{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:13:28Z","timestamp":1791821608043,"version":"4.3.4"},"reference-count":70,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>Age, sex, and apolipoprotein E (APOE<\/jats:italic>) are the strongest risk factors for late-onset Alzheimer disease (AD). The role of APOE<\/jats:italic> in AD varies with sex and ancestry. While the association of APOE<\/jats:italic> with AD biomarkers also varies across sex and ancestry, no study has systematically investigated both sex-specific and ancestry differences of APOE<\/jats:italic> on cerebrospinal fluid (CSF) biomarkers together, resulting in limited insights and generalizability.<\/jats:p><\/jats:sec>Objective<\/jats:title>To systematically investigate the association of sex and APOE<\/jats:italic>-\u03b54 with 3 core CSF biomarkers across ancestries.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>This cohort study examined 3 CSF biomarkers (amyloid \u03b21-42 [A\u03b242], 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.<\/jats:p><\/jats:sec>Exposure<\/jats:title>Sex (male or female) and APOE<\/jats:italic>-\u03b54.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>The associations of sex and APOE<\/jats:italic>-\u03b54 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<\/jats:italic>-\u03b52 allele.<\/jats:p><\/jats:sec>Results<\/jats:title>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<\/jats:italic>-\u03b54 dosage scores were associated with lower A\u03b242 values (\u03b2 [SE], \u22120.58 [0.02], P<\/jats:italic>\u2009&amp;lt;\u2009.001), indicating more severe pathology; these associations were seen in men and women separately and jointly. The association with APOE<\/jats:italic>-\u03b54 was statistically greater in men (\u03b2 [SE], \u22120.63 [0.03]; P<\/jats:italic>\u2009&amp;lt;\u2009.001) vs women (\u03b2 [SE], \u22120.52 [0.03]; P<\/jats:italic>\u2009&amp;lt;\u2009.001) of European ancestry (P<\/jats:italic>\u2009=\u2009.01 for interaction). Women had higher levels of p-tau, indicating more severe neurofibrillary pathology. The association between APOE<\/jats:italic>-\u03b54 dosage and p-tau was in the expected direction (higher APOE<\/jats:italic>-\u03b54 dosage for higher p-tau values) in both sexes, but the difference between sexes was significant only in those of African ancestry (\u03b2 [SE], 0.10 [0.18]; P<\/jats:italic>\u2009=\u2009.57 for men; \u03b2 [SE], 0.66 [0.17]; P<\/jats:italic>\u2009&amp;lt;\u2009.001 for women; P<\/jats:italic>\u2009=\u2009.03 for interaction). Women also had higher levels of total tau, indicating more neuronal damage. The association between APOE<\/jats:italic>-\u03b54 dosage and total tau was stronger in women than in men in the African cohort (\u03b2 [SE], 0.20 [0.22]; P<\/jats:italic>\u2009=\u2009.36 for men and \u03b2 [SE], 0.65 [0.22], P<\/jats:italic>\u2009=\u2009.004 for women [P<\/jats:italic>\u2009=\u2009.16 for interaction]) and European cohort (\u03b2 [SE], 0.36 [0.03]; P<\/jats:italic>\u2009&amp;lt;\u2009.001 in women and \u03b2 [SE], 0.27 [0.03], P<\/jats:italic>\u2009&amp;lt;\u2009.001 in men [P<\/jats:italic>\u2009=\u2009.053 for interaction]); no significant associations were found in the Asian cohort. Sensitivity analysis excluding APOE-<\/jats:italic>\u03b52 carriers yielded similar results.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this cohort study, the association of the APOE<\/jats:italic>-\u03b54 risk allele with tau accumulation was higher in women than in men. These findings underscore the importance of considering sex differences in APOE<\/jats:italic>-\u03b54\u2019s association with AD biomarkers and tau pathology mechanisms in AD. Although this study provides robust evidence of complex interplay between sex and APOE<\/jats:italic>-\u03b54 for European ancestry, further research is needed to fully understand other ancestry differences.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.0562","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T15:10:12Z","timestamp":1741705812000},"page":"e250562","source":"Crossref","is-referenced-by-count":27,"title":["Sex Differences in Apolipoprotein E and Alzheimer Disease Pathology Across Ancestries"],"prefix":"10.1001","volume":"8","author":[{"given":"Xiaoyi","family":"Xu","sequence":"first","affiliation":[{"name":"NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, Missouri"},{"name":"Division of Biostatistics, Washington University School of Medicine, St Louis, 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