Sex Differences in Apolipoprotein e and Alzheimer Disease Pathology Across Ancestries

Abstract

Importance: Age, sex, and apolipoprotein E (APOE) are the strongest risk factors for late-onset Alzheimer disease (AD). The role of APOE in AD varies with sex and ancestry. While the association of APOE with AD biomarkers also varies across sex and ancestry, no study has systematically investigated both sex-specific and ancestry differences of APOE on cerebrospinal fluid (CSF) biomarkers together, resulting in limited insights and generalizability. Objective: To systematically investigate the association of sex and APOE-ϵ4 with 3 core CSF biomarkers across ancestries. Design, Setting, and Participants: This cohort study examined 3 CSF biomarkers (amyloid β1-42 [Aβ42], phosphorylated tau 181 [p-tau], and total tau, in participants from 20 cohorts from July 1, 1985, to March 31, 2020. These individuals were grouped into African, Asian, and European ancestries based on genetic data. Data analyses were conducted from June 1, 2023, to November 10, 2024. Exposure: Sex (male or female) and APOE-ϵ4. Main Outcomes and Measures: The associations of sex and APOE-ϵ4 with biomarker levels were assessed within each ancestry group, adjusting for age. Meta-analyses were performed to identify these associations across ancestries. Sensitivity analyses were conducted to exclude the potential influence of the APOE-ϵ2 allele. Results: This cohort study included 4592 individuals (mean [SD] age, 70.8 [10.2] years; 2425 [52.8%] female; 119 [2.6%] African, 52 [1.1%] Asian, and 4421 [96.3%] European). Higher APOE-ϵ4 dosage scores were associated with lower Aβ42 values (β [SE], -0.58 [0.02], P