From hormones to neurodegeneration: how FSH drives Alzheimer's disease

Abstract

The role and function of follicle-stimulating hormone in the gonads have been extremely studied. However, recent research has begun to explore the relationship between elevated follicle-stimulating hormone levels and the prevalence of extragonadal disorders, particularly in perimenopausal and postmenopausal women. These disorders include endometrial cancer, osteoporosis, obesity, and atherosclerosis. This review provides new insights into the relationship between follicle-stimulating hormone and the development of age-related diseases, with a focus on Alzheimer's disease. Follicle-stimulating hormone does not act alone in promoting Alzheimer's disease but often works in conjunction with inflammation, lipid accumulation, and vascular alterations. Furthermore, follicle-stimulating hormone synergizes with obesity, gut microbiota, autophagy, and aging, creating conditions that facilitate the onset and progression of Alzheimer's disease. This review also summarizes the therapeutic potential of FSH-blocking antibodies in treating these diseases.

Keywords: Alzheimer’s disease; FSH-blocking antibodies; aging; follicle-stimulating hormone; lipid accumulation; neuroinflammation.

Figure 1

The role of FSH-FSHR signaling in neurons and hippocampus. FSH promotes the formation of amyloid plaques through Aβ peptide aggregation and the development of NFTs. Additionally, FSH triggers the release of ApoE via the C/EBPβ–δ-secretase pathway, which further elevates levels of IL-6 and IL-1β. The action of FSH is antagonized by FSH-Ab, which binds to FSHR and inhibits it’s signaling.

Figure 2

The two-hit hypothesis explains the effects of peripheral risky factors including FSH in AD. In the first step, FSH contributes to BBB breakdown, vascular stiffness, and a decline in CBF, leading to the leakage of risk factors through mechanisms involving inflammation, lipid accumulation, and vascular alterations. Building on the step 1, these peripheral risk factors exacerbate neuroinflammation, cerebral lipid deposition, CAA, and intracranial atherosclerosis, ultimately resulting in Alzheimer’s disease-like pathology.

Figure 3

Potential association of FSH and other risk factors in AD. FSH exhibits potential synergistic effects with obesity, gut microbiota dysbiosis, impaired mitophagy, genetic factors (ApoE), and aging, all of which contribute to the development and progression of AD.