Associations of Sex, Race, and Apolipoprotein e Alleles with Multiple Domains of Cognition among Older Adults

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 32427 participants who met inclusion criteria, there were 19007 females (59%), 4453 Black individuals (14%), and 27974 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 12538 (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..