{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T04:09:22Z","timestamp":1778299762610,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,5]]},"group-title":"Neuroscience","reference-count":104,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Institutes of Health\/the National Institute on Aging","award":["R01AG056478"],"award-info":[{"award-number":["R01AG056478"]}]},{"name":"the National Institutes of Health\/the National Institute on Aging","award":["R01AG055865"],"award-info":[{"award-number":["R01AG055865"]}]},{"name":"the National Institutes of Health\/the National Institute on Aging","award":["AG056478-04S1"],"award-info":[{"award-number":["AG056478-04S1"]}]},{"name":"the Goldrich Foundation"},{"name":"The Snyder Foundation"},{"name":"the Ray Charles Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Women face a twofold higher lifetime risk of Alzheimer\u2019s disease (AD) than men, yet the mechanisms underlying female-biased vulnerability and sex-specific disease signatures across the retina-brain axis remain unknown. By integrating clinicopathological and proteomic datasets from paired retinal and brain tissues from 182 donors, we identified sex-divergent molecular and pathological features across the AD continuum. Despite comparable retinal and cerebral amyloid and tau burdens between sexes, females exhibited a more severe neuroinflammatory\u2013neurodegenerative phenotype with intensified gliosis and tissue atrophy, whereas males displayed a dominant vasculopathy, marked by increased retinal vascular A\u03b2\n                  <jats:sub>40<\/jats:sub>\n                  deposition, tight-junction disruption, and cerebral amyloid angiopathy. In females, this profile coincided with inflammation-associated estrogen receptor (ER)-\u03b1 remodeling and reduced global and astrocytic-nuclear ER-\u03b2, which associated more strongly with cognitive decline than in males. These results indicate that comparable AD proteinopathy is associated with divergent downstream consequences across the retina-brain axis and identify astrocytic ER\u03b1\/ER\u03b2 imbalance as a sex-linked glial mechanism associated with female vulnerability in AD.\n                <\/jats:p>","DOI":"10.64898\/2026.04.30.722000","type":"posted-content","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:05:14Z","timestamp":1778025914000},"source":"Crossref","is-referenced-by-count":0,"title":["Sex-specific retina\u2013brain signatures link ER\u03b1\/ER\u03b2 imbalance with gliosis in Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"given":"Saba","family":"Shahin","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Philippe","family":"Vit","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Altan","family":"Rentsendorj","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dieu-Trang","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie","family":"Swerdlow","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhakta Prasad","family":"Gaire","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Kissel","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larkin","family":"Hagerman","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayzhah","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander V.","family":"Ljubimov","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States"},{"name":"Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States"},{"name":"Department of Biomedical Sciences, Division of Applied Cell Biology and Physiology, Cedars-Sinai Medical Center, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debra","family":"Hawes","sequence":"additional","affiliation":[{"name":"Department of Pathology, Children\u2019s Hospital, Los Angeles, CA, United States"},{"name":"Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lon S.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehdi","family":"Mirzaei","sequence":"additional","affiliation":[{"name":"M.M. 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