Sex Differences in Apolipoprotein E and Alzheimer Disease Pathology Across Ancestries
Authors: Xiaoyi Xu, Jiseon Kwon, Ruiqi Yan, Catherine Apio, Soomin Song, Gyujin Heo, Qijun Yang, Jigyasha Timsina, Menghan Liu, John Budde, Kaj Blennow, Henrik Zetterberg, Alberto Lleó, Agustin Ruiz, José Luis Molinuevo, Virginia Man-Yee Lee, Yuetiva Deming, Amanda J. Heslegrave, Tim J. Hohman, Pau Pastor, Elaine R. Peskind, Marilyn S. Albert, John C. Morris, Taesung Park, Carlos Cruchaga, Yun Ju Sung
Journal: JAMA Network Open (2025)

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 &amp;amp;lt; .001), indicating more severe pathology; these associations were seen in men and women separately and jointly. The association with APOE -ε4 was statistically greater in men (β [SE], −0.63 [0.03]; P &amp;amp;lt; .001) vs women (β [SE], −0.52 [0.03]; P &amp;amp;lt; .001) of European ancestry ( P = .01 for interaction). Women had higher levels of p-tau, indicating more severe neurofibrillary pathology. The association between APOE -ε4 dosage and p-tau was in the expected direction (higher APOE -ε4 dosage for higher p-tau values) in both sexes, but the difference between sexes was significant only in those of African ancestry (β [SE], 0.10 [0.18]; P = .57 for men; β [SE], 0.66 [0.17]; P &amp;amp;lt; .001 for women; P = .03 for interaction). Women also had higher levels of total tau, indicating more neuronal damage. The association between APOE -ε4 dosage and total tau was stronger in women than in men in the African cohort (β [SE], 0.20 [0.22]; P = .36 for men and β [SE], 0.65 [0.22], P = .004 for women [ P = .16 for interaction]) and European cohort (β [SE], 0.36 [0.03]; P &amp;amp;lt; .001 in women and β [SE], 0.27 [0.03], P &amp;amp;lt; .001 in men [ P = .053 for interaction]); no significant associations were found in the Asian cohort. Sensitivity analysis excluding APOE- ε2 carriers yielded similar results. Conclusions and Relevance In this cohort study, the association of the APOE -ε4 risk allele with tau accumulation was higher in women than in men. These findings underscore the importance of considering sex differences in APOE -ε4’s association with AD biomarkers and tau pathology mechanisms in AD. Although this study provides robust evidence of complex interplay between sex and APOE -ε4 for European ancestry, further research is needed to fully understand other ancestry differences.