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

Background

“SuperAgers” are older adults (ages 80+) whose cognitive performance resembles that of adults in their 50s to mid‐60s. Factors underlying their exemplary aging are underexplored in large, racially diverse cohorts. Using eight cohorts, we investigated the frequency of APOE genotypes in SuperAgers compared to middle‐aged and older adults.

Method

Harmonized, longitudinal memory, executive function, and language scores in Non‐Hispanic White (NHW) and Non‐Hispanic Black (NHB) participants were obtained from the ADSP Phenotype Harmonization Consortium. Scores were age‐ and sex‐adjusted. SuperAgers (NHW = 1,625; NHB = 106) included individuals 80+ years of age with a memory score equal to or exceeding individuals aged 50‐64 and language and executive function domain scores within normal limits who remain cognitively normal across visits. SuperAgers were compared to Alzheimer’s disease (AD) cases (NHW = 8,400; NHB = 925) and cognitively normal controls (NHW = 7,355; NHB = 1,305), as well as age‐defined subgroups (Young = ages 50‐64, Older = ages 65‐79, Oldest‐Old = age 80+). We performed binary logistic regression analyses comparing APOE‐ε2 and APOE‐ε4 alleles (0 = none, 1 = 1+ alleles present) among SuperAgers and their counterparts, covarying for sex and education. We corrected for multiple comparisons using the Benjamini‐Hochberg procedure.

Results

Across racial groups, SuperAgers had significantly higher proportions with APOE‐ε2 alleles and lower proportions with APOE‐ε4 alleles compared to cases (Table 1, Figure 1). Similar differences were observed between SuperAgers and Young and Old Controls, although differences were restricted to APOE‐ε4 in NHB comparisons. NHW SuperAgers had lower proportions with APOE‐ε4 alleles compared to Oldest‐Old Controls; APOE‐ε2 proportions did not differ.

Conclusion

Within our large, harmonized cohort, larger proportions of SuperAgers had APOE‐ε2 alleles and smaller proportions had APOE‐ε4 alleles than AD cases across both NHW and NHB participants. Crucially, higher proportions of NHW SuperAgers had APOE‐ε2 alleles than younger controls (ages<80) and lower proportions had APOE‐ε4 alleles than all controls including age‐matched controls (ages 80+). This work provides the strongest evidence to date that APOE is associated with SuperAging. APOE‐ε2 did not differentiate NHB SuperAgers from controls nor APOE‐ε4 from other oldest‐old adults in present analyses. Future work will extend to whole genome analysis to identify novel genomic drivers of SuperAging.