuli mirror the real world, not the potentially toxic stimuli acting in isolation. And, which combinations are important to a specific individual would be a function of that person's unique characteristics, such as genetic makeup.

8B3. Synergy Effects on Dose Rates

Dose rates may also be affected by synergy. When two or more items with adverse health effects (in isolation) are combined, smaller doses of each in combination can produce an equal or greater adverse health effect (this synergy is also true for the case of positive health effects).

As an example, assume hypothetically that heavy cell tower radiofrequency (RF) exposure could be a strong contributing factor to AD, and high-fat diet could be a strong contributor. If people are exposed simultaneously to cell towers and fat-containing diets, then perhaps only modest levels of cell tower exposure and modest fat diets could in combination have an adverse effect equivalent to that from high levels of exposure of each in isolation. Thus, if the initial tests in isolation were at low doses of the stimuli, the results could be misleading. So, each of the combination experiments would have to cover a wide parametric range to be credible.

These conclusions reflect the challenge of preventing or reversing not only AD, but all other chronic diseases that have a wide spectrum of causative factors. The only glimmer of hope for true prevention or reversal is that, for any complex system characterized by many variables, there are typically a few main variables that drive performance and need to be addressed with high priority. That may explain why

1) Dale Bredesen was able to get positive results for his treatment of AD/MCI [4,5],

2) the Sherzais were able to get positive results for their treatment of AD [6], and

3) Terri Wahls was able to reverse her multiple sclerosis (as summarized in Chapter 9, sub- section D of [2]).

Unfortunately, given the rapidly increasing number of potentially harmful exposures to advanced and untested technologies in our biosphere, identifying and eliminating these hazards may become increasingly difficult. This is especially true for those diseases with long latency periods (like AD). Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

8C. Health Policy

8C1. Health Policy Framework

While the main objective of this monograph is identification of potential contributing factors to AD, some brief statements about the health policy that could exploit these findings might prove useful. The health policy that derives from the above findings would contain two main components: persuasion and mandates. Persuasion would be applied to influence Lifestyle/Individual Choice, which is the "low- hanging fruit" of foundational causes. Mandates would be applied to alter Inadequate Regulation, the next level up on the "fruit tree". Effective persuasion and mandates depend strongly on the most scientifically accurate biomedical information being placed in the biomedical literature, and then communicated to the public in a straightforward manner.

This monograph has taken a large step in identifying the voluminous potential AD foundational causes that need to be eliminated for AD prevention or possible AD reversal. An expanded study would be able to 1) sample more abstracts for analysis, and 2) examine phrases further down the frequency spectrum, to identify additional potential foundational causes for AD.

However, while the addition of more AD foundational causes obtainable with an expanded study would provide a more complete picture of such causes, the elimination of the specific and categorical causes identified in this monograph may be adequate to prevent or (alone or in concert with treatments) reduce/halt/reverse AD progression in selected cases.

8C2. Health Policy Implementation

8C2a. Eliminating Potential AD Contributing Factors

There are three key issues in implementing elimination of any potential AD contributing factor for any person.

1) What is the exposure level (duration, strength) of this individual to a given AD contributing factor, and is this exposure level in the toxic range? For some types of AD contributing factors, exposures can be estimated readily. These types of AD contributing factors include some aspects of diet, some drugs, and perhaps some occupational exposures. For most AD contributing factors for most people, the exposure levels at both any point in time and as a function of time are unknown. To obtain that data, myriad exposure meters measuring radiation (ionizing, non-ionizing), chemicals ingested, inhaled, entering the body through the skin, etc, would be required on a continual basis. For the foreseeable future, many exposures relevant to AD contributing factors will be unknown because of the absence of these critical measurement systems on a continuing basis.

2) Assuming a particular individual's exposure to a given contributing factor is known and potentially harmful, its elimination needs to be placed in some priority order. If one examines the research papers on potential causes, almost every researcher believes his/her findings are a critical contribution to AD. Not many, if any, papers emphasize prioritization among potential contributing factors. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

3) Assuming a particular individual's exposure to a given AD contributing factor is known and harmful, and its priority for elimination is known and high, then determination of the individual's motivation to eliminate the potential AD contributing factor is required. Having motivation to eliminate AD contributing factors to which one is effectively "addicted" may be the most difficult step in the above process.

A parallel issue is understanding what is meant in practice by "elimination". What is the speed, breadth, and depth with which a potential contributing factor has to be removed for it to be considered "eliminated", in order to halt/reverse the progression of AD or any disease? For example, does a poor diet have to be improved by 50% to be effective in disease reversal? 90%? In the multiple sclerosis reversal study summarized in Chapter 9, sub-section D of [2], Dr. Terri Wahls was shown to have reversed her MS. Dr. Wahls' symptom removal and especially damage reversal were not effective until her diet achieved near-"pristine" status. There is no reason to believe that:

1) similar dietary improvement would not be required to reverse AD (for those cases where the damage may not yet be irreversible or genetic predisposition is not overly dominant), or

2) similar improvement in other types of AD cause removal would not be required to reverse AD.

The degree of AD cause removal required for reversal (with or without the requirement for additional AD treatments) would probably be different among patients. The major roadblock would be individual choice. It would require high discipline and compliance on the part of the patient. For those patients who are willing to do whatever it takes to reverse AD (like Dr. Wahls' motivations to reverse multiple sclerosis), and who have no intrinsic limitations based on strong genetic predisposition or irreversible damage, the findings in this monograph offer a starting point for an effective protocol.

References - Chapter 8

Chapter 9

METHODOLOGY FROM APRIL 2017 MONOGRAPH

9A. Methodology for Identifying AD Foundational Causes

(adapted from reference [1])

9A1. Overview

This study focuses on identifying direct (and some indirect) AD foundational causes. It extrapolates and extends the identification techniques used in the chronic kidney disease (CKD) study [2] and in the eBook on identifying foundational causes for "all" diseases [3]. In the CKD study, approximately 900 direct and indirect potential foundational causes of CKD were identified (as well as direct and indirect treatments), and in the eBook, approximately 800 potential pervasive foundational causes of disease were identified ('pervasive' meant that the foundational cause listed contributed to some threshold number of different diseases).

The present study had two main components, with a different approach and different search engine for each component. The earlier component involved

1) using a novel targeted query to retrieve records with high probability of containing AD foundational causes, and then

2) performing a visual inspection (reading) of the retrieved records.

The later component involved retrieving all the records in the AD core literature, then using advanced text mining techniques to extract phrases from text fields (and MeSH terms from the MeSH field) that had high probability of being foundational causes.

9A2. Database/Search Engine Selection

The first step in designing and developing a specific query for retrieving records is identifying the databases(s) and search engine(s) that will be used in the retrieval process, since the query format has to be tailored to the database and search engine characteristics. Medline was selected as the database to be used, since it is the main repository of records from the premier biomedical journals. The Thomson- Reuters version of the Medline search engine was used for the initial visual inspection component of the AD study, since the Thomson search engine had the proximity search capability compatible with query terms. The Pubmed version of the Medline search engine was used for the later "streamlined" component of the AD study, since the phrase extraction approach did not require proximity searching.

9A3. Visual Inspection Component

To define candidate query terms, an AD core literature consisting of about 100,000 Medline records was downloaded and examined. The higher frequency MeSH terms associated with the AD core literature records were visually inspected, and those MeSH terms that appeared to relate to foundational causes were evaluated for relevance. Nominally, ten records that contained each candidate causes MeSH Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

term were examined, and if relevance was about 70% or beyond, the MeSH term was selected. In borderline cases, more MeSH terms were sampled until definitive conclusions could be drawn. Relevant does not mean unanimity or consensus was achieved for causes. Non-agreement with the majority could have been attributable to poor research, research with a pre-determined agenda (e.g., [3, 4]), or selection of a "window" in parameter space different from where the cause was operable. But, if cause was found operable in a few of the sampled papers for a given MeSH term, the term was deemed sufficiently important to select for the query.

These higher frequency MeSH terms were then matrixed with all MeSH terms in the retrieval. Lower frequency MeSH term candidates were identified through strong co-occurrence with the higher frequency terms, and the lower frequency terms were subsequently validated. Then, a separate database was generated consisting of all the records that included these high and low frequency selected MeSH terms. In this new database, the higher frequency abstract phrases were examined, and those that appeared to relate to potential causes were evaluated for relevance. A similar procedure to that used for causes MeSH term selection was followed. The higher frequency abstract phrases, and some generic abstract phrases related to causes (e.g., expos*, induc*, etc), were matrixed with all abstract phrases to identify lower frequency phrase candidates through strong co-occurrence.

Eventually, all the MeSH terms were read and examined, and a few low frequency terms that were missed with the co-occurrence procedure were added to the list. The same was not possible with the abstract phrases. While there were thousands of MeSH terms (readable, although visually intensive), there were millions of abstract phrases.

As stated in the Introduction, only foundational causes were evaluated in this study. There were six main types of foundational causes:

 Lifestyle,  Iatrogenic,  Biotoxic,  Occupational/Environmental,  Psychosocial/Socioeconomic, and  Genetics.

Since the purpose of this study is to identify specific causes to eliminate in order to prevent/halt/reverse AD, and since relatively little can be done at this time to alter the genetics foundational causes, the genetics causes were not included in the final queries.

The overall query structure was of the generic form [Cause][Produces][Symptom]. Two of the three would be specified in the query, directly or implicitly, and the retrieval would provide the third.

Examples from causes query:

a. Cause near Produces: steroid-induc* or diet-induc* OR antibiotic near/1 cause*. These are generic or specific members of classes of potential causes in proximity to Produces-type terms. The classes tend to be drugs, diets, chemicals, radiation sources, etc. The Produces-type terms are necessary since drugs, diets, etc can be either beneficial or harmful, depending on circumstances (e.g., a chemotherapeutic drug can be helpful for treating cancer, but may also produce cognitive decline).

b. Produces near Symptom: cause* near/5 "cognitive decline" NOT "cognitive decline cause*"

c. Cause near Symptom: *Bacterium or pentachloro* in title, with either Symptom in title or in MeSH. If abstracts are searched, stronger proximity conditions are required; e.g., *Bacterium near/5 Symptom. Unlike case a) above, in this case the causes are specific members of classes of potential causes that usually don't have beneficial effects, and therefore don't require proximity to causes-like terms; the causative nature is implied by the substance.

Note on the above. The model used was [cause-produce-symptom], but a somewhat broader form could be: [cause-produce-adverse effects], of which Symptom is one way of describing an adverse effect. Thus, "toxic*" or "adverse effect*", or "harm*" in the title by itself, along with the Symptom in the title or MeSH tends to be accompanied by the cause and the effect it has.

Additionally, many research articles addressing causes use the language [cause- activates/inhibits/blocks-signaling pathway(s)] (e.g., "MicroRNA-222 promotes tumorigenesis via targeting DKK2 and activating the Wnt/beta-catenin signaling pathway"). The signaling pathways were not used as part of the queries in this study, but a future more comprehensive and expanded study could include the signaling pathways in the queries; their incorporation would be straightforward. Many research papers, especially at the more fundamental biological level, may not mention diseases or symptoms, but are written in the language of effects on signaling pathways, and these papers could be accessed by the appropriately-written queries. To close the loop in this case, the link between altered signalling pathway and either AD or its surrogate endpoints/characteristics would have to be established.

The final query used is shown in Appendix 9A-1. The Thomson Medline AD core literature (from 1994-2014) consisted of 76663 records, and intersection of the query terms with this literature yielded 10,733 records. The most recent 5,000 were inspected visually, and the relevant foundational causes were extracted.

9A4. Streamlined Component

9A4a. Overview

An AD core literature consisting of 99,610 records was downloaded from Pubmed on 25 April 2015. Three streamlined sub-components were applied to this downloaded literature to extract AD foundational causes.

The first sub-component used only MeSH Qualifiers to filter downloaded records and extract potential foundational causes. The second sub-component used MeSH terms (relatively unambiguously Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

related to foundational causes) to filter downloaded records and extract potential foundational causes. The third sub-component used text terms (applied to the title and abstract fields) to filter downloaded records and extract potential foundational causes. The results of the Visual Inspection component and the Streamlined component were integrated to produce the final AD foundational causes, as shown in the taxonomy of Table 2-7C.

9A4b. MeSH-Based Approach

9A4b1. MeSH Qualifiers Approach

An offshoot of the MeSH Qualifier concept was used for identifying foundational causes. MeSH Headings have a number of Qualifiers associated with them to allow focus on items of interest. Thus, the MeSH term Cadmium/toxicity allows records to be retrieved related to the toxicity of Cadmium. These MeSH Qualifiers may be perceived as linking terms to the MeSH Headings, allowing for "surgical" extraction of MeSH Headings that meet desired criteria. Thus, if MeSH Qualifiers strongly related to foundational causes can be identified, they can be used to identify MeSH Headings that are potential foundational causes of disease. There were 83 topical MeSH Qualifiers (in Pubmed) used for indexing and cataloging in conjunction with MeSH Heading descriptors when this concept was developed. All 83 were examined in more or less detail for applicability to identifying foundational causes of disease. For the initial Visual Inspection approach query, three were selected as producing relevant results when used in isolation: chemically induced, toxicity, poisoning.

The streamlined approach was performed one year after the Visual Inspection approach, with one year's experience working with the selected MeSH Qualifiers. The MeSH Qualifiers were re-examined for the streamlined approach, and four were selected (after extensive validation) as producing highly relevant results when used in isolation: adverse effects, toxicity, pathogenicity, poisoning. A few limited combinations of the remaining MeSH Qualifiers were examined for the streamlined approach, but none were deemed to have sufficient relevance. All MeSH terms that contained at least one of these Qualifiers were extracted, and the related records examined for potential foundational causes. While this MeSH Qualifier linking approach was developed for, and applied to, potential foundational causes, it can be easily modified for identifying potential treatments, identifying potential biomarkers, identifying potential mechanisms, etc.

9A4b2. MeSH Headings Approach

MeSH Headings related relatively unambiguously to foundational causes were identified two ways. First, results from past studies were examined, especially [2, 3], and relevant MeSH Headings were extracted. Second, a few of the most unambiguous MeSH terms identified from past studies were entered into Pubmed as query terms, and all the MeSH terms in the resultant retrieval (i.e., those that co-occurred with the entry MeSH terms) were examined for relevance. The final list of relevant MeSH terms (Appendix 9A-2) was intersected with the total list of MeSH terms in the retrieved database, and the resulting records were examined for potential AD foundational causes. Again, while this focused MeSH Heading approach was developed for identifying potential foundational causes, it could (with some work) be adapted to identifying potential treatments, potential biomarkers, potential mechanisms, etc. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

9A4c. Text-Based Approach

9A4c1. Title Linking Phrases Approach

Because of MeSH terms' limitations (not all Medline records have MeSH descriptors, not all MeSH terms are included in those records that have MeSH terms, not all MeSH descriptors used have appropriate Qualifiers attached. etc), a text-based approach for identifying causes was added to the analysis. Because of the large number of phrases in a record's abstract compared to the title, and computer storage and software limitations, the bulk of the analysis was performed on the title phrases. A more limited analysis was performed on the abstract phrases, and is shown in Section 9A4c3 - Abstract Linking Phrases Approach.

There were millions of title phrases that had to be evaluated for potential causes. Only the highest frequency phrases could be inspected visually. To access the lower frequency terms, a number of linking terms were identified. The linking terms were generated through visually inspecting many records containing foundational causes in the titles, and identifying those terms that appeared frequently with the foundational causes. These linking terms include -induced, caused by, induced by, -contaminated, exposure to, exposure(s) [at end of phrase], exposed to, poisoning [at end], -exposed [at end], -related, - associated, -infected, abuse*, toxicity. The phrases that included the linking terms eventually had to be separated from the linking terms to identify the specific foundational causes. Other linking terms were virus* and generic bacterial headings, but these did not have to be separated from the phrases.

9A4c2. Title Dot Product Approach

Finally, potential foundational causes from myriad other sources (including past foundational causes studies, government-approved lists of toxic substances, MeSH-derived causes, etc) were intersected with the full list of title phrases, and added to the potential foundational causes identified in the Linking Phrases approach. While the title phrase linking terms were developed specifically for identifying causes, a similar approach could be used to develop linking terms for identifying potential treatments, potential biomarkers, or potential mechanisms. Moreover, there could be substantial benefits gained by using abstracts for phrase generation rather than titles, and even full-text rather than abstracts. While use of proximity queries with the linking terms in the title were not required, they would be required for use in abstracts or full-text. Adding proximity capability would be a minor modification to the form of the query developed below. The major issue would be switching to a database search engine that had the capability of proximity searching.

9A4c3 - Abstract Linking Phrases Approach

Given the size and breadth of abstracts relative to titles, most of the linking terms used to extract causes from the title were relatively inefficient in extracting foundational causes from the abstract. Variants of induc* and expos* were used to link to potential foundational causes in abstract records, and these extracted terms received the same treatment as those from the title.

The myriad potential foundational causes from the Visual Inspection component and the Streamlined component were combined. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

9A5 - Validation of Potential Foundational Causes

There were 9427 potential foundational causes that resulted from combination of the above sources. Each of these terms had to be validated before inclusion in the final AD potential foundational causes taxonomy. The validation process was as follows.

The Thomson-Reuters Medline search engine was the main vehicle used for validation, although in some cases Thomson-Reuters Science Citation Index Expanded (SCI) had to be used, and in a very few cases, Pubmed was used. A query consisting of two components was entered into the search engine. The first component covered the core AD literature: Alzheimer* OR dementia in title or MeSH. The second component was the potential foundational cause to be validated (e.g., smoking). The two components were intersected (e.g., (Alzheimer* OR dementia) AND smoking), and some/all of the records retrieved were read. The evidence for linkages between the potential foundational cause and Alzheimer's Disease directly or surrogate endpoints was evaluated critically. This was a difficult process, compounded by the fact that adverse effects of toxic stimuli may be under-reported/mis-reported [4].

Because of the presence of duplicate terms and concepts, not all the 9427 potential foundational cause terms had to be read with the same level of certainty. Many could be eliminated by inspection, as long as the duplication was perceived.

Appendix 9A-1 - AD Causes Query - Visual Inspection Approach

A comprehensive query was developed to retrieve records focused on AD causes, and the retrieved records were examined visually. The query is lengthy, and is presented in Appendix 9A-1 of the attached pdf file (see file SUPPLEMENTARY_FINAL.pdf).

Appendix 9A-2 - Unambiguous MeSH Terms - Streamlined Approach

The relatively unambiguous MeSH terms associated with AD causes records were identified, and collected into a query. The query is lengthy, and is presented in Appendix 9A-2 of the attached pdf file (see file SUPPLEMENTARY_FINAL.pdf).

References - Chapter 9

Chapter 10

References

10A. Overview

Section 10B contains the references for the Executive Summary and each chapter. Section 10C contains a bibliography of relevant treatment references obtained by different approaches.

10B. Executive Summary and Chapter References

10B0. Executive Summary References

[1] Bredesen DE. Reversal of cognitive decline: A novel therapeutic program. Aging. 2014;6(9):707-17.

[2] Bredesen DE, Amos EC, Canick J, Ackerley M, Raji C, Fiala M, et al. Reversal of cognitive decline in Alzheimer's disease. Aging. 2016;8(6):1250-8.

[3] Bredesen DE. The End of Alzheimer's: the First Program to Prevent and Reverse Cognitive Decline. 2017. Avery, New York, NY.

[4] Sherzai D, Sherzai A. The Alzheimer's Solution. 2017. HarperCollins, New York, NY.

[5] Kostoff RN, Zhang Y, Ma J, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's Disease. Georgia Institute of Technology. 2017. PDF. https://smartech.gatech.edu/handle/1853/56646.

[6] Kostoff RN. Pervasive Causes of Disease. Georgia Institute of Technology. 2015. PDF. http://hdl.handle.net/1853/53714

[7] Kostoff RN. Under-reporting of adverse events in the biomedical literature. JDIS. 2016;1(4):10-32. doi:10.20309/jdis.201623.

[8] Kostoff RN, Lau CGY. Modified Health Effects of Non-ionizing Electromagnetic Radiation Combined with Other Agents Reported in the Biomedical Literature. Chapter 4 in: Geddes (ed.). Microwave Effects on DNA and Proteins. Springer; 1st ed. 2017 edition (March 15, 2017). DOI 10.1007/978-3-319-50289-2_4.

[9] Chauhan P; Verma HN, Sisodia R, Kesari KK. Microwave radiation (2.45 GHz)-induced oxidative stress: Whole-body exposure effect on histopathology of Wistar rats. Electromagnetic biology and medicine. 2017; 36:1; 20-30.

[10] Kesari KK, Siddiqui MH, Meena R, Verma HN, Kumar S. Cell phone radiation exposure on brain and associated biological systems. Indian journal of experimental biology. 2013; 51:3; 187-200.

10B1. Chapter 1 References

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10B2. Chapter 2 References

[1] CLUTO. 2017. http://glarosdtcumnedu/gkhome/views/cluto, University of Minnesota

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10B3. Chapter 3 References

[1] Kostoff RN, Zhang Y, Ma J, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's Disease. Georgia Institute of Technology. 2017. PDF. https://smartech.gatech.edu/handle/1853/56646.

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10B4. Chapter 4 References

[1] Kostoff RN, Patel U. Literature-related discovery and innovation: Chronic Kidney Disease. Technological Forecasting and Social Change. 2015;91:341-351. http://dx.doi.org/10.1016/j.techfore.2014.09.013.

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10B6. Chapter 6 References

[1] Kostoff RN, Zhang Y, Ma J, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's Disease. Georgia Institute of Technology. 2017. PDF. https://smartech.gatech.edu/handle/1853/56646.

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10B7. Chapter 7 References

10B71. References not associated with Table 2-7

[1] Kostoff RN, Zhang Y, Ma J, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's Disease. Georgia Institute of Technology. 2017. PDF. https://smartech.gatech.edu/handle/1853/56646.

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[4] Laurence Anthony Concordance Software http://www.laurenceanthony.net/software.html

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10B8. Chapter 8 References

[1] Kostoff RN, Zhang Y, Ma J, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's Disease. Georgia Institute of Technology. 2017. PDF. https://smartech.gatech.edu/handle/1853/56646.

[2] Kostoff RN. Pervasive Causes of Disease. Georgia Institute of Technology. 2015. PDF. http://hdl.handle.net/1853/53714

[3] Kostoff RN. Under-reporting of adverse events in the biomedical literature. JDIS. 2016;1(4):10-32. doi:10.20309/jdis.201623

[4] Bredesen DE. Reversal of cognitive decline: A novel therapeutic program. Aging. 2014;6(9):707-17.

[5] Bredesen DE. The End of Alzheimer's: the First Program to Prevent and Reverse Cognitive Decline. 2017. Avery, New York, NY.

[6] Sherzai D, Sherzai A. The Alzheimer's Solution. 2017. HarperCollins, New York, NY.

10B9. Chapter 9 References

[1] Kostoff RN, Zhang Y, Ma J, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's Disease. Georgia Institute of Technology. 2017. PDF. https://smartech.gatech.edu/handle/1853/56646.

[2] Kostoff RN, Patel U. Literature-related discovery and innovation: chronic kidney disease. Technol Forecast Soc Chang. 2015; 91:341–351. Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al

[3] Kostoff RN. Pervasive Causes of Disease. Georgia Institute of Technology. 2015. PDF. http://hdl.handle.net/1853/53714

[4] Kostoff RN. Under-reporting of adverse events in the biomedical literature. JDIS. 2016;1(4):10-32. doi:10.20309/jdis.201623Appendices - Chapter 9

10C. AD Treatment Bibliography

10C1. Example references for each existing AD treatment

When validating candidate existing AD treatments, many records were examined. Some candidate AD treatments had hundreds of associated records. For most treatments that were finally validated, one record was selected as evidence, but sometimes two records were selected. A total of 666 records were selected, and are listed in Appendix 10C1-a of the attached pdf file (see file SUPPLEMENTARY_FINAL.pdf).

10C2. Additional AD treatment articles based on references in AD treatment review papers

Another source of AD treatment documents was the references in comprehensive AD treatment review papers. As part of the AD Background section in the present monograph, many large-scale AD treatment reviews were examined. Those references that described AD treatments were selected, and are listed in Appendix 10C2-a of the attached pdf file (see file SUPPLEMENTARY_FINAL.pdf).

10C3. Additional AD treatment references based on linking terms in title

A third source of AD treatment documents was records whose titles contained the linking terms described previously. The precision of this approach was very high. The retrieval using this approach was enormous, and only documents published in the last five years were selected. They are listed in Appendix 10C3-a of the attached pdf file (see file SUPPLEMENTARY_FINAL.pdf).

ACKNOWLEDGEMENTS

Mr. Fred Rascoe provided valuable assistance in the publication process for SMARTech.

ABOUT THE AUTHORS

Ronald Neil Kostoff received a Ph. D. in Aerospace and Mechanical Sciences from Princeton University in 1967. He has worked for Bell Laboratories, Department of Energy, Office of Naval Research, and MITRE Corp. He has published over 200 peer-reviewed articles, served as Guest Editor of four journal Special Issues since 1994, obtained two text mining system patents, and presently is a Research Affiliate at Georgia Institute of Technology.

He has published on numerous medical topics in the peer-reviewed literature, including:  potential treatments for Multiple Sclerosis, Parkinson's Disease, Raynaud's Phenomenon, Cataracts, SARS, Vitreous Restoration, and Chronic Kidney Disease;  potential causes of Chronic Kidney Disease;  potential causes of Alzheimer's Disease; and  potential impacts of Electromagnetic Fields on health.

He is listed in:  Who's Who in America, 60th Edition (2006),  Who's Who in Science and Engineering, 9th Edition (2006), and  2000 Outstanding Intellectuals of the 21st Century, 4th Edition, (2006).

Alan Porter received a BS in Chemical Engineering from Caltech and a PhD in Psychology from UCLA. He is Professor Emeritus of Industrial & Systems Engineering, and of Public Policy, at Georgia Tech, where he is Co-director of the Program in Science, Technology & Innovation Policy (STIP). He is also Director of R&D for Search Technology, Inc., Norcross, GA. He is author or co-author of some 230 articles and books, including Tech Mining (Wiley, 2005). Publications are available at: http://www.researchgate.net/profile/Alan_Porter4.

Research contributions include: * Bibliometric analyses, including metrics for interdisciplinarity (integration and diffusion scores) * Research assessments of various NSF programs * Tracking nanotechnology developments, including Nano-Enabled Drug Delivery (NEDD)

Henry Augustus Buchtel received a Ph.D. in Physiological Psychology from McGill University in 1969. He received postdoctoral training in Neurophysiology Institutes in Italy (Pisa and Parma) and at the National Hospital for Nervous Diseases, Queen Square, London UK. He has held joint appointments at the University of Michigan in the Department of Psychiatry and at the Veterans Administration Medical Center since 1980, and has been Chief of the Neuropsychology Section since 2008.

He has published on various neuropsychological topics in peer-reviewed journals, including: 1) Effects of seizure disorders and their treatments in patients with intractable epilepsy 2) Cognitive abilities in patients receiving radiation treatment for brain tumors 3) Technical aspects of the intracarotid amobarbital test and analogues

He is on the editorial board of the neuropsychology journal Cortex (since 1983) and Journal of Clinical and Experimental Neuropsychology (since 2009), and is a Fellow of the American Psychological Association and the Association of Psychological Science.