Association Between Menopausal Hormone Therapy and Alzheimer Disease Neuropathology

Although evidence suggests that the neurophysiologic impact of estrogen decline during menopause may contribute to increased risk of Alzheimer disease (AD) in women, the effect of menopausal hormonal therapy (MHT) on AD risk requires further study. We sought to examine the associations between MHT use and neuropathologic, clinical, and imaging/fluid biomarker outcomes.

In this cohort study, we tested the association between estrogen-only MHT use and dementia outcomes in female participants using 2 independent, large-scale data sets: National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants included women 50 years and older with self-reported use of estrogen-only MHT or no self-reported use of MHT. Clinical, imaging/fluid biomarker, and neuropathologic outcomes were examined. Research was performed at academic medical centers.

Neuropathologic data were collected from NACC for 258 MHT users (mean age of death = 81.9, SD = 19.5) and 2,701 non-MHT users (mean age of death = 82.2, SD = 11.0). The ADNI cohort included 110 MHT users (mean age = 76.5, SD = 7.5) and 1,948 non-MHT users (mean age = 73.2, SD = 8.9). The odds of increased AD pathology on autopsy (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 secondary outcomes including 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) and lower odds of symptoms of memory/functional decline (OR 0.67, 95% CI 0.61-0.74, p < 0.0001).

Our findings demonstrate small but significant associations between MHT use during later life and a range of AD-related neuropathologic and clinical outcomes in 2 large cohorts of female participants. Although our results do not address causality and have limited generalizability due to the retrospective nature of the study, they suggest a protective effect of MHT use in the dementia course.