Evaluating the Association of Genotype and Cognitive Resilience in SuperAgers

Importance: "SuperAgers" are oldest-old adults (ages 80+) whose memory performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary memory are underexplored in large, racially diverse cohorts.

Objective: To determine the frequency of genotypes in non-Hispanic Black and non-Hispanic White SuperAgers compared to middle-aged (ages 50-64), old (ages 65-79), and oldest-old (ages 80+) controls and Alzheimer's disease (AD) dementia cases.

Design: This multicohort study selected data from eight longitudinal cohort studies of normal aging and AD.

Setting: Variable recruitment criteria and follow-up intervals, including both population-based and clinical-based samples.

Participants: Inclusion in our analyses required genotype, that participants be age 50+, and are identified as either non-Hispanic Black or non-Hispanic White. In total, 18,080 participants were included in the present study with a total of 78,549 datapoints.

Main Outcomes And Measures: Harmonized, longitudinal memory, executive function, and language scores were obtained from the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC). SuperAgers, controls, and AD dementia cases were identified by cognitive scores using a residual approach and clinical diagnoses across multiple timepoints when available. SuperAgers were compared to AD dementia cases and cognitively normal controls using age-defined bins (middle-aged, old, oldest-old).

Results: Across racialized groups, SuperAgers had significantly higher proportions of -ε2 alleles and lower proportions of -ε4 alleles compared to cases. Similar differences were observed between SuperAgers and middle-aged and old controls. Non-Hispanic White SuperAgers had significantly lower proportions of ε4 alleles and significantly higher proportions of -ε2 alleles compared to all cases and controls, including oldest-old controls. In contrast, non-Hispanic Black SuperAgers had significantly lower proportions of ε4 alleles compared to cases and younger controls, and significantly higher proportions of -ε2 alleles compared only to cases.

Conclusions And Relevance: In the largest study to date, we demonstrated strong evidence that the frequency of -ε4 and -ε2 alleles differ between non-Hispanic White SuperAgers and AD dementia cases and cognitively normal controls. Differences in the role of in SuperAging by race underlines distinctions in mechanisms conferring resilience across race groups given likely differences in genetic ancestry.

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