Prevention of Alzheimer's Disease: Lessons Learned and Applied

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.

Keywords: Alzheimer's disease; N-of-1 trials; dementia; lifestyle; precision medicine; prevention; risk reduction.

Figure 1. Model of a Dementia Prevention Initiative

Panel A: Hypothetical model of the development of clinical dementia. Prior to diagnosis, there would be evidence of cognitive decline, which reflects neurodegenerative changes including cellular dysfunction and loss, synaptic dysfunction, and loss of connectivity. Presumably, these downstream changes are caused by accumulation of one or more pathologies. If more than one pathology is present, then each pathology should have its own risk factor or factors (i.e., Risk Factor A causes Pathology A, while Risk Factor B causes Pathology B). Panel B: Application of model in N-of-1 trial (described in detail in text). Six different risk factors were identified during the clinical evaluation presumably working through different pathways with the end result being neurodegeneration, cognitive decline, and if unchecked, eventually clinical dementia. A personalized prevention plan directed at root causes of impairment, if successful would prevent the conversion of cognitive decline to dementia (marked by X in Panel B). As root causes may interact or potentiate each other’s effect on neurodegeneration (connecting arrows on the left side of Panel B), multimodal approaches are more likely to have an effect than singular approaches.