Evaluating the association ofAPOEgenotype and cognitive resilience in SuperAgers
Authors: Durant Alaina , Mukherjee Shubhabrata , Lee Michael L. , Choi Seo-Eun , Scollard Phoebe , Klinedinst Brandon S. , Trittschuh Emily H. , Mez Jesse , Farrer Lindsay A. , Gifford Katherine A. , Cruchaga Carlos , Hassenstab Jason , Naj Adam C. , Wang Li-San , Johnson Sterling C. , Engelman Corinne D. , Kukull Walter A. , Keene C. Dirk , Saykin Andrew J. , Cuccaro Michael L. , Kunkle Brian W. , Pericak-Vance Margaret A. , Martin Eden R. , Bennett David A. , Barnes Lisa L. , Schneider Julie A. , Bush William S. , Haines Jonathan L. , Mayeux Richard , Vardarajan Badri N. , Albert Marilyn S. , Thompson Paul M. , Jefferson Angela L. ,   The Alzheimer’s Disease Neuroimaging Initiative (ADNI),   Alzheimer’s Disease Genetics Consortium (ADGC),   The Alzheimer’s Disease Sequencing Project (ADSP), Crane Paul K. , Dumitrescu Logan , Archer Derek B. , Hohman Timothy J. , Gaynor Leslie S. 
Published: January 2025

AbstractImportance“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.ObjectiveTo determine the frequency ofAPOEgenotypes 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.DesignThis multicohort study selected data from eight longitudinal cohort studies of normal aging and AD.SettingVariable recruitment criteria and follow-up intervals, including both population-based and clinical-based samples.ParticipantsInclusion in our analyses requiredAPOEgenotype, 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 MeasuresHarmonized, 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).ResultsAcross racialized groups, SuperAgers had significantly higher proportions ofAPOE-ε2 alleles and lower proportions ofAPOE-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 ofAPOE-ε4 alleles and significantly higher proportions ofAPOE-ε2 alleles compared to all cases and controls, including oldest-old controls. In contrast, non-Hispanic Black SuperAgers had significantly lower proportions ofAPOE-ε4 alleles compared to cases and younger controls, and significantly higher proportions ofAPOE-ε2 alleles compared only to cases.Conclusions and RelevanceIn the largest study to date, we demonstrated strong evidence that the frequency ofAPOE-ε4 and -ε2 alleles differ between non-Hispanic White SuperAgers and AD dementia cases and cognitively normal controls. Differences in the role ofAPOEin SuperAging by race underlines distinctions in mechanisms conferring resilience across race groups given likely differences in genetic ancestry.Key PointsQuestionDoes the frequency ofAPOE-ε4 andAPOE-ε2 alleles explain the exceptional memory of non-Hispanic Black and non-Hispanic White SuperAgers?FindingsIn this multicohort, multiracial study, SuperAgers had significantly higher proportions ofAPOE-ε2 alleles and lower proportions ofAPOE-ε4 alleles compared to Alzheimer’s disease dementia cases. Non-Hispanic White SuperAgers had significantly lower proportions ofAPOE-ε4 alleles and significantly higher proportions ofAPOE-ε2 alleles compared to all cases and controls, including oldest-old (ages 80+) controls. In contrast, non-Hispanic Black SuperAgers had significantly lower proportions ofAPOE-ε4 alleles compared to cases and younger controls, and only significantly higher proportions ofAPOE-ε2 alleles compared to cases.MeaningThis is the largest study to date to identify differences inAPOE-ε4 allele frequency based on SuperAger status, and the first study of SuperAgers to find a relationship betweenAPOE-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.