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bioRxiv · 10.1101/2025.08.22.671724

Sex-dependent interferon signaling drives female-biased vulnerability in Alzheimer's disease

Lopez-Atalaya, J. P.·Lopez-Lopez, V.·Iniesta, G.·Galan-Ganga, M.·Exposito-Coca, A.·Bhojwani-Cabrera, A.·Guillot-Fernandez, M.·GIRALT, A.
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Abstract

Alzheimers disease (AD) disproportionately affects women, yet the neurobiological mechanisms underlying this sex bias remain poorly understood. Here, we identify a sex-dependent activation of type I interferon (IFN-I) signaling as a contributor to this disparity. Transcriptomic profiling of brain from AD patients revealed selective enrichment of IFN-I pathway in females. This immune signature was mirrored in the APP/PS1 mouse model of AD, where females exhibited more pronounced amyloid accumulation, neuroinflammation, and neurodegeneration. Acute IFN-I activation reproduced pathological features of AD, whereas chronic IFN-I elevation in APP/PS1 mice aggravated disease progression. In contrast, pharmacological targeting of IFN-I response by inhibiting the cGAS-STING pathway in APP/PS1 female mice reduced neuropathological burden, and preserved cognitive performance. Together, these findings identify interferon signaling as a modifiable and sex-linked driver of AD pathology. Our study uncovers a critical neuroimmune mechanism contributing to female-biased vulnerability and highlights interferon modulation as a promising therapeutic strategy in AD.

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Lopez-Atalaya, J. P., Lopez-Lopez, V., Iniesta, G., Galan-Ganga, M., Exposito-Coca, A., Bhojwani-Cabrera, A., Guillot-Fernandez, M., GIRALT, A.. 2025-08-28. Sex-dependent interferon signaling drives female-biased vulnerability in Alzheimer's disease. https://doi.org/10.1101/2025.08.22.671724

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