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

Alzheimer’s 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.