{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T09:48:40Z","timestamp":1785923320813,"version":"3.56.0"},"reference-count":31,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Background: The interaction between sex, APOE \u03b54 status, and clinical progression in Alzheimer\u2019s Disease (AD) remains a subject of debate. While females are often considered at higher risk for AD, the underlying structural neuroanatomical trajectories and how they are modulated by genotype are not fully elucidated. This study aims to evaluate how sex and the APOE \u03b54 genotype interact to influence longitudinal brain atrophy across three clinical groups. Methods: We analyzed longitudinal data from 2400 participants from the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI), stratified by clinical group (i.e., cognitively normal, mild cognitive impairment, and AD), sex, and APOE \u03b54 carrier status. Using Type III Sum of Squares ANCOVA, we modeled the longitudinal variation in brain volume, controlling for baseline brain volume, and baseline severity of neurocognitive impairment and age at entry. Results: While main effects of sex and APOE genotype were not significant, the triple interaction (APOE * Sex * Clinical Group) was marginally significant (p = 0.051). Post hoc analysis revealed a distinct pattern of structural dimorphism within the AD cohort among APOE \u03b54-negative individuals with females exhibiting significantly greater structural preservation compared to males (Mean difference = 11.32, p = 0.051). Among APOE \u03b54 carriers, atrophy trajectories for males and females were statistically indistinguishable (p = 0.922), potentially suggesting that the \u03b54 allele exerts a dominant neurodegenerative influence that overrides sex-specific physiological differences. Conclusions: These emerging findings highlight the importance of jointly considering biological sex and APOE \u03b54 status to improve the characterization of Alzheimer\u2019s disease heterogeneity and support precision medicine approaches.<\/jats:p>","DOI":"10.3390\/life16081290","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T09:16:22Z","timestamp":1785921382000},"page":"1290","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sex-Specific Structural Vulnerability in Alzheimer\u2019s Disease: Insights from APOE \u03b5 4-Negative Patients"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0214-9278","authenticated-orcid":false,"given":"Wanessa","family":"Michelin","sequence":"first","affiliation":[{"name":"Department of Social and Behavioral Sciences, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0643-8439","authenticated-orcid":false,"given":"Joana O.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Social and Behavioral Sciences, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"},{"name":"Associate Laboratory I4HB, Institute for Health and Bioeconomy, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"},{"name":"Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, 4200-135 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2427-6330","authenticated-orcid":false,"given":"Bruno","family":"Peixoto","sequence":"additional","affiliation":[{"name":"Department of Social and Behavioral Sciences, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"},{"name":"Associate Laboratory I4HB, Institute for Health and Bioeconomy, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2026, March 31). 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