Reproductive Aging, FSH, and Apolipoprotein Biology in Alzheimer’s Disease

Alzheimer’s disease (AD) affects women more than men, with risk increasing during and after the menopausal transition. Estrogen deficiency has long been a leading explanation for this sex difference, but emerging evidence suggests that follicle-stimulating hormone (FSH) may represent an additional, contributory endocrine factor. This narrative and mechanistic review integrates evidence on reproductive aging, AD pathobiology, and sex differences in AD, with particular emphasis on endocrine, metabolic, protein-clearance, inflammatory, and vascular mechanisms. PubMed and Google Scholar were searched for peer-reviewed human studies, animal models, and mechanistic investigations published through September 2026, prioritizing primary research and systematic reviews concerning FSH signaling, ApoE biology, and AD pathophysiology. Circulating FSH rises markedly across the menopausal transition and has been associated with cerebral amyloid burden in women, although the magnitude of this association is modest relative to established genetic risk factors such as APOE ε4 and causal directionality has not been established in humans. Preclinical studies further suggest that elevated FSH may influence pathways relevant to AD, including C/EBPβ–δ-secretase signaling, neuronal glucose metabolism, mitochondrial function, autophagic-lysosomal clearance, and apolipoprotein biology. Several steps within these proposed mechanisms, including the predominance of Gαi coupling by neuronal FSH receptors and any direct FSH action on microglia, remain incompletely established. Dysregulation across these interrelated systems may contribute to Aβ accumulation, tau pathology, impaired protein clearance, and chronic neuroinflammation, while reproductive aging is also associated with vascular and blood-brain barrier changes that may precede classical AD pathology. Taken together, current evidence supports a model in which sustained FSH elevation may act as one component of the broader biological changes accompanying reproductive aging that influence AD vulnerability. Further human and mechanistic studies are needed to determine the magnitude, cellular pathways, and therapeutic relevance of this contribution.