Durant, Alaina; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-eun; Scollard, Phoebe; Klinedinst, Brandon S.; Trittschuh, Emily H.; Mez, Jesse B.; Farrer, Lindsay A.; Gifford, Katherine A.; Cruchaga, Carlos C.; Hassenstab, Jason J.; Naj, Adam C.; Wang, Li San; Johnson, Sterling C.; Engelman, Corinne D.; Kukull, W. A.; Keene, C. Dirk; Saykin, Andrew J.; Cuccaro, Michael L.; Kunkle, Brian W.; Kunkle, M. A.; Martin, Eden R. R.; Bennett, David Alan; Barnes, Lisa Laverne; Schneider, Julie A.; Bush, William S.; Haines, Jonathan L.; Mayeux, Richard P.; Vardarajan, Badri Narayan; Albert, Marilyn S. S.; Thompson, Paul M.; Jefferson, Angela Lee; Crane, Paul K.; Dumitrescu, Logan C.; Archer, Derek B.; Hohman, Timothy J.; & Gaynor, Leslie S. (2026). Evaluating the association of apolipoprotein E genotype and cognitive resilience in SuperAgers. Alzheimer’s and Dementia, 22(1), e71024. https://doi.org/10.1002/alz.71024
“SuperAgers” are adults age 80 and older whose memory abilities are similar to those of middle-aged adults. Because memory usually declines with age, researchers are interested in understanding what makes SuperAgers different. In this study, we examined whether differences in the apolipoprotein E (APOE) gene are associated with being a SuperAger. The APOE gene has different forms, called alleles—most commonly APOE-ε2, APOE-ε3, and APOE-ε4. The APOE-ε4 allele is known to increase risk for Alzheimer’s disease, while APOE-ε2 is often considered protective.
We analyzed data from 18,080 participants across eight research cohorts. Using standardized clinical diagnoses and cognitive test scores measuring memory, executive function (skills like planning and problem-solving), and language, we identified SuperAgers, cognitively normal controls, and individuals with Alzheimer’s disease dementia within different age groups. We examined these patterns separately in non-Hispanic White (NHW) and non-Hispanic Black (NHB) participants.
Among NHW participants, SuperAgers were significantly less likely to carry the APOE-ε4 allele and more likely to carry the APOE-ε2 allele compared to both individuals with Alzheimer’s disease and cognitively normal controls, including those over age 80. A similar pattern was observed in NHB SuperAgers, suggesting fewer APOE-ε4 alleles and more APOE-ε2 alleles, although the smaller sample size meant that not all comparisons were statistically significant.
Overall, the results provide strong evidence that APOE allele frequency is related to SuperAger status. However, more research—especially with larger samples of NHB SuperAgers—is needed to determine whether the biological mechanisms that support exceptional cognitive resilience differ across racial groups.
FIGURE 1
Flow diagram for participant classification of SuperAgers, cases, and controls. (A) Flowchart depicting inclusion and exclusion criteria for identifying SuperAgers, AD dementia cases, controls. (B) Flowchart depicting selection order of SuperAgers, cases, and controls. Age range of participants indicated by line segment with arrows on each end. Age of participant classification is indicated by position of shorter, labeled line segments. Closed circles at the end of line segments indicate inclusion of age, such that age range is less-than-or-equal-to or greater-than-or-equal-to the age with which the circle aligns, while open circles indicate exclusion of age, such that age range is less-than or greater-than the age with which the circle aligns. Sequence of selection is indicated by line height, higher lines indicating earlier selection. AD, Alzheimer’s disease; ADSP-PHC, Alzheimer’s Disease Sequencing Project – Phenotype Harmonization Consortium; CN, cognitively normal; EXF, executive functioning; LAN, language; MEM, memory.