Shahin, S.; Vit, J.-P.; Rentsendorj, A.; Fuchs, D.-T.; Swerdlow, N.; Gaire, B. P.; Robinson, E.; Kissel, A.; Hagerman, L.; Williams, A.; Ljubimov, A. V.; Hawes, D.; Schneider, L. S.; Mirzaei, M.; Black, K. L.; Koronyo, Y.; Koronyo-Hamaoui, M.

Women face a twofold higher lifetime risk of Alzheimer's 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-neurodegenerative phenotype with intensified gliosis and tissue atrophy, whereas males displayed a dominant vasculopathy, marked by increased retinal vascular A{beta}40 deposition, tight-junction disruption, and cerebral amyloid angiopathy. In females, this profile coincided with inflammation-associated estrogen receptor (ER)- remodeling and reduced global and astrocytic-nuclear ER-{beta}, 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/ER{beta} imbalance as a sex-linked glial mechanism associated with female vulnerability in AD.