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Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults

Skylar Walters et al. JAMA Neurol. .

Abstract

Importance: Sex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele.

Objective: To investigate whether sex and race modify APOE ε4 and ε2 associations with cognition.

Design, setting, and participants: This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022.

Main outcomes and measures: Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons.

Results: Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (β = -0.071, SE = 0.014; P = 9.6 × 10-7), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (β = -0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals.

Conclusions and relevance: In this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.

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Conflict of interest statement

Conflict of Interest Disclosures: Ms Walters reported grants from National Institutes of Health (NIH) during the conduct of the study. Dr Mez reported grants from NIH during the conduct of the study and grants from the Department of Defense outside the submitted work. Dr Kunkle reported grants from the National Institute on Aging (NIA) during the conduct of the study. Dr Cruchaga reported research support from GSK and Eisai, being a member of the advisory board of Vivid Genomics and Circular Genomics, and owning stocks. Dr Pericak-Vance reported grants from NIH during the conduct of the study. Dr Haines reported grants from NIH during the conduct of the study. Dr Jefferson reported grants from NIH during the conduct of the study. Dr Kukull reported research grants from NIH/NIA during the conduct of the study. Dr Saykin reported grants from NIH to Indiana University and support from multiple NIH grants during the conduct of the study as well as support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in-kind contribution of PET tracer precursor); Bayer Oncology (scientific advisory board); Eisai (scientific advisory board); Siemens Medical Solutions USA (dementia advisory board); National Heart, Lung, and Blood Institute (MESA observational study monitoring board); and Springer-Nature Publishing (editorial office support as editor-in-chief for Brain Imaging and Behavior) outside the submitted work. Dr Thompson reported grants from Biogen during the conduct of the study. Dr Barnes reported serving as deputy editor for Alzheimer’s and Dementia for the Alzheimer’s Association outside the submitted work. Dr Schneider reported grants from NIA during the conduct of the study. Dr Hohman reported grants from NIH during the conduct of the study and being a member of a scientific advisory board for Vivid Genomics outside the submitted work. Dr Dumitrescu reported grants from NIH during the conduct of the study. No other disclosures were reported.

Figures

Figure.
Figure.. APOE × Sex × Race Interactions on Executive Function Performance at Baseline Among Participants With Normal Cognition
Sex- and race-specific associations between baseline executive function among cognitively unimpaired individuals in APOE ε4 and APOE ε2. P values are presented for both race-stratified sex × APOE interactions and intersectional APOE × sex × race interactions. APOE ε4 was coded additively, and APOE ε2 was coded dominantly. aFalse discovery rate–corrected P < .05.
See this image and copyright information in PMC

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