227 Current and Future Treatments in Alzheimer’sDisease Alireza Atri, MD, PhD1,2 1 Banner Sun Health Research Institute, Banner Health, Sun City, Address for correspondence Alireza Atri, MD, PhD, Banner Sun Health Arizona Research Institute, 10515 W Santa Fe Drive, Sun City, AZ 85351 2 Center for Brain/Mind Medicine, Department of Neurology, Brigham (e-mail: [email protected]). and Women’s Hospital, Harvard Medical School, Boston, Massachusetts Semin Neurol 2019;39:227–240. Abstract The foundation of current Alzheimer’s disease (AD) treatment involves pharmacolo- gical and nonpharmacological management and care planning predicated on patient- centered psychoeducation, shared goal-setting, and decision-making forged by a strong triadic relationship between clinician and the patient-caregiver dyad. Food and Drug Administration (FDA) approved AD medications, cholinesterase-inhibitors (ChEIs), and the N-methyl-d-aspartate (NMDA) antagonist memantine, when utilized as part of a comprehensive care plan, while generally considered symptomatic medica- tions, can provide modest “disease course-modifying” effects by enhancing cognition, and reducing loss of independence. When combined, pharmacologic and nonpharma- cologic treatments can meaningfully mitigate symptoms and reduce clinical progres- sion and care burden. AD pharmacotherapy first involves identification and elimination of potentially harmful medications and supplements. First line treatment for neurop- sychiatric symptoms and problem behaviors is nonpharmacological and involves psychoeducation, trigger identification, and implementation, iterative evaluation, and adjustment of behavioral and environmental interventions. Intensive research efforts are underway to develop more accurate and practical AD diagnostic biomarkers Keywords and clinical tools and better therapeutics. Ongoing research studies for primary ► cognitive impairment and secondary prevention of AD and clinical trials evaluating symptomatic and ► dementia disease-modifying treatments in symptomatic AD are directed at diverse therapeutic ► cholinesterase- targets including neurochemicals, amyloid and tau pathological processes, mitochon- inhibitor dria, inflammatory pathways, neuroglia, and multimodal lifestyle interventions. Alzheimer’s disease (AD), the most common cause of mid-to- The current treatment paradigm in Alzheimer’s disease late life cognitive impairment and dementia, is pathologi- (AD) involves a multipronged approach of combining pharma- cally defined by deposits of amyloid-β (Aβ42)-plaques and cological and nonpharmacological approaches to mitigate hyperphosphorylated-tau (p-tau) tangles. Complex, inter- progressive loss of cognitive and functional abilities. No new This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. acting, and incompletely understood biopsychosocial and AD medications have been approved by Food and Drug Admin- pathological processes lead to heterogeneous AD clinical istration (FDA) since 2002 (other than a capsule preparation phenotypes (i.e., cognitive-behavioral syndromes related to that combines two available medications). However, over the AD). AD biopathological processes develop over one to two last decade multiple lines of evidence from randomized, “preclinical” decades before symptoms manifest insidiously; double-blind, and placebo-controlled trials (RCT), and pro- this preclinical period is increasingly targeted in research spective long-term observational cohort studies have emerged and may represent the best opportunities to potentially to support the clinical effectiveness of AD medications, in delay or prevent onset of dementia stages of AD.1,2 mono-, or add-on-dual combination therapy to at least Issue Theme Dementia; Guest Editor, Copyright © 2019 by Thieme Medical DOI https://doi.org/ Arash Salardini, MD Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1678581. New York, NY 10001, USA. ISSN 0271-8235. Tel: +1(212) 584-4662. 228 Current and Future Treatments in Alzheimer’sDisease Atri Table 1 Risk factors for AD dementia Modifiable Nonmodifiable (in early life, midlife ages 45–65 y, or later life ages > 65 y) Vascular risks: Age Diabetes (later life) Gender (female > male) Hypertension (midlife) Family history (first- or second-degree relative or multiple generations) Dyslipidemia (midlife) Race Metabolic Syndrome and obesity (midlife) Down’sSyndrome Smoking tobacco (later life) ApoE-ε4 allele Low physical activity (later life) Cerebral amyloidosis–abiomarkeroftheADpathologicalprocessa Cerebral hypoperfusion Cerebrovascular injury or stroke Depression (later life) Severe head trauma or traumatic brain injury Hearing loss (midlife) Low cognitive reserve: low education, intelligence, professional or social attainment/occupation (early life and potentially midlife) Low social contact (later life) Abbreviations: AD, Alzheimer’s disease; ApoE, Apolipoprotein E. aIt is currently a nonmodifiable risk factor but primary and secondary prevention trials utilizing amyloid-modifying drugs are in progress and early results support that cerebral amyloid plaque burden can be lowered; whether this translates to clinical benefit or of lowering risk of progression to MCI or dementia, potentially making this be a modifiable risk factor, is to be determined. modestly (with small to medium effect sizes) mitigate symp- cellular, network, and systems. The current AD treatment toms and retard the expected trajectory of progressive paradigm is one of multifaceted management of symptoms decline.3 aimed at retaining quality of life, mitigating the burden of The last decade has brought several major advances illness and reducing long-term clinical decline. Successful involving explication of AD risk factors (see ►Table 1)and long-term pharmacotherapy with FDA-approved AD medica- AD diagnostics. In vivo AD biomarkers of the pathological tions, initially involving monotherapy with a cholinesterase- process are now available in the clinic. Measurements of inhibitor (ChEI) and ultimately involving add-on dual-combi- amyloid-Beta42 (Aβ42), tau (τ), and phospho-tau (p-tau) nation treatment with a ChEI and memantine, requires devel- proteins in cerebrospinal fluid (CSF), as well as Aβ42-plaque oping, implementing and sustaining a solid foundation of burden on amyloid-PET (positron emission tomography), can psychoeducation, nonpharmacological and behavioral care now aid clinical, as well are research, diagnosis of AD with a strategies, and clarity in care goals and expectations; this is high level of certainty. Though breakthroughs to affect newer predicated on a strong therapeutic alliance between the AD therapeutics have yet to materialize, learning from clinician and the patient–caregiver dyad. dozens of large and varied clinical trial programs have provided cornerstones of ongoing intensive research efforts Management of AD that aim at primary and secondary prevention, as well as ►Table 2 broadly outlines the multifactorial tailored man- symptomatic and disease-modifying treatments for AD. agement of AD. Evaluation and management of AD requires a This paper will (1) review current multifactorial manage- solid foundation of open, honest, and compassionate com- ment of AD, with a focus on practical aspects of psychoedu- munication; shared goal setting; and a triadic partnership cation and behavioral approaches, clinical evidence, and between the clinician, patient and care-partner(s). Evalua- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. considerations for treatment with FDA-approved AD medi- tion and management should be a patient–caregiver dyad- cations; and (2) briefly summarize experimental pharmaco- centered and dynamic processes that involve multipronged logical approaches under research investigation that are and, ideally, integrated interdisciplinary team approaches. likely to form the bases of future combination therapies in Treatment of AD is not curative and successful management the AD clinical spectrum. to mitigate the burden of illness relies on four basic pillars: (1) timely and accurate syndromic and etiological diagnoses Current Treatments in AD combined with proactive educational and care planning that are customized to the patient–caregiver dyad (the dyad)– There is no cure for AD dementia. It is increasingly recognized without accurate diagnosis and tailored psychoeducation, that the complex and incompletely understood pathological appropriate dyad-centered treatment, and care can’tbe processes culminating in AD dementia can begin decades prior provided; (2) nonpharmacological interventions and beha- to the manifestation of clinical symptoms, by which time vioral approaches; (3) pharmacological interventions; and extensive and likely irreversible processes have wrought wide- (4) holistic care planning that is proactive, pragmatic and spread destruction on multiple levels: molecular, intracellular, dynamic, and includes monitoring and adjustment of the Seminars in Neurology Vol. 39 No. 2/2019 Current and Future Treatments in Alzheimer’sDisease Atri 229 Table 2 Key Elements of effective multifactorial management of AD Patient-caregiver dyad-centered evaluation, diagnosis and disclosure, and care planning processes • Timely detection of symptoms, accurate assessment and diagnosis, iterative psychoeduction, and appropriate disclosure. • Shared goal setting for diagnostic, disclosure and management processes; sustained psychoeducation and tailoring of a proactive