Estrogen deprivation exacerbates Alzheimer’s disease pathology through neuronal CTSS signaling

Alzheimer’s disease (AD) exhibits a pronounced sex bias, with women facing disproportionately higher risk and more severe pathology. Postmenopausal estrogen decline is implicated in this vulnerability, yet the molecular mechanisms linking estrogen loss to AD pathogenesis remain incompletely understood. Here, we demonstrate that ovariectomy (OVX) in female 5xFAD mice significantly exacerbates amyloid-β (Aβ) pathology, cognitive deficits, neuroinflammation, and reduces synaptic markers. Pharmacological blockade of estrogen receptor signaling recapitulated these effects, confirming their dependence on estrogen receptor pathways. Single-nucleus RNA sequencing (snRNA-seq) revealed widespread transcriptional reprogramming across brain cell types following estrogen deprivation, with prominent upregulation of the lysosomal protease cathepsin S ( Ctss ) and the AD risk gene ApoE . Remarkably, partial genetic reduction of CTSS prevented OVX-induced Aβ accumulation, glial activation, and synaptic decline in female 5xFAD mice, establishing CTSS as a critical downstream mediator of estrogen deficiency-driven pathology. Our findings provide mechanistic insight into sex-biased AD vulnerability and identify CTSS as a promising therapeutic target for mitigating AD risk in postmenopausal women.