Sex-specific vulnerability to Alzheimer's disease (AD) has been increasingly recognized, with menopause representing a decisive neuroendocrine transition. Estrogen and progesterone modulate synaptic plasticity, glucose metabolism, and amyloid-tau homeostasis, yet the impact of their decline and replacement remains controversial. AD biomarkers provide objective means to assess menopausal hormone therapy (MHT) mechanistic effects beyond cognitive endpoints.
Objective
To determine how MHT influences validated AD biomarkers in peri- and postmenopausal women.
Methods
A systematic review was conducted following PRISMA guidelines (PROSPERO CRD420251149404). PubMed, Embase, Web of Science, and Cochrane Library were searched through September 2025 for interventional and observational studies evaluating MHT and AD biomarkers after non-surgical menopause. Eligible biomarkers included cerebrospinal fluid (CSF) and plasma markers, and amyloid-, tau- or FDG-PET imaging. Study quality was assessed using RoB-2 and ROBINS-I tools, and evidence certainty with GRADE.
Results
Fourteen studies met inclusion criteria. Early or continuous transdermal 17β-estradiol was linked with lower CSF and plasma p-tau181 and preserved glucose metabolism in AD-vulnerable cortical regions. Neuroimaging studies showed decreased amyloid deposition and sustained metabolic benefits years after discontinuation. Conversely, oral conjugated equine estrogens and estrogen-progestin regimens led to neutral or unfavorable biomarker trends, particularly when initiated more than five years after menopause.
Conclusions
MHT's effects on AD biomarkers depend on timing, formulation and hormonal composition. Early transdermal estradiol appears to reinforce neuroprotective biomarker profiles, whereas delayed or combined therapies may nullify these benefits. Genotype-stratified trials with harmonized biomarker reports are needed to define optimal neuroprotective windows for women.
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