Impacts of Menopausal Hormone Therapy on Alzheimer's Disease Biomarkers: A Systematic Review
Amanda Rodrigues1, Carolina Moura2, Filipe Valério3, Gabriel Tudella4, Anderson Silva5, Carlos Monforte1, Diogo Santos6
1Medicine, Faculdade de Ciências Médicas da Santa Casa de São Paulo, 2Neurology, Hospital Universitário Antonio Pedro, 3Medicine, Universidade Federal Fluminense (UFF), 4Medicine, Universidade Federal de Santa Maria, 5Pharmacological Sciences, Universidade Federal de Pernambuco, 6Neurology, Irmandade da Santa Casa de Misericórdia de São Paulo
Objective:
To determine how menopausal hormone therapy (MHT) influences validated biomarkers of Alzheimer’s disease (AD) in peri- and postmenopausal women, considering formulation, timing and genotype.
Background:
Sex-specific vulnerability to AD has been increasingly discussed, with menopause representing a critical neuroendocrine transition. Estrogen and progesterone modulate synaptic plasticity, glucose metabolism, and amyloid and tau homeostasis, yet the clinical impact of their decline and replacement remains controversial. AD biomarkers, such as amyloid, tau, and neuroimaging measures, offer an objective approach to assess MHT’s mechanistic effects beyond cognitive endpoints.
Design/Methods:
A systematic review was conducted following PRISMA guidelines and registered in PROSPERO (CRD420251149404). Searches of PubMed, Embase, Web of Science, and Cochrane Library through September 2025 identified interventional and observational studies evaluating MHT and AD biomarkers in women after natural menopause. Eligible biomarkers included cerebrospinal fluid (CSF) Aβ42, total tau, phosphorylated tau, plasma markers, and amyloid-, tau-, or FDG-PET imaging. Study quality was assessed using RoB-2 and ROBINS-I tools, and evidence certainty was rated with GRADE.
Results:
From 2480 records, 1429 abstracts were screened, 24 full texts reviewed and 14 studies met inclusion criteria. Early or continuous estradiol-based MHT, especially transdermal 17β-estradiol, was associated 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. In contrast, oral conjugated equine estrogens and combined estrogen-progestin regimens were linked to neutral or unfavorable patterns, mainly when initiated over five years after menopause.
Conclusions:
MHT’s impact on AD biomarkers depends on timing, formulation and composition. Early transdermal estradiol appears to support neuroprotective biomarker profiles, whereas delayed or combined therapies may negate these effects. Harmonized biomarker protocols and genotype-stratified trials are needed to establish optimal therapeutic windows for neuroprotection in women.
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