Sex-specific reproductive and hormonal factors in relation to Alzheimer’s disease-related biomarkers: A Systematic Review

Menopausal status and elevated FSH levels show more consistent associations with Alzheimer's biomarkers than hormone therapy. However, the evidence is mixed and further longitudinal studies are needed.

Summary and findings

This systematic review evaluated associations between reproductive and hormonal factors and Alzheimer's disease-related biomarkers. A total of 101 studies were included, focusing on factors such as menopausal transition and follicle-stimulating hormone levels. Findings indicated that earlier menopause and higher FSH concentrations were associated with greater amyloid burden and reduced cerebral glucose metabolism.

Abstract

<title>Abstract</title> <p> <bold>Objective:</bold> To systematically evaluate associations between female- and male-specific reproductive and hormonal factors and Alzheimer's disease (AD)-related biomarkers, identify consistently associated exposures, and assess differences across biomarker domains. The focus was on amyloid, tau, neurodegeneration, neuronal injury, cerebral metabolism, and cerebrovascular or white-matter biomarkers. <bold>Methods:</bold> This systematic review was registered in PROSPERO (CRD420261363648). MEDLINE (Ovid), Embase, and Web of Science were searched from inception to 26 February 2026. Two reviewers independently screened studies, assessed eligibility, and extracted data. Studies examining reproductive factors, hormonal exposures including endogenous factors and exogenous factors, and reproductive endocrine disorders in relation to AD-related biomarkers were included. Risk of bias was assessed using the Newcastle-Ottawa Scale and the RoB2 tool. <bold>Findings:</bold> Of 35,331 records identified, 101 studies met inclusion criteria, with most studies being judged as having a moderate risk or having some concern for bias. Evidence was strongest for female reproductive and hormonal factors. Menopausal transition and earlier menopause were associated with greater amyloid burden, reduced cerebral glucose metabolism, smaller global and regional brain volumes, cortical thinning, and poorer white-matter integrity in several studies. Higher follicle-stimulating hormone (FSH) concentrations were consistently associated with greater amyloid pathology in women. Hypertensive disorders of pregnancy, objectively measured nighttime vasomotor symptoms, and premenopausal bilateral oophorectomy were also linked to less favorable biomarker profiles. Associations were most evident in amyloid, neurodegeneration, and white-matter outcomes, whereas findings for tau pathology and neurofilament light were less consistent. Evidence regarding menopausal hormone therapy (MHT) was mixed; most longitudinal studies and randomized trials reported no clear associations with AD biomarkers, although some findings supported a potential critical-window effect, with more favorable outcomes when therapy was initiated near menopause. Evidence in men was sparse and insufficient to draw firm conclusions. <bold>Conclusions:</bold> Menopausal status, age at menopause, and elevated FSH levels, showed more consistent associations with AD-related biomarkers than exogenous hormone exposures such as MHT. Menopause-related endocrine changes, earlier menopause, and selected female-specific reproductive health conditions may contribute to AD vulnerability, although longitudinal evidence remains limited and causal relationships cannot be established. </p>

Limitations

• Not reported in abstract.

Elsewhere in the HMG (Human Menopausal Gonadotropin) corpus