Estradiol-Containing MHT May Impact Alzheimer Disease-Related Biomarkers in Postmenopausal Women

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Estradiol-containing menopausal hormone therapy (MHT) initiated in early postmenopause may influence trajectories of Alzheimer disease-related biomarkers, according to research presented at The Menopause Society’s 2025 Annual Meeting. In particular, amyloid-β measures were found to be influenced; however, the differences did not consistently reach statistical significance.

The investigators wrote that these findings may partially support the critical window hypothesis and suggest a need for larger studies to confirm neuroprotective effects of MHT during early postmenopause.¹

Alzheimer disease is the most common cause of dementia (60%–80% of cases) and is a general term for memory loss and other impaired cognitive abilities serious enough to interfere with daily life. Although the Alzheimer’s Association said that it is unclear how plaques and tangles play a role within Alzheimer disease, it is believed that they play a role in blocking communication among nerve cells, which then causes the memory failure, personality changes, and difficulties carrying out daily activities.²

While blood biomarkers of Alzheimer disease are emerging as a tool for predicting Alzheimer disease and Alzheimer disease-related dementia, it is not known if and how MHT may affect these biomarkers in women who are postmenopausal. For this reason, the investigators conducted a secondary analysis of the data generated in the Early Versus Late Intervention Trial with Estradiol (ELITE; NCT00114517)—a trial examining the effects of oral 17B-estradiol on the progression of early atherosclerosis and cognitive decline in healthy women who are postmenopausal³—to evaluate the effect of MHT on longitudinal changes in plasma Alzheimer disease biomarkers.^1,3

The ELITE data utilized for this trial included 643 healthy postmenopausal women stratified into early (< 6 years) or late (≥ 10 years) postmenopause. These women were randomly assigned to receive 1 mg daily oral 17-β estradiol or placebo, with women who had an intact uterus also receiving vaginal progesterone or placebo. Concentrations of Alzheimer disease biomarkers, including Aβ40, Aβ42, Aβ42/Aβ40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau-181 (ptau181) were measured in baseline and 2.5-year post-randomization plasma samples from 438 women using SIMOA technology. Linear mixed-effects models were used to assess the MHT effect on the rates of change in each biomarker level, stratified by early or late postmenopause category and ApoE4 genotype to evaluate any effect modification by those factors.^1,3

The findings demonstrated that, among all participants, MHT significantly accelerated the decline in Aβ40 compared with placebo (p = .049); however, MHT’s effects on other biomarkers were not considered statistically significant. In early postmenopausal women, MHT-treated patients presented numerically greater declines in Aβ42 and greater increases in Aβ42/Aβ40 ratio compared with placebo, though the differences were not statistically significant. GFAP levels also declined in both randomized groups among early postmenopausal women, with slightly greater declines in the MHT group. Additionally, MHT was correlated with a more pronounced decline in Aβ40 and Aβ42 compared with placebo among ApoE4 carriers in early postmenopause. Similarly, differences did not reach statistical significance. MHT did not appear to have effects on any biomarker in the late postmenopausal women.¹

These data can have significant implications for postmenopausal women, as they demonstrate that MHT containing estradiol can have negative impacts on certain biomarkers; however, not all the biomarkers had shown accelerated declines.¹ Regardless, women who are postmenopausal can discuss with their pharmacists and health care professionals the best approaches to maintaining their health amid menopause without hindering their neurological health. Pharmacists are crucial to providing patients with reliable, accurate information during counseling.

REFERENCES

1. Yang Z, Rufino D, Yassine H, et al. S-10 – Impact of Menopausal Hormone Therapy on Longitudinal Changes in Blood Biomarkers of Alzheimer’s Disease by Menopausal Stage: A Secondary Analysis from the ELITE. Presented at: The Menopause Society Annual Meeting; Orlando, Florida. October 21–25, 2025.

2. Alzheimer’s Association. What is Alzheimer’s Disease? Accessed October 17, 2025. https://www.alz.org/alzheimers-dementia/what-is-alzheimers#basics

3. ELITE: Early Versus Late Intervention Trial With Estradiol. ClinicalTrials.gov identifier: NCT00114517. Updated January 18, 2023. Accessed October 17, 2025. https://www.clinicaltrials.gov/study/NCT00114517