Prevention of Alzheimer's Disease: Lessons Learned and Applied

James E. Galvin, MD, MPH

Disclosures

J Am Geriatr Soc. 2017;65(10):2128-2133. 

In This Article

Abstract and Introduction

Abstract

Alzheimer's disease (AD) affects more than 5 million Americans, with substantial consequences for individuals with AD, families, and society in terms of morbidity, mortality, and healthcare costs. With disease-modifying treatment trials unsuccessful at the present time and only medications to treat symptoms available, an emerging approach is prevention. Advances in diagnostic criteria, biomarker development, and greater understanding of the biophysiological basis of AD make these initiatives feasible. Ongoing pharmacological trials using anti-amyloid therapies are underway in sporadic and genetic forms of AD, although a large number of modifiable risk factors for AD have been identified in observational studies, many of which do not appear to exert effects through amyloid or tau. This suggests that prevention studies focusing on risk reduction and lifestyle modification may offer additional benefits. Rather than relying solely on large-sample, long-duration, randomized clinical trial designs, a precision medicine approach using N-of-1 trials may provide more-rapid information on whether personalized prevention plans can improve person-centered outcomes. Because there appear to be multiple pathways to developing AD, there may also be multiple ways to prevent or delay the onset of AD. Even if these precision approaches alone are not successful in preventing AD, they may greatly improve the likelihood of amyloid- or tau-specific therapies to reach their endpoints by reducing comorbidities. Keeping this in mind, dementia may be a disorder that develops over a lifetime, with individualized ways to build a better brain as we age.

Introduction

Alzheimer's disease (AD) affects more than 5 million Americans, with substantial costs to individuals with AD, families, and society.[1] Projections by the Alzheimer Association are that, if nothing is done, by 2050, there will be more than 16 million people with AD in the United States and more than 60 million worldwide. Over the past 25 years, only five symptomatic medications have met their primary clinical trial endpoints in Phase III clinical trials and successfully come to market; of these, four are still available. Since 2003, every symptom- and disease-modifying agent has failed in Phase II or III trials because of challenges with safety or efficacy. This led to a bold initiative put forth in the National Alzheimer Plan Act to develop a disease-modifying treatment (DMT) by 2025.[2] Two important concepts are associated with success to reach this target date. First, only medications that have already entered Phase II testing can make it to market by 2025.[2] Second, if a DMT were available by 2025, then the 2050 projection of 16 million Americans with AD would be reduced by 5.7 million cases, with societal savings of $367 billion.[1] To complement efforts to develop a DMT for individuals with symptomatic AD, a concerted effort is underway to initiate preventive measures in asymptomatic individuals. Such efforts are also consistent with the 2025 target goal.

An important question, is whether AD can be prevented. A large number of modifiable (e.g., exposures, lifestyle and social habits) and nonmodifiable (e.g., age, sex, genetics) risk factors have been identified (Table 1). Recent revisions to the clinical criteria for AD[3] and mild cognitive impairment (MCI)[4] helped clarify the role of biomarkers in defining the pathological cascade, and the addition of research criteria for presymptomatic disease[5] sets the stage for better modeling of the preclinical and prodromal stages of disease.[6] Efforts developing and validating fluid (blood and cerebrospinal fluid) and imaging biomarkers make it possible to explore underlying pathological changes in amyloid, tau, dopamine transport, inflammation, signaling pathways, and in the future, alpha-synuclein and TDP-43 in symptomatic, prodromal, and presymptomatic individuals. Advances in genetic, epigenetic, and "omic" (e.g., proteomic, lipidomic, metabolomic) approaches will permit the modeling of transcriptional, translational, and posttranslational changes. Furthermore, precision medicine approaches with demonstrable benefits in oncology are being applied to neurodegenerative disorders. Thus, the platform is in place to begin prevention initiatives.

These efforts have a great potential for pharmaceutical and nonpharmacological approaches, with earlier identification of at-risk individuals, expanding opportunities for faster and earlier diagnoses, better stratification of at-risk individuals, higher enrollment into randomized clinical trials (RCTs) by reducing screen failure rates, and eventually more-effective treatments. Although the focus of this article is on AD, the principles discussed are relevant to related neurodegenerative disorders (e.g., Parkinson's disease, Lewy body dementia, vascular dementia). Assuming that curing AD remains a substantial unsolved challenge, preventing or simply delaying the onset of dementia could significantly change the face of disease.

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