Polygenic hazard scores in superagers: Supergenes or superresilience?

Abstract

Background Unusually successful cognitive aging (e.g. SuperAging) may reflect underlying resistance to age‐associated cognitive decline and the neuropathologic markers of Alzheimer’s disease (AD). However, it is unknown whether these individuals vary in their genetic protection from AD relative to other clinically normal elderly individuals. Method The Northwestern SuperAgers cohort (n=41) was limited to clinically normal individuals who were at least 80 years old but performed at or above normative values for average 50 to 65‐year‐olds on delayed recall of the Rey Auditory Verbal Learning Test and within one standard deviation of the average normative range for their age, or better, on non‐episodic memory tests including the 30‐item Boston Naming Test, Trail Making Test Part‐B and Category Fluency Test (Animals). The UC San Diego (UCSD) Shiley Marcos Alzheimer’s Disease Research Center and Alzheimer’s Disease Neuroimaging Initiative (ADNI) comparison cohorts (n=17 and 46, respectively) included all clinically normal individuals with available genetic data who were at least 80 years old but did not meet the criteria for SuperAgers outlined above. Polygenic hazard scores (PHS) were downloaded from ADNI and calculated for each participant as described (Desikan et al., 2017) for the Northwestern and UCSD cohorts. Briefly, the PHS combines an individual’s genotype for 31 AD‐associated SNPs in addition to APOE. Result All three cohorts were similar in age (range: 80‐101) and years of education (range: 12‐20). However, there were significantly more women in the Northwestern SuperAgers cohort (p < 0.001). The mean PHS in each cohort was negative, indicating that these individuals had less than average population risk for AD. However, there were no significant differences in PHS between cohorts. Conclusion As a group, SuperAgers did not have lower polygenic risk for AD than clinically normal elderly individuals, suggesting determinants of superior memory performance in older age cannot be solely explained by having unusually low risk for AD as assessed by common genetic variants. Given the sex differences in these cohorts, future work should consider whether sex‐specific polygenic risk for AD contributes to the superior memory performance of SuperAgers.

Medical characterization of cognitive SuperAgers: Investigating the medication profile of SuperAgers

“…Thus, distinctive medication profiles cannot fully account for memory performance differences between SuperAgers and cognitively average older adults. However, our previous findings point to slower brain atrophy and psychosocial factors, as potential contributors to youthful memory performance 2–4 …”

“…However, our previous findings point to slower brain atrophy and psychosocial factors, as potential contributors to youthful memory performance. [2][3][4]…”

“…Their youthful memory phenotype offers a unique model for identifying factors for optimizing healthspan. Initial investigations have identified biologic, genetic, and psychosocial features that distinguish SuperAgers from their average episodic memory peers 2–4 . However, medications have not been characterized.…”

“…Initial investigations have identified biologic, genetic, and psychosocial features that distinguish SuperAgers from their average episodic memory peers. [2][3][4] However, medications have not been characterized.…”

Broadening the identification of superior cognition in older age

“…Likewise, studies focused on better-than-expected memory performance in older age provide important paradigms for informing mechanisms of reserve, resilience, resistance, and compensation (e.g.). [1][2][3][4][5][6][7][8] Carmona and colleagues 9 extend this work by drawing from the population-based Pietà Study in Brazil to explore whether "highperformance older adults (HPOA)" are present and to identify potential sociodemographic, clinical, and lifestyle features that set them apart from typical agers (called "standard performance older adults (SPOA). "…”