{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T13:04:18Z","timestamp":1780405458738,"version":"3.54.1"},"reference-count":149,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Glob. Women\u2019s Health"],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Two thirds of Alzheimer's disease (AD) patients are female. Genetic and chronic health risk factors for AD affect females more negatively compared to males.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This multimodal neuroimaging study aimed to examine sex differences in cognitively unimpaired older adults on: (1) amyloid-\u03b2 via 18F-AV-45 Florbetapir PET imaging, (2) neurodegeneration via T1 weighted MRI volumetrics, (3) cerebral blood flow via ASL-MRI. We identified AD risk factors including genetic (<jats:italic>APOE<\/jats:italic> genotype status) and health markers (fasting glucose, mean arterial pressure, waist-to-hip ratio, and android and gynoid body fat) associated with neuroimaging outcomes for which we observed sex differences.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Participants were sedentary, amyloid-\u03b2 positive older adults (<jats:italic>N<\/jats:italic>\u2009=\u2009112, ages 65\u201387 years) without evidence of cognitive impairment (CDR\u2009=\u20090).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Multivariate analysis of covariance models adjusted for intracranial volume, age, and years of education demonstrated lower volume [<jats:italic>F<\/jats:italic> (7, 102)\u2009=\u20092.67, <jats:italic>p<\/jats:italic>\u2009=\u20090.014] and higher blood flow <jats:italic>F<\/jats:italic> (6, 102)\u2009=\u20094.25, <jats:italic>p<\/jats:italic>\u2009\u2264\u20090.001) among females compared to males in regions of interest connected to AD pathology and the estrogen receptor network. We did not observe sex differences in amyloid-\u03b2 levels. Higher than optimal waist to hip ratio was most strongly associated with lower volume among female participants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Findings suggest genetic and chronic health risk factors are associated with sex-specific AD neuroimaging biomarkers. Underlying sex-specific biological pathways may explain these findings. Our results highlight the importance of considering sex differences in neuroimaging studies and when developing effective interventions for AD prevention and risk reduction.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgwh.2025.1531062","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T05:29:29Z","timestamp":1747286969000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["APOE4 and chronic health risk factors are associated with sex-specific preclinical Alzheimer\u2019s disease neuroimaging biomarkers"],"prefix":"10.3389","volume":"6","author":[{"given":"Genna M.","family":"Losinski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mickeal N.","family":"Key","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric D.","family":"Vidoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Clutton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill K.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Burns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Watts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1001\/jama.1997.03550160069041","article-title":"Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis","volume":"278","author":"Farrer","year":"1997","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.jalz.2017.02.001","article-title":"2017 Alzheimer\u2019s disease facts and figures","volume":"13","year":"2017","journal-title":"Alzheimers Dement"},{"key":"B3","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1093\/aje\/153.2.132","article-title":"Is the risk of developing Alzheimer\u2019s disease greater for women than for men?","volume":"153","author":"Hebert","year":"2001","journal-title":"Am J Epidemiol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1212\/wnl.49.6.1498","article-title":"Lifetime risk of dementia and Alzheimer\u2019s disease. 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