Abstract
INTRODUCTION: The apolipoprotein E (APOE) ɛ4 allele is a well-established risk factor for neurocognitive impairment (NCI), with varying impacts between men and women. This study investigates the distinct roles of sex and gender in modifying APOE ɛ4-related NCI. METHODS: Biological sex was inferred from sex chromosomes, and a femininity score (FS) was used as a proxy for gender. We analyzed 276,596 UK Biobank participants without prior NCI to assess whether sex and FS modified the effect of APOE ɛ4 on NCI. RESULTS: NCI risk was higher in APOE ɛ4 carriers compared to non-carriers (hazard ratio [HR] = 2.48 in females; HR = 1.96 in males) with significant interaction by sex (P < 0.0001). FS was associated with an increased NCI risk after accounting for sex (HR = 1.07, 95% confidence interval: 1.04-1.10, P < 0.0001) with no significant differences by sex or APOE ɛ4 carrier status. DISCUSSION: Our findings show that APOE ɛ4 increases NCI risk more in females, while FS independently elevates risk across sexes. HIGHLIGHTS: Apolipoprotein E (APOE) ɛ4 increases neurocognitive impairment (NCI) risk, with a greater impact in females (hazard ratio [HR] = 2.48) than males (HR = 1.96).Sex significantly modifies the effect of APOE ɛ4 on NCI (P < 0.0001f).Femininity score increases NCI risk (HR = 1.07) independently of sex and APOE ɛ4.Understanding the distinct sex and gender contributions to APOE ɛ4-related NCI can improve interventions.