Research Article: “Exceptional brain aging” without Alzheimer’s disease: triggers, accelerators, and the net sum game

Date Published: June 1, 2018

Publisher: BioMed Central

Author(s): Prashanthi Vemuri.


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.

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.

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.

Partial Text

The two primary histopathological changes to the brain due to Alzheimer’s disease (AD) are the deposition of amyloid and tau [1]. These two AD-related brain changes are the primary underlying causes of neurodegeneration and cognitive dysfunction which ultimately leads to dementia. As human longevity increases, and AD dementia increasingly becomes a major societal burden, finding pathways that lead to brain aging without AD pathologies (ADP) are critical. Currently, much of the research has been focused on resilience or cognitive reserve [2], wherein the focus has been on discovering how and why individuals are able to remain clinically unimpaired or cognitively normal despite ADP. However, it is important to investigate, using surrogates of amyloid and tau pathologies via cerebrospinal fluid (CSF) and positron emission tomography (PET), why majority of individuals develop ADP as they age and how some oldest old individuals are able to age without significant ADP. The latter individuals are called “exceptional agers” without ADP. While the absence of ADP can be defined using various thresholds, we refer to the absence of ADP as not reaching the neuropathological definition of AD in pathology studies and the imaging cutoffs of amyloid and tau positivity in imaging studies. Amyloid and tau PET scans of an exceptional ager in comparison to a clinically unimpaired individual and an AD dementia individual are shown in Fig. 1.Fig. 1Tau and amyloid positron emission tomography (PET) scans in a typical clinically unimpaired, typical AD, and an exceptional ager (> 85-year-old APOE4 carrier)

Several pathology and observational studies have provided evidence for aging without ADP [4, 5] and have focused on optimal or successful aging without cognitive decline [6–8] in the oldest old. In addition, specific evidence for “exceptional brain aging” without ADP comes from these three different lines of investigation.

Given the possibility of “exceptional aging”, how does one discover the important protective factors. Three inter-related ideas or hypotheses are presented here that, when taken together, can aid in discovering protective pathways and help design effective preventive strategies.

While important strides have been made in identifying risk factors for AD dementia incidence, future efforts need to be directed towards discovering the timing and mechanism of action of each of these risk factors on AD processes. In this work, three inter-related ideas are presented that are important to consider while studying risk factors and may help us move towards developing effective preventive strategies to maneuver individuals away from the AD pathway towards the pathway of “exceptional brain aging” without ADP.




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