Women who used estrogen-only hormone therapy after menopause had substantially lower odds of developing dementia and showed less severe Alzheimer's-related brain pathology than women who never took it, according to a large observational study from Stanford Medicine — the latest data point in a long-running scientific reassessment of hormone therapy's effects on the aging brain.
The study, published Aug. 12 in Neurology, drew on two federally funded research cohorts totaling more than 21,000 women: a group of 2,959 women whose brains were examined at autopsy, and a separate group of 728 living participants who underwent brain scans and biomarker testing. Among the roughly 1,953 women who had used estrogen-only therapy, researchers found 35% lower odds of Alzheimer's disease-related pathology — amyloid plaques and tau tangles — at autopsy, and 39% lower odds of a clinical dementia diagnosis during their lifetimes, compared with the 19,509 women who never used hormone therapy. In the autopsy group, 18% of hormone therapy users showed no detectable signs of Alzheimer's pathology, versus 10% of non-users.
A reversal, with caveats
The findings arrive after two decades in which hormone therapy use collapsed — from about 4.4% of U.S. women in 2007 to just 1.7% in 2023 — largely because the 2002 Women's Health Initiative trial linked combined estrogen-progestin therapy to higher rates of dementia and other health risks. This new analysis looked only at estrogen-only regimens, typically prescribed to women who have had a hysterectomy, and found the opposite association.
"More research needs to be done before we can make recommendations to women about their use of these therapies in relation to their brain health."
Jennifer Bruno, Stanford Medicine, study author
Outside researchers urged caution. Allison Aiello of Columbia University noted that participants in the new study began hormone therapy around age 70 on average, decades later than how it is typically prescribed today — usually starting in a woman's late 40s or 50s and stopping before 60 — meaning the results may not translate to current practice. Pauline Maki of the University of Illinois Chicago flagged a "healthy user bias," pointing out that hormone therapy users in observational studies tend to have higher incomes and better access to healthcare, and stressed that randomized controlled trials have so far failed to show a cognitive benefit from hormone therapy.
Because the study is observational, it can show only association, not causation, and it looked at how hormone therapy was used decades ago rather than under contemporary prescribing guidelines. The researchers say the next step is examining whether the timing, dose or duration of estrogen-only therapy — or genetic factors such as APOE status — help explain which women see the largest apparent benefit, and whether any of it holds up in a clinical trial.
