"Exceptional brain aging" without Alzheimer's disease: triggers, accelerators, and the net sum game

Abstract

Background: As human longevity increases and Alzheimer's disease (AD) increasingly becomes a significant societal burden, finding pathways or protective factors that facilitate exceptional brain aging without AD pathophysiologies (ADP) will be critical. The goal of this viewpoint is two-fold: 1) to present evidence for "exceptional brain aging" without ADP; and 2) to bring together ideas and observations from the literature and present them as testable hypotheses for biomarker studies to discover protective factors for "exceptional brain aging" without ADP and AD dementia.

Discovering pathways to exceptional aging: There are three testable hypotheses. First, discovering and quantifying links between risk factor(s) and early ADP changes in midlife using longitudinal biomarker studies will be fundamental to understanding why the majority of individuals deviate from normal aging to the AD pathway. Second, a risk factor may have quantifiably greater impact as a trigger and/or accelerator on a specific component of the biomarker cascade (amyloid, tau, neurodegeneration). Finally, and most importantly, while each risk factor may have a different mechanism of action on AD biomarkers, "exceptional aging" and protection against AD dementia will come from "net sum" protection against all components of the biomarker cascade. The knowledge of the mechanism of action of risk factor(s) from hypotheses 1 and 2 will aid in better characterization of their effect on outcomes, identification of subpopulations that would benefit, and the timing at which the risk factor(s) would have the maximal impact. Additionally, hypothesis 3 highlights the importance of multifactorial or multi-domain approaches to "exceptional aging" as well as prevention of AD dementia.

Conclusion: While important strides have been made in identifying risk factors for AD dementia incidence, further efforts are needed to translate these into effective preventive strategies. Using biomarker studies for understanding the mechanism of action, effect size estimation, selection of appropriate end-points, and better subject recruitment based on subpopulation effects are fundamental for better design and success of prevention trials.

Keywords: AD prevention; Biomarker cascade; Exceptional Aging.

Fig. 1

Tau and amyloid positron emission tomography (PET) scans in a typical clinically unimpaired, typical AD, and an exceptional ager (> 85-year-old APOE4 carrier)

Fig. 2

a Prevalence of elevated amyloid levels (A+) versus vascular disease (V+) in clinically unimpaired individuals based on data from Vemuri and Knopman [11]. Vascular pathologies show a steady increase in the prevalence (exponential growth curve models) but the amyloid positivity curves exhibit a slow saturation similar to logistic growth curve models. b Data from our previous study [25] illustrates the slow longitudinal cognitive decline seen in a clinically unimpaired 80-year-old male without amyloid and cerebrovascular pathologies (in blue) in comparison with significantly greater decline seen in a clinically unimpaired individual of the same age with both elevated amyloid and cerebrovascular pathologies (in red)

Fig. 3

Framework for the second hypothesis and examples of triggers and accelerators of some of the components of the biomarker cascade. AD, Alzheimer’s disease; APOE, apolipoprotein E

Fig. 4

Impact of intellectual enrichment (e.g., education, occupation, cognitive activity) and Other neurodegenerative processes on the Alzheimer’s disease (AD) trajectories. Cognition curves are superimposed on the ADP curves (amyloid or tau) shown in blue. The horizontal line indicates the cognitive impairment threshold. The time at which cognitive function meets the threshold allows us to deduce the ADP levels at the same time point on the superimposed ADP curves. a Illustration of individuals with high (green curve) and low (red dashed line) intellectual enrichment and the ADP levels (shown by the circles) at which cognitive impairment would be observed in both groups of individuals. b Illustration of individuals with only AD path (green curve) and AD path in addition to other neurodegenerative pathologies (red dashed line) and the ADP levels (shown by the circles) at which cognitive impairment would be observed in both groups of individuals