Sex-specific retina-brain signatures link ERα/ERβ imbalance with gliosis in Alzheimer's disease

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.

doi:10.64898/2026.04.30.722000

bioRxiv · 10.64898/2026.04.30.722000

Sex-specific retina-brain signatures link ERα/ERβ imbalance with gliosis in Alzheimer's disease

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.

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Abstract

Women face a twofold higher lifetime risk of Alzheimers 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.

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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.. 2026-05-05. Sex-specific retina-brain signatures link ERα/ERβ imbalance with gliosis in Alzheimer's disease. https://doi.org/10.64898/2026.04.30.722000

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