Evaluating the association of APOE genotype and cognitive resilience in SuperAgers
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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 APOE 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 APOE 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 APOE -ε2 alleles and lower proportions of APOE -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 APOE- ε4 alleles and significantly higher proportions of APOE -ε2 alleles compared to all cases and controls, including oldest-old controls. In contrast, non-Hispanic Black SuperAgers had significantly lower proportions of APOE- ε4 alleles compared to cases and younger controls, and significantly higher proportions of APOE- ε2 alleles compared only to cases.
Conclusions and Relevance
In the largest study to date, we demonstrated strong evidence that the frequency of APOE -ε4 and -ε2 alleles differ between non-Hispanic White SuperAgers and AD dementia cases and cognitively normal controls. Differences in the role of APOE in SuperAging by race underlines distinctions in mechanisms conferring resilience across race groups given likely differences in genetic ancestry.
Key Points
Question
Does the frequency of APOE -ε4 and APOE -ε2 alleles explain the exceptional memory of non-Hispanic Black and non-Hispanic White SuperAgers?
Findings
In this multicohort, multiracial study, SuperAgers had significantly higher proportions of APOE -ε2 alleles and lower proportions of APOE -ε4 alleles compared to Alzheimer’s disease dementia cases. Non-Hispanic White SuperAgers had significantly lower proportions of APOE- ε4 alleles and significantly higher proportions of APOE -ε2 alleles compared to all cases and controls, including oldest-old (ages 80+) controls. In contrast, non-Hispanic Black SuperAgers had significantly lower proportions of APOE- ε4 alleles compared to cases and younger controls, and only significantly higher proportions of APOE- ε2 alleles compared to cases.
Meaning
This is the largest study to date to identify differences in APOE- ε4 allele frequency based on SuperAger status, and the first study of SuperAgers to find a relationship between APOE- ε2 allele frequency and SuperAger status. As has been found in studies of middle-aged (ages 50-64) and old (ages 65-79) adults, genetic resiliency in oldest-old (80+) age likely differs by genetic ancestry.
