Centenarians as Models of Resistance and Resilience to Alzheimer's Disease and Related Dementias

Abstract

The majority of research to understand the pathogenesis of and contributors to Alzheimer's disease (AD) pathology, dementia, and disease progression has focused on studying individuals who have the disease or are at increased risk of having the disease. Yet there may be much to learn from individuals who have a paradoxical decreased risk of AD suggesting underlying protective factors. Centenarians demonstrate exceptional longevity that for a subset of the cohort is associated with an increased health span characterized by the delay or escape of age-related diseases including dementia. Here, I give evidence of the association of exceptional longevity with resistance and resilience to AD and describe how cohorts of centenarians and their offspring may serve as models of neuroprotection from AD. Discoveries of novel genetic, environmental, and behavioral factors that are associated with a decreased risk of AD may inform the development of interventions to slow or prevent AD in the general population. Centenarian cohorts may also be instrumental in serving as controls to individuals with AD to identify additional risk factors.

Keywords: centenarian; dementia; health span; longevity; neurodegenerative; resilience; resistance.

Figure 1.. Centenarians and centenarian offspring who are resistant to Alzheimer’s disease (AD).

This theoretical model shows the expected increase of AD pathology with increasing age (blue solid line). Centenarians who are resistant to AD and therefore avoid both clinical and pathological hallmarks of AD are expected to have negligible levels of AD pathology at the extreme ages of 100+ years (red dotted line). Centenarian offspring who are resistant to AD (orange dashed line) are expected to have a muted effect of resistance to AD due to receiving only half of their genetics from their centenarian parent. This model also demonstrates the added advantage of being able to study centenarian offspring across a wider range of older adulthood relative to centenarian cohorts using longitudinal assessments.

Figure 2.. Centenarians and centenarian offspring who are resilient to Alzheimer’s disease (AD).

This theoretical model shows the expected declines in cognitive function and/or brain structure integrity associated with increasing levels of AD pathology (blue solid line). Centenarians who are resilient to AD pathology (red dotted line) are expected to exhibit no or only minimal functional and structural changes despite high levels of AD pathology, whereas centenarian offspring who are resilient to AD pathology (orange dashed line) are expected to have a muted effect of resilience due to receiving only half of their genetics from their centenarian parent.