Reproductive Aging, FSH, APO Proteins, and Alzheimer’s Disease: Endocrine Mechanisms Linking Ovarian Decline to Neurodegeneration

Alzheimer’s disease (AD) disproportionately affects women, with risk increasing sharply during and after the menopausal transition. While declines in estrogen have traditionally been emphasized, emerging evidence suggests that elevations in follicle-stimulating hormone (FSH) may represent a critical and underappreciated driver of neurodegenerative vulnerability. This review synthesizes current evidence linking reproductive aging to AD pathobiology, with a focus on endocrine, metabolic, and inflammatory mechanisms. We examine how sustained FSH elevation interacts with key molecular pathways implicated in AD, including C/EBPβ–δ-secretase signaling, mitochondrial dysfunction, impaired glucose metabolism, and disruptions in autophagic and lysosomal clearance. These processes converge to promote amyloid-β accumulation, tau pathology, and chronic neuroinflammation. In parallel, FSH influences apolipoprotein biology - particularly ApoE - through effects on lipid metabolism, protein lipidation, and clearance dynamics, thereby modulating both amyloid kinetics and inflammatory responses in an isoform-dependent manner. Reproductive aging is further characterized by systemic shifts in vascular integrity, blood–brain barrier function, and immunometabolic regulation, all of which may amplify susceptibility to neurodegenerative processes. Importantly, these upstream disturbances precede classical pathological hallmarks, reframing amyloid and tau accumulation as downstream manifestations of broader regulatory failure. Collectively, this work positions FSH not merely as a biomarker of ovarian decline, but as an active endocrine mediator of neurodegeneration. Targeting FSH signaling and its downstream pathways may therefore represent a promising and mechanistically grounded approach for mitigating AD risk, particularly in women.