{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:02:42Z","timestamp":1782280962097,"version":"3.54.5"},"posted":{"date-parts":[[2025,1,2]]},"group-title":"Neuroscience","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T00:00:00Z","timestamp":1735776000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The biological mechanisms underlying women\u2019s increased Alzheimer\u2019s disease (AD) prevalence remain undefined. Previous case\/control studies have identified sex-biased molecular pathways, but sex-specific relationships between gene expression and AD endophenotypes, particularly sex chromosomes, are underexplored. With bulk transcriptomic data across 3 brain regions from 767 decedents, we investigated sex-specific associations between gene expression and post-mortem \u03b2-amyloid and tau as well as antemortem longitudinal cognition. Of 23,118 significant gene associations, 10% were significant in one sex and not the other (sex-specific). Most sex-specific gene associations were identified in females (73%) and associated with tau tangles and longitudinal cognition (90%). Four X-linked genes,\n                  <jats:italic>MCF2<\/jats:italic>\n                  ,\n                  <jats:italic>HDAC8<\/jats:italic>\n                  ,\n                  <jats:italic>FTX<\/jats:italic>\n                  , and\n                  <jats:italic>SLC10A3<\/jats:italic>\n                  , demonstrated significant sex differences in their associations with AD endophenotypes (i.e., significant\n                  <jats:italic>sex x gene<\/jats:italic>\n                  interaction). Our results also uncovered sex-specific biological pathways, including a female-specific role of neuroinflammation and neuronal development, reinforcing the potential for sex-aware analyses to enhance precision medicine approaches in AD.\n                <\/jats:p>","DOI":"10.1101\/2025.01.02.631098","type":"posted-content","created":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T20:00:12Z","timestamp":1735848012000},"source":"Crossref","is-referenced-by-count":1,"title":["Sex-specific Associations of Gene Expression with Alzheimer\u2019s Disease Neuropathology and Ante-mortem Cognitive Performance"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8567-2532","authenticated-orcid":false,"given":"Mabel","family":"Seto","sequence":"first","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital\/Harvard Medical School, Boston, MA, USA"},{"name":"Center for Alzheimer\u2019s Research and Treatment, Department of Neurology, Brigham and 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Gifford","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory and Alzheimer\u2019s Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela L.","family":"Jefferson","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory and Alzheimer\u2019s Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2505","authenticated-orcid":false,"given":"Philip L.","family":"De Jager","sequence":"additional","affiliation":[{"name":"Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA"},{"name":"Cell Circuits Program, Broad Institute, Cambridge, MA, 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