ALZHEIMER’S

Introduction

Alzheimer’s disease is a chronic, progressive neurological disorder that causes profound cognitive and behavioral impairments. Alzheimer’s disease is the most common cause of in older adults, afflicting approximately 5.5 million Americans. Genetic, , and environmental risk factors for the development of the disease have been identified but the cause of Alzheimer’s is not known. The available treatments cannot modify the course of the disease or provide a cure, they can only provide symptomatic relief, and the prognosis for someone who has Alzheimer’s disease is grim; the average lifespan after diagnosis is 8-10 years. The cost of caring for patients who have Alzheimer’s is very high and as the number of people who develop Alzheimer’s increases in the next few decades the monetary strain upon society will be significant.

Epidemiology

As with any disease, the incidence and prevalence statistics of Alzheimer’s disease are always retrospective, but available evidence clearly shows that it is a very common, serious, and growing public health problem. The Centers for Disease Control and Prevention (CDC) estimated that in 2017, 5.5 million Americans had Alzheimer’s disease.1 Alzheimer’s disease is the 5th leading cause of death in the United States in adults 65 years of age and older,1 and it is the most common cause of dementia, accounting for approximately 60%-80% of all cases.2

Alzheimer’s disease primarily afflicts older people. Most cases of Alzheimer’s disease are diagnosed in people who are 60 years or older, and the

1 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com prevalence of the disease increases with each decade of life, growing to 20%-40% of the population by age 85.3 Female gender, even given the greater longevity of women, is a risk factor for the development and progression of Alzheimer’s disease,3-5 and Alzheimer’s disease and Alzheimer’s related dementia are more common in the African American population.6,7

Etiology and Pathophysiology

Exposure to environmental contaminants, specific lifestyle factors coupled with chronic medical conditions, and genetics are considered to be the three categories of risk factors that contribute to the development of Alzheimer’s disease. How and in whom they come together to cause the disease and their relative importance are not known. Age is considered to be the biggest risk factor for Alzheimer’s disease.

Environmental Contaminants

Exposure to environmental contaminants such as air pollution, industrial chemicals, metals, and pesticides has been associated with an increased risk for the development of Alzheimer’s disease,8 and many of these are well- known neurotoxins. However, there is no definitive evidence of a cause and effect relationship between exposure to an environmental contaminant and development of Alzheimer’s disease.8

Lifestyle and Medical Conditions

Diabetes, hypertension, obesity, sedentary lifestyle, smoking, and many other and lifestyle factors have been identified as possible risk factors for, and/or have been associated with the development of

2 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Alzheimer’s disease.9-16 Traumatic injury (TBI) is strongly associated with Alzheimer’s disease.17

Genetics

Alzheimer’s disease has a strong genetic component, it is considered to be very heritable.18 In the development of Alzheimer’s disease there are genetic causes and genetic risk factors. The number of Alzheimer’s cases that have a clear genetic cause, with little to no environmental influence, is a very small number of the total. Most but not all of these cases are early onset familial Alzheimer’s disease.

A family history of Alzheimer’s disease is a significant risk factor for developing the disease. An individual who has a first-degree relative (i.e., sibling or parent) with Alzheimer’s disease has a 10%-30% greater risk for developing the disease,19 and someone who has two or more siblings that have Alzheimer’s disease, that person has a three-fold risk of developing Alzheimer’s compared to the general population.19

Late-onset Alzheimer’s is the most common form of the disease. Although genetic risk factors for late-onset Alzheimer’s have been identified, how they increase risk is not understood.19 Genetic risk factors are not present in all patients who have Alzheimer’s.

Alzheimer’s disease causes three distinct pathophysiological changes in the brain: 1) the formation of amyloid deposits, 2) neurofibrillary tangles, and 3) neuritic plaques.19 These pathological changes cause permanent damage to and synapses. The amyloid plaques are essentially comprised of clumps of amyloid-β peptides, protein constituents which are produced by

3 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com abnormal processing of amyloid precursor protein (APP); APP is part of the cell membrane of neurons, but its exact function is not known.

The amyloid plaques and the neuritic plaques damage neuronal synapses, interfere with normal synaptic transmission, and may cause or contribute to inflammation and oxidative damage in the brain. The neurofibrillary tangles are intracellular support structures in the neurons called microtubules that have had a breakdown in a specific protein called tau. The tau protein is essential for maintaining the integrity of the microtubules - and thus the structural soundness of neurons - and when tau is damaged by Alzheimer’s disease the microtubules are damaged, and the cannot function and will eventually die.19

The formation of amyloid plaques and neurofibrillary tangles is the hallmark of Alzheimer’s disease, but it is not completely clear how these pathological changes can cause the clinical characteristics and the cognitive decline associated with the disease. In addition, these lesions are found in the of people who do not have Alzheimer’s disease,19 although the areas of the brain that are affected and the total number of the pathological lesions are different.3

Clinical Features of Alzheimer’s Disease

The clinical features of Alzheimer’s disease are varied and complex. Although Alzheimer’s is a progressive disease for all patients, there can be distinct differences between patients in terms of how they progress. The changes occur slowly and incrementally but some patients may have periods - plateaus - in which they are stable. Early-onset Alzheimer’s disease takes a more rapidly progressive course. However, all patients will eventually be unable to socialize or perform self-care.

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The presentation or progression of Alzheimer’s disease is often described as having four stages:20,21 • Pre-clinical: Brain changes and biomarkers of Alzheimer’s, but no obvious sign/symptoms of the disease. • Mild: Early stage, inability to remember words, losing objects, difficulty performing relatively simple tasks • Moderate: Behavioral and personality changes, forgetting personal information, about time, place, or person. • Severe: Medical complications, need for constant care, inability to communicate clearly and coherently.

Cognitive impairments are the most prominent clinical feature in patients who have Alzheimer’s disease, but physical impairments, language, speech, and visuospatial impairments, and significant behavioral and emotional disorders are also common. These can be very disabling in the later stages of the disease and all of them, the cognitive and physical impairments, visuospatial impairments, language/speech disorders, and the behavioral and emotional disorders, profoundly affect quality of life.

Cognitive Impairments

Cognitive impairments are the most striking feature of Alzheimer’s disease. They typically follow a characteristic pattern and begin with problems, and memory disorders are one of the most prominent features of Alzheimer’s disease.3,22 The patient will forget a recent conversation. Names and dates and the location of familiar items cannot be recalled. Initially, the memory problems of Alzheimer’s disease can be relatively mild and ascribed to aging, but eventually it becomes clear to family, friends, and occasionally

5 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com the patient that this forgetfulness is serious and indicates the presence of a disease process.

The memory impairments of Alzheimer’s disease are not like the memory lapses that are associated with aging; they are progressive, interfere with the activities of daily living, and their presence can be confirmed using a standardized memory test.3,23 If the patient’s memory capabilities are below a certain point on standardized memory tests, the patient is said to have mild cognitive impairment, a precursor to Alzheimer’s disease. The term mild cognitive impairment may seem to some as imprecise and vague, but there is a diagnostic procedure that is used to define and detect mild cognitive impairment, and this pathology has important prognostic significance. Mild cognitive impairment is considered to represent an early stage in the progression from normal mental status to Alzheimer’s disease,23 and approximately 50% of patients who have mild cognitive impairment will develop Alzheimer’s disease within four years.3

Difficulties with what are often called higher intellectual functions are also common.3 The patient with Alzheimer’s cannot reason, or at least reason effectively. Further, the patient has difficulty concentrating, abstract thinking and the ability to plan and organize are seriously diminished, and simple tasks that require judgement - or any of the other skills that were mentioned - cannot be performed. The physical impairments of Alzheimer’s disease are usually the most pronounced in the later stages. Patients can be incontinent of feces and urine. They are often immobile, and the complications of immobility such as pneumonia, aspiration, , or complications of pressure ulcers are the usual causes of death from Alzheimer’s disease.22,24

6 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Language difficulties are quite common in the early stages of Alzheimer’s disease.25,26 Patients have difficulty finding the right word to say, their speech content is rambling, and they may have a condition called paraphasia in which unintended sounds, syllables, and words are spoken. , a communication disorder, develops in the Alzheimer’s patients. In the later stages of the disease patients can develop expressive aphasia, global aphasia, and receptive aphasia. Visuospatial abilities - roughly defined as perceiving spatial relations between objects - deteriorate as the disease progresses, presenting another challenge for this patient population.18 Ordinary day-to-day, self-care activities such as dressing, driving, using eating utensils, reading, locating something in the environment, navigating distances or finding one’s way from one place to another are affected. A patient may lose the ability to distinguish colors. Almost anything that requires coordination of the visual field with motor activities can be difficult or impossible to perform.3

The behavioral and emotional disturbances and personality changes that are associated with Alzheimer’s disease can be devastating for the patient and for family members. They also present significant management challenges because they are intimately and inextricably linked to cognitive, physical, language impairments of the disease that are organic in nature and cannot be changed. They are often resistant to treatment, and they are numerous and complex. Behavioral and emotional disturbances that are common to Alzheimer’s disease include agitation, confusion, delusions, , mood dysregulation, physical and verbal , , sleep disturbances, social withdrawal and .22

The diagnosis of Alzheimer’s disease is made by taking a careful history, a physical exam, targeted laboratory tests and imaging studies, and

7 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com neuropsychiatric testing. Much of the diagnostic procedure is used to rule out the presence of other illnesses because Alzheimer’s disease is a clinical diagnosis; it cannot be confirmed by laboratory testing or imaging. Signs, Symptoms and the Stages of Alzheimer’s15

PRECLINICAL Development of the amyloid plaques and neurofibrillary tangles. The patient has no signs or symptoms of Alzheimer’s disease.

MILD ALZHEIMER’S DISEASE Confusion Delays in accomplishing simple tasks Difficulty with simple tasks, i.e., handling money, following directions Memory loss Mood changes Poor judgment MODERATE ALZHEIMER’S DISEASE Aggressive behavior Coping problems Delusions, Difficulty with thinking logically Difficulty recognizing family and friends Impulsive behavior Inability to learn new tasks Increasing confusion and memory loss Increased Paranoid behavior and thinking Problems with reading, speaking and writing Problems recognizing friends and family members Shortened attention span Wandering

SEVERE ALZHEIMER’S DISEASE Inability to communicate Inability to perform self-care

The initial presentation of many patients who have Alzheimer’s disease can feature many of the that were previously discussed. But approximately 20%-40% of all patients who have Alzheimer’s disease have an atypical presentation,3 and Alzheimer’s disease can be misdiagnosed as depression, , or many other medical or psychiatric disorders. Alzheimer’s disease then is a progressive disorder and as patients move

8 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com through the pre-clinical, mild, moderate, and severe stages the various impairments associated with the disease gradually worsen. Activities of daily living become increasingly difficult and eventually, impossible. The patient cannot work, cannot socialize appropriately, cannot provide self-care, and the patient’s behavioral and emotional problems become unmanageable.

Eventually physical impairments become so significant that the patient requires constant care. Patients typically succumb to immobility-related illnesses such as aspiration, infections, or pneumonia, usually within 5-10 years from the time of diagnosis.27 It was mentioned previously that Alzheimer’s disease is the most common cause of dementia. Dementia is a commonly used and often misunderstood term and should be explained here. Dementia is a syndrome, not a disease itself, and Alzheimer’s disease and dementia are not synonymous.

There are many causes of dementia, and the signs of dementia are an important part of the clinical picture of Alzheimer’s disease. Larson (2018) writes that dementia “... characterized by a decline in involving one or more cognitive domains ... severe enough to interfere with daily function and independence.”28 Seeley and Miller (2015) write that dementia “... is an acquired deterioration in cognitive abilities that impairs the successful performance of activities of daily living.”3 These definitions emphasize key points about dementia and Alzheimer’s disease.

First, an important distinguishing aspect of dementia is an inability to successfully perform the activities of daily living, caused by impaired cognitive and intellectual capacity. Second, dementia is a syndrome because there is a multitude of etiologies of dementia.

9 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM- 5) criteria for dementia are listed below.29

1. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains: • Complex attention • Executive function • Language • Learning and memory • Perceptual-motor ability • Social cognition 2. The cognitive effects interfere with independence in everyday activities. At a minimum, assistance should be required with complex activities of daily living such as managing or paying bills. 3. The cognitive effects do not occur extensively in the context of . 4. The cognitive deficits are not better explained by another (i.e., major depressive disorder, ).

Early Onset Alzheimer’s Disease

Most cases of Alzheimer’s disease happen to the elderly, but early-onset Alzheimer’s disease accounts for approximately 5.0% - 10% of all cases of the disease.30 Early-onset Alzheimer’s disease is typically described as evidence of the disease in people who are under the age of 65, but there is no universally accepted definition for an age cut-off point.31 Approximately one-half of all cases of early-onset Alzheimer’s disease can be considered as inherited.32 However, although the genetics of this form of the disease is well understood, it is a dominantly inherited disease but not a fully penetrant disease.33

10 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com As mentioned above, the early-onset form of Alzheimer’s disease has a more rapidly progressive course, and it appears to affect different areas of the brain than late-onset Alzheimer’s disease.29 The risk factors and the pathophysiological mechanisms may be distinct in the two forms, as well, and patients who have the early-onset form have been found to have a greater number of amyloid plaques and neurofibrillary tangles.33 Despite these differences, and the general observation that the clinical characteristics of early-onset and late-onset are separate, Palasí, et al., (2015) noted that when early-onset and late-onset Alzheimer’s disease are closely examined “... there is no current consensus about which cognitive domains are more impaired in each group.”34

Diagnosis of Alzheimer’s Disease

The diagnosis of Alzheimer’s disease, as previously mentioned, is a clinical diagnosis, based on a physical examination, taking a careful health history, targeted laboratory tests and imaging studies, and neuropsychiatric testing. Because Alzheimer’s disease is a clinical diagnosis there can be some disagreement about what diagnostic criteria are applicable. The diagnostic criteria for Alzheimer’s dementia are listed as:22 • Interference with ability to function at work or at usual activities. • Decline from a previous level of functioning and performing. • Changes are not attributable to delirium or a major psychiatric disorder. • The patient has cognitive impairment, and its presence is established by an examination of the patient, information from a knowledgeable informant, and objective bedside mental status examination or neuropsychological testing. • Cognitive impairment is present if the patient has a minimum of two of the following domains: ability to acquire and remember new information, reasoning and handing of complex tasks, poor judgment, visuospatial

11 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com abilities, language functions, changes in personality, and behavior or comportment. There must be impairment in these abilities for the diagnosis to be made. • The onset of changes is insidious. • There is a clear and obvious history of decline. • Initial and most prominent cognitive deficits are amnestic presentation, i.e., impaired learning, poor recall of recently learned information, and non-amnestic presentations such as a language deficit, a visuospatial deficit, or a dysexecutive presentation, i.e., impaired reasoning, judgment, or problem solving. • No evidence of substantial concomitant , dementia with Lewy bodies (DLB), behavioral variant , semantic or non-fluent/agrammatic variants of primary progressive aphasia, or evidence of a neurologic or non-neurologic disease or use of that could affect cognition.

Treatment of Alzheimer’s Disease

Alzheimer’s disease cannot be cured, it can only be managed and doing so is an enormous challenge. If the patient has no significant comorbidities, the patient will be relatively healthy in the physical sense and will be ambulatory until late in the progression of the disease. But for both patient and the patient’s caretakers, the cognitive deficits and the behavioral and emotional issues associated with Alzheimer’s disease - which in many instances are inextricably linked - can create enormously frustrating situations.

It is impossible to improve a patient’s memory, executive function, and language difficulties. Cognitive deficits cannot be reversed and the patient’s condition always declines, and behavioral and emotional problems will always occur. But with skillful application of environmental and psychosocial

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Drug

Drug therapy for the treatment of Alzheimer’s disease is intended to: 1) provide symptomatic relief from the physical and psychological complications, and 2) slow the progression of the disease and/or alter the pathophysiologic mechanisms of Alzheimer’s disease.

Drug therapy for the treatment of Alzheimer’s disease is not discussed in great detail here, however clinicians should know that while medications can be helpful for providing symptomatic relief, slowing the progression of the disease, and addressing the pathophysiological mechanisms of the disease, drug therapy is considered to be second-line treatment; the preferred approach is environmental and psychosocial interventions.27 The generic names of drugs are listed first and trade names are in parentheses in the following sections.

Symptomatic Treatment

A wide variety of medications have been used to provide patients with symptomatic relief from the emotional, physical, and psychological complications associated with Alzheimer’s disease including, but not limited to antidepressant, antiepileptic, first- and second-generation antipsychotic, antiparkinsonian, anxiolytic, beta-blocker, calcium channel blocker, hypnotic or soporific, and tricyclic antidepressants drugs.35-39 While these drugs can and do provide some benefit, the evidence for their effectiveness in treating agitation, depression, psychosis, sleep disturbances, and other symptoms in patients who have Alzheimer’s disease is modest or lacking.35,36,38,39

13 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Although all drugs have a risk-benefit ratio, for some of the aforementioned medications such as the antipsychotic and the drugs, the risks can be significant, and they appear to greatly outweigh the benefits for this patient population.40

Disease Progression Slowing or Pathophysiology Alteration

The two types of drugs that are used for this purpose are memantine (Namenda) and the acetylcholinesterase inhibitors donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon). Tacrine [Cognex] is a cholinesterase inhibitor that was the first drug of this class that was used to treat Alzheimer’s disease. It is no longer available as its use caused severe gastrointestinal side effects and hepatotoxicity. , diarrhea, and nausea are common adverse effects of donepezil, and nausea and vomiting are common adverse effects of galantamine. Agitation, , , falling, abdominal , anorexia, diarrhea, nausea, vomiting, weight loss, and tremor are common adverse effects of rivastigmine.

Memantine is classified as an N-methyl-D-aspartate (NMDA) receptor antagonist.41This drug is a competitive antagonist of the NMDA type of .

Glutamate is the primary excitatory neurotransmitter. It is thought that Alzheimer’s disease causes excessive stimulation of NMDA receptors, and this continued and excessive stimulation may be a cause of both cognitive impairments associated with Alzheimer’s disease and neuronal damage.36 Memantine has been reported to be effective at improving cognition and a patient’s ability to perform activities of daily living, and decreasing the level of agitation in patients with mild to moderate Alzheimer’s disease.36,42-44

14 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Commonly seen side effects of memantine include confusion, constipation, dizziness, and headache.41 Memantine is usually dosed once a day and it is available as an oral solution, regular-release, and extended-release tablets. It is also available as a combination product with donepezil and this combination of memantine and donepezil (Namzaric) has been shown to be helpful.36

The acetycholinesterase inhibitors function by reversibly inhibiting acetylcholinesterase, the enzyme that is responsible for enzymatic degradation of the neurotransmitter acetylcholine. Alzheimer’s disease damages cholinergic neurons thus decreasing the production of acetylcholine, and this process is thought to be in part responsible for some of the clinical signs of Alzheimer’s disease. The acetylcholinesterase inhibitors have been reported to provide a mild to moderate level of improvement in cognition and global functioning.45,46

There is no evidence that one of these drugs is superior to the other. 45 Commonly seen side effects of therapy with the acetylcholinesterase inhibitors include diarrhea, nausea, and vomiting.47 These drugs are usually dosed once a day and are available as regular release tablets, transdermal patches, or disintegrating tablets.

Many other medications and supplements have been used to try and alter the course of Alzheimer’s disease. Oxidative and inflammation are part of the pathological process of Alzheimer’s disease. There is evidence that antioxidants such as can slow the decline of the functional abilities of patients who have mild to moderate Alzheimer’s disease,36 but non-steroidal anti-inflammatories have not been shown to have any significant benefit for these patients.48

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Agitation, aggressive behavior, and psychosis are very common in patients who have Alzheimer’s disease. Atypical and conventional antipsychotics would seem to be the most intuitive choice in these situations, and these drugs are often used to treat these behaviors in patients who have Alzheimer’s disease.49 However, the antipsychotics - both atypical and conventional - can have significant side effects, i.e., extrapyramidal effects, arrhythmias, , sedation, and an increased risk for mortality in elderly patients (possibly); the evidence for the effectiveness of these drugs in this clinical situation is modest, at best, and they may be especially dangerous for elderly patients who have Alzheimer’s disease.50,51

Environmental and Psychosocial Interventions

It is recommended that behavioral and environmental approaches should be used to treat neuropsychiatric behavior problems and emotional issues in patients who have Alzheimer’s disease.27 The commonly used psychotropic medications like the antipsychotics do not have Food and Drug Administration (FDA) approval for this purpose, and psychotropic medications should only be used for treating neuropsychiatric behavior problems and emotional issues in patients who have Alzheimer’s disease if 1) non-pharmacologic interventions have failed, 2) the patient has major depression with or without suicidal ideation, 3) the patient has a psychosis that is causing great harm or has the potential to do so, and 4) the patient is very aggressive and may cause harm to self or to others.52

It is often assumed that the neuropsychiatric behavior problems and the emotional issues that are so distressing and difficult are simply inevitable for patients who have Alzheimer’s disease. The precipitating cause of agitation, aggression, inappropriate actions and speech, and other behaviors such as

16 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com wandering, is almost always due to internal and/or external stimuli that are not obvious to family members, caregivers, and healthcare clinicians.52,53

The patient who has Alzheimer’s disease has cognitive deficits that affect the patient’s ability to cope, communicate, understand the environment, and to provide self-care. Someone with these cognitive deficits and language impairments cannot organize an appropriate response to express their needs or frustrations. These issues combine to place the patient in a tremendous amount of stress, and the patient reacts. The behavior and the language of the Alzheimer’s patient may be difficult and inappropriate, but the patient is usually reacting to an identifiable stressor. Considering neuropsychiatric behavior problems and emotional outbursts as normal for a patient who has Alzheimer’s dementia is in one sense treating the patient as less than whole.

Treatment and management of neuropsychiatric behavior problems and emotional problems in patients who have Alzheimer’s disease is an important part of their care. However, ensuring and attending to the patient’s comfort and safety is equally as important. It can be easy to focus on the aspects of care for the Alzheimer’s patient that is the most dramatic, for example, managing psychotic behavior; but basic patient needs should not be neglected and doing so is likely to greatly attenuate the issues that are the most challenging.

The DICE Method

The optimal approach to neuropsychiatric behavior problems and emotional difficulties can be summarized very simply - make every effort to understand the situation from the patient’s point of view. Kales, et al, (2014) noted that the ideal approach is “… to conceptualize behaviors as stemming from unmet needs, environmental overload, and interactions of individual, caregiver, and

17 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com environmental factors.”52 A useful approach that has been developed is called the DICE approach: Describe, Investigate, Create, and Evaluate.52

The DICE approach is a systematic way of identifying and treating neuropsychiatric behavior problems. It begins with and operates under the assumption that such difficult management issues with Alzheimer’s patients are caused by a stressor that can be identified and corrected, and that these issues can be solved with creativity and patience. The steps in the DICE method are explained below. Also, in the example below, a patient exhibiting agitation is raised but the DICE approach can be used for any problem that may arise between an Alzheimer’s patient and a caregiver. In addition, the DICE approach can be used while an event is happening or retrospectively.

Describe

The staff, family member, or the caretaker reports that the patient has become agitated and aggressive and this behavior is new. In the first step of the DICE approach the clinician, caretaker, or family member should clearly describe the situation; simply reporting that the patient has become agitated and aggressive is not helpful without context. This step requires an organized approach to work best. Clinicians should focus on who, when, what, and where, for example:

• Who is there when the patient is agitated? The same person and only that person or can it be anyone? • When does this behavior happen? Is it only at a specific time of the day, does it happen throughout the day, is it periodic in nature, or is it continuous? • What is happening when the behavior occurs? This is probably the most important variable. Does the behavior happen during meals, when the

18 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com patient is going to sleep, during bathing, or when a new person enters the room? Was the patient recently prescribed a new medication or does the behavior begin shortly after a dose of medication is given? Is the patient in a situation that could be described as frightening or threatening? The questions to ask can be nearly endless, but it is often obvious what the precipitating situation involves. • Where relates to whether there are environmental conditions that may be precipitating the behavior? Is there a lot of background noise, a lot of people in the area (or too few), or a lot of new activity happening?

Additionally, has the patient been asked why he/she is upset and/or behaving in a certain way? Asking someone who has Alzheimer’s disease to explain feelings and motivations may not always be successful, but it should be done. It is important to listen to the patient. Is the patient making a specific complaint? What is the patient saying when the events(s) occur?

Investigate

The investigation stage of DICE is closely linked with the description stage, but one of the areas to focus on in the investigation stage is basic needs, i.e., comfort, hunger, presence of pain, etc. In addition, it is important to remember that many people who have dementia are elderly and have chronic medical problems. Neuropsychiatric behavioral problems are often caused by emotional or but the possibility of an acute illness or exacerbation of an existing one should always be considered.

• Check the patient’s temperature, blood pressure, pulse, and respiratory rate, if needed. Has the patient’s vision or hearing changed? Could the patient have developed a new medical issue? • Is the patient incontinent of stool or urine?

19 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com • Could the patient be too cold or warm? • Could the patient be hungry or thirsty? • Is the patient’s position uncomfortable? • Does the patient have an injury? The patient may have suffered an injury but is unable to tell anyone. • Was the patient recently prescribed a new medication or does the behavior begin shortly after a dose of medication is given? Was the patient supposed to receive a dose of medication but the dose was not given? • Could the patient be in pain? • Has the patient’s daily activity schedule been changed or the patient’s sleep pattern disrupted? • Is there anything about the physical and emotional interaction between the patient caretakers, family members, or staff that may be contributing?

Create

Creating a treatment plan should be a collaborative effort between all health clinicians and, if they are involved in day-to-day care, the family members. The health clinician needs to focus on the behavior that is problematic at the time, but also on root causes and prevention. Strategies for the two can be different. The patient who is agitated may need to be in a place that is quiet and away from others, and underlying causes such as over-stimulation and pain need to be addressed. Specific problems that are easily identifiable such as a fever or incontinence can easily be treated. Finding creative solutions that address less obvious precipitating factors or ones not easily changed can be difficult.

Evaluate

20 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com In this final step, the creative solution is evaluated for its effectiveness, its negative and positive consequences, and how easy it was to apply. The interventions should also be routinely assessed to ensure they were successful and, if successful, that they are being done correctly.

Kohlman Evaluation of Living Skills

The Kohlman Evaluation of Living Skills (KELS) is a standardized assessment tool that may be used for individuals to assess their self-care, safety and health, money management, transportation and telephone, and work and leisure. It is a helpful scoring tool that is often used by occupational health team members for patients diagnosed with Alzheimer’s disease to measure level of functioning for activity of daily living (ADL) and independent living skills, and to identify treatment options. A final KELS score of one (1) suggests an inability to complete tasks successfully.56

Often, a full neuropsychological evaluation is not practical or needed related to the types of ADL impairment that exists. A person with a dementia diagnosis and already observed to have impaired ADLs generally will not require further cognitive testing. The use of the KELS to evaluate ADL function, along with observations and collateral data from family and caregivers is usually sufficient. An occupational therapist referral may focus on a patient’s ADL impairment through use of the KELS and explore further treatment options to regain activity skills.

Prevention of Alzheimer’s Disease

Alzheimer’s disease is devastating and there is no cure, so prevention of the disease is an area of intensely focused research. Han, et al, (2014) noted that disease prevention can be primary, secondary, or tertiary.54 Primary prevention of Alzheimer’s disease focuses on modifiable risk factors and

21 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com targeting the pathophysiological processes of the disease. Secondary prevention focuses on early detection of the disease before clinical signs and symptoms begin, and tertiary prevention focuses on changing the course of the disease to make it easier to live with and prevent complications.

Pharmacological approaches to tertiary prevention have been unsuccessful, early detection is still unreliable, and targeting the pathophysiological processes of the disease have not worked. The most promising approach to date is focusing on modifiable risk factors such as cardiovascular disease, diabetes, diet, hypertension, metabolic syndrome, physical activity, psychosocial issues such as depression and isolation, and smoking. Changing behaviors in relation to these risk factors has health benefits. However, the evidence for the effectiveness of this approach in preventing Alzheimer’s disease, i.e., increasing physical activity directly decreasing the risk of developing Alzheimer’s disease, is far from unequivocal.45-48 The literature often describes an association between change in a specific behavior and change in the risk for Alzheimer’s disease, but as Sindi, et al, (2015) noted, when the evidence for preventive interventions is examined, it is considered inadequate.55

Case Study of Alzheimer’s Disease

Gerald is a 68-year old male who was brought to the emergency department by his wife who reported that he was acting delusional and accusing her of having an affair. She reported being afraid of Gerald because he was becoming irrationally enraged with her, despite the fact she had become his daily caregiver over the past several years in the early period of being diagnosed with Alzheimer’s disease. He also carried diagnoses of hypothyroidism, type 2 diabetes, gastroesophageal reflux disease (GERD), and hypertension. A year prior, Gerald had been hospitalized for chest pain,

22 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com and it was discovered he had single vessel disease of the right main coronary artery and a cardiac stent was placed. There had been no acute concerns until last month when he complained of urinary urgency and diagnosed with a urinary tract (UTI) that cleared with a course of antibiotic therapy.

The family history was reviewed with Gerald’s wife who reported that his father’s health history was essentially unknown as he had left the family before Gerald was born, and his mother was deceased; however, she had spent the latter years of her life in a skilled nursing facility after a “stroke and quickly deteriorated mentally afterward”. Siblings were many (eight total), all older than Gerald, and most were deceased for various chronic medical conditions like cardiac disease and kidney failure that had been diagnosed while elderly; one brother lived to be 90 years old with a diagnosis of Parkinson’s disease and mild dementia and another brother was reported to have committed suicide at age 28.

While in the emergency department Gerald’s wife reported days when he appeared like his “old self” but that increasingly he didn’t seem like himself and was expressing suspicious thoughts and anxiety related to his wife’s everyday activities. She expressed feeling embarrassed in front of others, including their adult children and grandchildren, by his angry outbursts that she was cheating on him. While in the hospital recently for treatment of a urinary tract infection (UTI), Gerald told the attending physician that his wife was cheating on him and that he wanted a divorce. Because he was showing signs of hostility, was called to consult and Gerald was started on Zyprexa 2.5 mg PO at bedtime and Zyprexa 2.5 mg PO every 4 hours PRN, not to exceed 2 doses in 24 hours, for hostility and aggression. However, he continued to be delusional while taking the Zyprexa and his wife was

23 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com concerned about side effects with diabetes so Zyprexa was stopped while still in the hospital. His wife reported that Gerald’s UTI symptoms had cleared within 5 days or so after treatment started and that she had dispensed his antibiotic medication after discharge home until the prescription was completed after the recommended 10 days.

A review of substance use history showed that Gerald had not used alcohol most of his life, and was essentially a non-smoker after a brief period of smoking cigarettes while a young officer in the military. There was no history of illicit drug use. Social history revealed Gerald had been married once to the same person for almost 45 years, had retired from full time U.S., military service as an Air Force officer and pilot, and both Gerald and his wife had adult children and grandchildren who were all involved in their lives.

All of Gerald’s medical needs and follow up had been appropriately managed through the Veteran’s Administration (VA) in his area with most of the medical treatment of dementia was supportive, such as in-home support and care aid service, occupational therapy for daily activity skills testing and to recommend daily activities and community support services related to recent cognitive changes, and nursing care for medication management in the home. Gerald’s wife and children had made the decision early on that he would remain at home for as many in-home health services as the VA provided.

In the emergency department, Gerald received laboratory testing of a complete metabolic panel (CMP), complete blood count (CBC) with differential, fasting lipid panel (FLP), TSH and free T4, eosinophil sedimentation rate (ESR), C-reactive protein (CRP), A1c, urinalysis, vitamin D level and vitamin B12 and folate levels. All of Gerald’s laboratory testing

24 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com was found to be normal with the exception of mildly decreased hemoglobin and hematocrit levels and mildly elevated potassium and mildly elevated creatinine level that indicated renal insufficiency. His glucose level was remarkably under control on Metformin 500 mg QHS and dietary changes were managed by his wife to ensure he received no added sugars and a proper calorie count appropriate for someone who had type 2 diabetes. Additionally, an electrocardiogram (ECG) showed a sinus rhythm with rate 72 although the medical history showed episodic atrial fibrillation and he was placed on aspirin 325 mg PO daily, which his wife was giving him every other day with food because of a history of several gastrointestinal (GI) bleeds and hospitalization with endoscopy and and endoscopic surgical clipping to stop the bleedings. Blood pressure and heart disease were managed with lifestyle changes and aspirin, as a brief trial of metoprolol 25 mg PO daily was not tolerated and his heart rate dropped too low with resulting dizziness. Overall, Gerald had been managed on very low amounts of medication for comorbid medical conditions and had not been treated until now for psychiatric issues related to Alzheimer’s dementia.

Gerald’s wife expressed being afraid of his anger and delusional thoughts, and also reported to the emergency team that she felt unable to take him home and that he needed to be evaluated for safety and possible medication management. His psychiatric symptoms were evaluated to be labile mood, anxiety, depression, episodic insomnia, oriented to person, place and situation, but confused about the date, cognitive changes, including needing assistance with activity of daily living (such as meal preparation, taking prescribed medication, home glucose checks, he required a guardian for all of his financial and other domestic needs), delusional thoughts, and recent hostility and aggression. His wife reported that if she didn’t remind him to get up in the morning and dress that he would stay in bed and lose track of

25 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com time or of any reasonable routine. However, once prompted and dressed in the morning, he generally had been pleasant, agreeable, and happy to accompany his wife on drives around town, and he socialized appropriately with others. Gerald’s wife stated that he was well loved and respected by friends and neighbors, which made it harder for her to accept his recent ramblings and anger.

Gerald was admitted to a hospital stabilization unit until a geropsychiatric consult was available. A review of prior testing included a brain CT to rule out tumor 3-years prior when behavior changes were reported by his wife. His medical record also showed a Kohlman Evaluation of Living Skills (KELS) had been done 14 months prior and the results indicated significant deficits: 1) Self-care – required prompting with hygiene and dressing but once shown what to do was able to follow through independently 2) Safety and health – was fully dependent on following safety standards in the home, such as how to manage cooking at the stove, unsafe to drive a car, and needed full support to take prescribed medication 3) Money management – guardian was assigned for money management (Gerald’s wife) 4) Transportation and telephone – no current driver’s license and had trouble dialing or using the phone for communication; wife was responsible for any emergency calls at the home 5) Work and leisure – disabled and reliance upon family for planning leisure events; an occupational therapist on the treatment team was needed to support progress with memory care and other activity planning, including

The final KELS score was [1], which indicated that he needed assistance and was unable to complete tasks successfully, including work and leisure.

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The treatment team at the hospital included a medical clinician, geriatric clinical nurse specialist, and social worker who reviewed Gerald’s progress and family support and decided that he would benefit from a brief hospital admission to evaluate symptoms and to review his current interdisciplinary treatment outcomes. In the hospital, his delusions about his wife increased to the level she could not visit for a few days, and his children took turns visiting for emotional support. The psychiatry team decided to begin a trial of sertraline, starting at 25 mg PO daily, for anxiety and depression. After a week he was reassessed as showing improvement in anxiety and mood, smiling more and talking calmly with others, and outbursts and fixations about his wife were less. Gerald’s wife was gradually able to enjoy hospital visits with him in the geropsych unit on a daily basis, and a plan for discharge included follow-up on an outpatient basis and for review of progress.

Discussion

As mentioned in earlier sections, the behavioral and emotional disturbances common to Alzheimer’s disease include agitation, confusion, delusions, depression, mood dysregulation, physical and verbal aggression, psychosis, sleep disturbances, social withdrawal, and wandering. Gerald’s diagnosis of Alzheimer’s disease had been made through a careful history, physical exam, and targeted laboratory tests. No current imaging studies or neuropsychiatric testing had been done, most of the diagnostic process in his case involved maternal family history, and Gerald’s diagnosis of Alzheimer’s disease was primarily a clinical diagnosis based on interdisciplinary evaluations that included occupational health and the incorporation of the KELS. He was diagnosed with mild to moderate Alzheimer’s disease, which included mild symptoms of early stage, such as

27 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com his difficulty performing relatively simple tasks and moderate symptoms of behavioral and personality changes.

Symptoms of agitation, aggressive behavior, and delusions/psychosis are common in patients diagnosed with Alzheimer’s disease. Atypical and conventional antipsychotics are often used to treat these behaviors in patients who have Alzheimer’s disease, however, these drugs can have significant side effects, including an increased risk for mortality in elderly patients. The selection of sertraline was a safe choice to target anxiety and depression, which could also contribute to delusional thought processes and aggression. Memantine would be a reasonable choice should agitation and aggression be partially remitted or persist despite treatment with an antidepressant. It is an effective drug to help decrease agitation in patients with mild to moderate Alzheimer’s disease. In Gerald’s case, he responded well on a low dose of sertraline with reduced anxious depression and anger and memantine was not needed.

Summary

Alzheimer’s disease is a chronic, progressive neurological disease that causes devastating cognitive impairments. The pathophysiological processes that are characteristic of Alzheimer’s disease, amyloid plaque deposits and neurofibrillary tangles in specific areas of the brain, develop many years before the clinical signs and symptoms begin. Alzheimer’s disease primarily affects people who are 60 or older; age is one of the biggest risk factors for the development of the disease. The disease is well described in the pathophysiological and clinical sense and thought to be caused by a confluence of environmental, genetic, and lifestyle issues and disease states, but it is still not clear how and when these interact to produce Alzheimer’s disease. Much about Alzheimer’s disease is still unknown.

28 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com There is no cure for Alzheimer’s disease and attempts at finding easily applied preventative measures have not been successful. The treatment for Alzheimer’s disease at this point focuses on symptomatic relief and to a lesser degree, altering or influencing several of the pathophysiological processes that are thought to cause the cognitive impairments. However, pharmacologic therapy has been relatively disappointing in its effectiveness, and environmental and psychosocial interventions are the preferred approach for care of the patient who has Alzheimer’s disease.

References Section

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading.

1. Centers for Disease Control and Prevention. (2017). Disease of the Week. Alzheimer’s Disease. September 18, 2017. Retrieve online from https://www.cdc.gov/dotw/alzheimers/index.html. 2. Larson EB. (2018). Evaluation of cognitive impairment and dementia. UpToDate. March 27, 2018. Retrieve online from https://www.uptodate.com/contents/evaluation-of-cognitive- impairment-and- dementia?search=evaluation%20of%20cognitive%20impairment%20a nd%20dementia&source=search_result&selectedTitle=1~150&usage_t ype=default&display_rank=1. 3. Seeley WW and Miller BL. (2015). Alzheimer’s disease and other . In: Kasper D, Fauci A, Hauser S, Longo D, Jameson L, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill. 4. Laws KR, Irvine K, Gale TM. (2018). Sex differences in Alzheimer's disease. Curr Opin Psychiatry. 2018;31(2):133-139. 5. Laws KR, Irvine K, Gale TM. (2016). Sex differences in cognitive impairment in Alzheimer's disease. World J Psychiatry. 2016;6(1):54- 65 6. Howell JC, Watts KD, Parker MW, et al. (2017). Race modifies the relationship between cognition and Alzheimer's disease cerebrospinal

29 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com fluid biomarkers. Alzheimers Res Ther. 2017 Nov 2;9(1):88. doi: 10.1186/s13195-017-0315-1. 7. Jackson JD, Rentz DM, Aghjayan SL, et al. (2017). Subjective cognitive concerns are associated with objective memory performance in Caucasian but not African-American persons. Age Ageing. 2017;46(6):988-993. 8. Yegambaram M, et al. (2015). Role of environmental contaminants in the etiology of Alzheimer's disease: a review. Curr Alzheimer Res. 12:116-46. 9. Silzer TK, Phillips NR. (2018). Etiology of type 2 diabetes and Alzheimer's disease: Exploring the mitochondria. Mitochondrion. 2018 Apr 17. pii: S1567-7249(17)30339-2. doi: 10.1016/j.mito.2018.04.004. [Epub ahead of print] 10. Wang JH, Wu YJ, Tee BL, Lo RY. (2018). Medical comorbidity in Alzheimer's disease: A nested case-control study. J Alzheimers Dis. 2018 Apr 11. doi: 10.3233/JAD-170786. [Epub ahead of print] 11. Paul KC, Jerrett M, Ritz B, et al. (2018). Type 2 diabetes mellitus and Alzheimer's disease: Overlapping biologic mechanisms and environmental risk factors. Curr Environ Health Rep. 2018 Mar;5(1):44-58. 12. Safouris A, Psaltopoulou T, Sergentanis TN, Boutati E, Kapaki E, Tsivgoulis G. (2015). Vascular risk factors and Alzheimer's disease pathogenesis: are conventional pharmacological approaches protective for cognitive decline progression? CNS Neurol Disord Drug Targets. 2015;14(2):257-69. 13. Wallin C, Sholts SB, Österlund N, et al. (2017). Alzheimer's disease and cigarette smoke components: effects of nicotine, PAHs, and Cd(II), Cr(III), Pb(II), Pb(IV) ions on amyloid-β peptide aggregation. Sci Rep. 2017 Oct 31;7(1):14423. doi: 10.1038/s41598-017-13759-5. 14. Nday CM, Eleftheriadou D, Jackson G. (2018). Shared pathological pathways of Alzheimer's disease with specific comorbidities: current perspectives and interventions. J Neurochem. 2018;144(4):360-389. 15. Berti V, Walters M, Sterling J, et al. (2018). Mediterranean diet and 3- year Alzheimer brain biomarker changes in middle-aged adults. . 2018 Apr 13. pii: 10.1212/WNL.0000000000005527. doi: 10.1212/WNL.0000000000005527. [Epub ahead of print] 16. Alford S, Patel D, Perakakis N, Mantzoros CS. (2018). Obesity as a risk factor for Alzheimer's disease: weighing the evidence. Obes Rev. 2018;19(2):269-280. 17. Gardner RC and Yaffe K. (2015). Epidemiology of mild traumatic brain injury and neurodegenerative disease. Mol Cell Neurosci. 2015; May;66(Pt B):75-80. 18. Sherva R, Kowall NW. (2017). Genetics of Alzheimer disease. UpToDate. November 22, 2017. Retrieved online from

30 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com https://www.uptodate.com/contents/genetics-of-alzheimer- disease?search=Genetics%20and%20alzheimer%27s&source=search_ result&selectedTitle=1~150&usage_type=default&display_rank=1#H6 562986. 19. Keene CD, Montine TJ, Kuller LH. (2018). Epidemiology, pathology, and pathogenesis of Alzheimer disease. UpToDate. January 19, 2018. Retrieved online from https://www.uptodate.com/contents/epidemiology-pathology-and- pathogenesis-of-alzheimer- disease?search=alzheimer%27s&source=search_result&selectedTitle= 2~150&usage_type=default&display_rank=2#H6036718. 20. Alzheimer’s Association. (2018). Stages of Alzheimer’s. 2018. Retrieved online from https://www.alz.org/alzheimers_disease_stages_of_alzheimers.asp. 21. Kern S, Zetterberg H, Kern J, et al. (2018). Prevalence of preclinical Alzheimer disease: Comparison of current classification systems. Neurology. 2018 Apr 13. pii: 10.1212/WNL.0000000000005476. doi: 10.1212/WNL.0000000000005476. [Epub ahead of print] 22. Wolk DA, Dickerson BC. (2017). Clinical features and diagnosis of Alzheimer disease. UpToDate. October 2017. Retrieved online from https://www.uptodate.com/contents/clinical-features-and-diagnosis- of-alzheimer- disease?search=alzheimers&source=search_result&selectedTitle=1~15 0&usage_type=default&display_rank=1#H3. 23. Hong YJ, Jang EH, Hwang J, Roh JH, Lee JH. (2015. The efficacy of cognitive intervention programs for mild cognitive impairment: A systematic review. Curr Alzheimer Res. 2015;12(6):527-542. 24. Mitchell SL. Palliative care of patients with advanced dementia. (2018). UpToDate. January 23, 2018. Retrieved online from https://www.uptodate.com/contents/palliative-care-of-patients-with- advanced-dementia?topicRef=5071&source=see_link#H423254519. 25. Toth, L., Hoffman, I., Gosztolya, G., et al. (2018). A speech recognition-based solution for the automatic detection of mild cognitive impairment from spontaneous speech. Curr Alzheimer Res. 2018;15(2):130-138 26. Szatloczki G, Hoffmann I, Vincze V, Kalman J, Pakaski M. (2015). Speaking in Alzheimer's Disease, is that an early sign? Importance of changes in language abilities in Alzheimer's disease. Front Aging Neurosci. 2015 Oct 20;7:195. doi: 10.3389/fnagi.2015.00195. eCollection 2015. 27. Rhodius-Meester HFM, Liedes H, Koene T, (2018). Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease. Alzheimers Res Ther. 2018 Feb 20;10(1):23. doi: 10.1186/s13195-018-0348-0.

31 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com 28. Larson EB. (2018). Evaluation of cognitive impairment and dementia. UpToDate. March 27, 2018. Retrieved online from https://www.uptodate.com/contents/evaluation-of-cognitive- impairment-and- dementia?search=Dementia&source=search_result&selectedTitle=1~1 50&usage_type=default&display_rank=1. 29. American Psychiatric Association (2013). Neurocognitive disorders: Major and mild neurocognitive disorders. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Publishing; Retrieved online at www.UCHC.edu. 30. Dai MH, Zheng H, Zeng LD, Zhang Y. (2017). The genes associated with early-onset Alzheimer's disease. Oncotarget. 2017;9(19):15132- 15143. 31. Chen Y, Sillaire AR, Dallongeville J, et al. (2017). Low prevalence and clinical effect of vascular risk factors in early-onset Alzheimer's disease. J Alzheimers Dis. 2017;60(3):1045-1054. 32. Ridge PG, Ebbert MT, Kauwe JS. (2013). Genetics of Alzheimer's disease. Biomed Res Int. 2013;2013:254954. doi: 10.1155/2013/254954. Epub 2013 Jul 25. 33. Panegyres PK, Chen HY. (2013). Differences between early and late onset Alzheimer's disease. Am J Neurodegener Dis. 2013;2(4):300- 306. 34. Palasí A, Gutiérrez-Iglesias B, Alegret M, et al. (2015). Differentiated clinical presentation of early and late-onset Alzheimer's disease: is 65 years of age providing a reliable threshold? J Neurol. 262(5):1238- 1246. 35. Wang J, Yu JT, Wang HF. http://www-ncbi-nlm-nih- gov.online.uchc.edu/pubmed/?term=Tan%20L%5BAuthor%5D&cautho r=true&cauthor_uid=24876182et al. (2015). Pharmacological treatment of neuropsychiatric symptoms in Alzheimer's disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2015;86(1):101-109. 36. Press D, Alexander M. (2018). Treatment of dementia. UpToDate. January 16, 2018. Retrieved online https://www.uptodate.com/contents/treatment-of- dementia?search=alzheimer%20treatment&source=search_result&sele ctedTitle=1~150&usage_type=default&display_rank=1. 37. Hessmann P, Dodel R, Baum E, et al. (2018). Antidepressant medication in a German cohort of patients with Alzheimer's disease. Int J Clin Pharmacol Ther. 2018;56(3):101-112. 38. McCleery J, Cohen DA, Sharpley, AL. (2014). Pharmacotherapies for sleep disturbances in Alzheimer’s disease. Cochrane Database Syst Rev. 2014 Mar 21;(3):CD009178. doi: 10.1002/14651858.CD009178.pub2.

32 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com 39. Defrancesco M, Marksteiner J, Fleischhacker WW, Blasko I. (2015). Use of benzodiazepines in Alzheimer's disease: A systematic review of literature. Int J Neuropsychopharmacol. 2015 May 19;18(10):pyv055. doi: 10.1093/ijnp/pyv055. 40. Porsteinsson AP, Smith JS, Keltz MA, Antonsdottir IM. (2014). Can antidepressant medication relieve agitation in Alzheimer’s disease? Expert Rev Neurother. 2014;14(9):969-971. 41. Lexicomp.® Drug information. Memantine. Retrieved online from https://www.uptodate.com/contents/memantine-drug- information?search=memantine&source=search_result&selectedTitle= 1~37&usage_type=default&display_rank=1#F192491 42. Zhang N, Wei C, Du H, Shi FD, Cheng Y. (2015). The effect of memantine on cognitive function and behavioral and psychological symptoms in mild-to-moderate Alzheimer's disease patients. Dement Geriatr Cogn Disord. 2015; 40(1-2):85-93. 43. Jiang J, Jiang, H. (2015). Efficacy and adverse effects of memantine treatment for Alzheimer's disease from randomized controlled trials. Neurol Sci. 2015; 36(9):1633-1641 44. Okuizumi K, Kamata T, Matsui D, Saito K, Matsumoto T, Fukuchi Y. (2018). Memantine in Japanese patients with moderate to severe Alzheimer's disease: meta-analysis of multiple-index responder analyses. Expert Opin Pharmacother. 2018;19(5):425-430. 45. Deardorff WJ, Feen E, Grossberg, GT. (2015). The use of cholinesterase inhibitors across all stages of Alzheimer's disease. Drugs Aging. Jul;32(7):537-47. doi: 10.1007/s40266-015-0273-x. 46. Cummings, JL, et al. (2015). A practical algorithm for managing Alzheimer's disease: what, when, and why? Ann Clin Transl Neurol. 2015;2(3):307-323. [=] 47. Khoury R, Rajamanickam J, Grossberg GT. (2018). An update on the safety of current for Alzheimer's disease: focus on rivastigmine. Ther Adv Drug Saf. 2018;9(3):171-178. 48. Miguel-Álvarez M, Santos-Lozano A, Sanchis-Gomar F, et al. (2015). Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer's disease: a systematic review and meta-analysis of treatment effect. Drugs Aging. 2015;32(2):139-147. 49. Declercq T, Petrovic M, Azermai M, et al. (2013). Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia. Cochrane Database Syst Rev. 2013 Mar 28;(3):CD007726. doi: 10.1002/14651858.CD007726.pub2. 50. Lopez OL, Becker JT, Chang YF, et al. (2013). The long-term effects of conventional and atypical antipsychotics in patients with probable Alzheimer's disease. Am J Psych. 2013;170(9):1051-1058.

33 Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com Ce4Less.com 51. Ballard C, Thomas A, Gerry S, et al. (2015). A double-blind randomized placebo-controlled withdrawal trial comparing memantine and antipsychotics for the long-term treatment of function and neuropsychiatric symptoms in people with Alzheimer's disease (MAIN- AD). J Am Med Dir Assoc. 2015; 16(4):16-22. 52. Kales HC, Gitlin LN, Lyketsos, CG, et al. (2014). Detroit Expert Panel on Assessment and Management of Neuropsychiatric Symptoms of Dementia. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc. 2014;62(4):762-769. 53. Rabins PV, Blass, DM. (2014). In the Clinic: Dementia. Ann Int Med. 2014 Aug 5;161(3): ITC1; quiz ITC16. 54. Han JY, Han SH. (2014). Primary prevention of Alzheimer’s disease: is it an attainable goal? J Korean Med Sci. 2014;29(7):886-892. 55. Sindi S, Mangialasche F, Kivipelto, M. (2015). Advances in the prevention of Alzheimer's disease. F1000Prime Rep. 2015 May 12;7:50. doi: 10.12703/P7-50. eCollection 2015. Review. 56. Mlinac, M. and Feng, M. (2016). Assessment of Activities of Daily Living, Self-Care, and Independence. Archives of Clinical , Volume 31, Issue 6, 1 September 2016, Pages 506– 516.

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