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

Alzheimer’s disease (AD) affects more women than men, and risk rises precipitously during and after the menopausal transition. Estrogen deficiency has been the most prominent hypothesis to explain this sex difference, but increasing evidence also implicates follicle-stimulating hormone (FSH) as an independent contributor to neurodegenerative risk. This narrative review integrates the literature on reproductive aging, AD pathobiology, and sex differences in AD, with an emphasis on endocrine, metabolic, and inflammatory mechanisms relevant to their relationship. PubMed and Google Scholar were searched for peer-reviewed human studies, animal models, and mechanistic investigations published through early 2026, prioritizing primary research and systematic reviews on FSH signaling, ApoE biology, and AD pathophysiology. FSH rises in a graded fashion across the menopausal transition and has been associated with multiple pathways implicated in AD, including C/EBPβ–δ-secretase signaling, mitochondrial function, neuronal glucose metabolism, and autophagic-lysosomal clearance - though the causal directionality of many of these relationships remains to be established in humans. Dysfunction in these interrelated systems has been associated with Aβ accumulation, tau pathology, and chronic neuroinflammation. FSH also appears to influence apolipoprotein biology, particularly ApoE, through actions on lipid metabolism, protein lipidation, and clearance, with downstream effects on Aβ aggregation and inflammatory signaling that differ by ApoE isoform. In addition, reproductive aging is associated with changes in vascular integrity and blood-brain barrier function that may precede classical AD pathology. This review describes the mechanistic pathways through which chronically elevated FSH may contribute to AD risk in women and discusses the potential therapeutic implications of FSH modulation, while acknowledging that much of the current mechanistic evidence derives from preclinical models and requires validation in human populations.