New study explores menopausal hormone therapy and Alzheimer neuropathology

A new cohort study published in Neurology found that estrogen-only menopausal hormone therapy (MHT) demonstrated a “small but significant” association with lower odds of Alzheimer disease (AD) pathology on autopsy, along with favorable associations across several clinical and biomarker outcomes.

Researchers examined the relationship between MHT use and AD-related neuropathologic, clinical, and imaging/fluid biomarker outcomes in female participants using 2 independent, large-scale data sets.

The study drew on data from the National Alzheimer's Coordinating Center (NACC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants included women aged 50 years and older with self-reported use of estrogen-only MHT or no self-reported MHT use. Research was conducted at academic medical centers.

Key data

• Neuropathologic data from NACC included 258 MHT users (mean age at death 81.9 years, SD 19.5) and 2,701 non-MHT users (mean age at death 82.2 years, SD 11.0)
• The ADNI cohort included 110 MHT users (mean age 76.5 years, SD 7.5) and 1,948 non-MHT users (mean age 73.2 years, SD 8.9)
• Odds of increased AD pathology on autopsy, the primary outcome, were significantly decreased in MHT users relative to nonusers (odds ratio [OR] 0.65, 95% CI 0.48-0.88, P = 0.005)
• MHT use was associated with significantly decreased amyloid pathologic load assessed through plasma (β = 0.44, 95% CI 0.16-0.73, P = 0.0025) and CSF (β = 0.07, 95% CI 0.002-0.13, P = 0.030)
• MHT use was associated with significantly lower odds of clinical dementia diagnoses (OR 0.61, 95% CI 0.55-0.67, P < 0.0001)
• MHT use was associated with lower odds of symptoms of memory or functional decline (OR 0.67, 95% CI 0.61-0.74, P < 0.0001)

Findings span neuropathologic, biomarker, and clinical measures

The associations between MHT use and reduced AD-related outcomes were consistent across multiple types of evidence, spanning autopsy-confirmed neuropathology, plasma and CSF amyloid biomarkers, and clinical dementia diagnoses. The authors described these associations as “small but significant” across the 2 large cohorts studied.

Study authors noted that the findings do not address causality and have limited generalizability because of the retrospective nature of the study, and they characterized the associations as suggesting a protective effect of MHT use in the dementia course rather than confirming one. However, findings “suggest a protective effect of MHT use in the dementia course,” they stated.

Reference:

Bruno J, Shaw JS, Hosseini SMH, for Alzheimer’s Disease Neuroimaging Initiative. Association between menopausal hormone therapy and alzheimer disease neuropathology. Neurology. 2026;107(5):e218413. doi:10.1212/WNL.0000000000218413