Basic Science and Pathogenesis.

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.