A large Stanford Medicine study published in Neurology on August 12 found that women who used estrogen-only menopausal hormone therapy (MHT) had a 35% lower risk of Alzheimer’s-related brain pathology and 39% lower odds of dementia over their lifetime compared to those who did not use the therapy.
Researchers analyzed post-mortem data from 21,462 women, including 258 estrogen-only MHT users and 2,701 non-users, examining brains for hallmark Alzheimer’s signs such as amyloid plaques, neurofibrillary tangles, and amyloid-plaque density. Among living participants, estrogen-only users also demonstrated better memory performance and independent functioning, with supporting biomarkers in blood and cerebrospinal fluid. The average participant age was 70 years old at the time of data collection.
The study drew from two major Alzheimer’s research databases—the National Alzheimer’s Coordinating Center and the Alzheimer’s Disease Neuroimaging Initiative—incorporating clinical diagnoses, brain imaging, biomarker data, and autopsy findings. Most estrogen-only MHT users in the study had likely undergone hysterectomies, as the therapy typically includes estrogen alone in such cases.
Key findings:
- Estrogen-only MHT users showed reduced Alzheimer’s pathology in autopsied brains.
- Lifetime dementia risk was 39% lower for estrogen-only users.
- Living participants on estrogen-only therapy performed better on memory tests and maintained greater functional independence.
- Earlier initiation of therapy—during or shortly after menopause—may yield greater neuroprotective benefits, though the study noted participants generally started treatment later in life.
The research contradicts some prior studies that linked menopausal hormone therapy to increased dementia risk, suggesting that timing and formulation (e.g., estrogen-only vs. combined estrogen-progestin) may play critical roles. Co-author Jennifer Bruno, PhD, highlighted estrogen’s neuroprotective effects in animal models, noting its role in reducing amyloid plaque formation.
Experts emphasized that while the study provides strong observational evidence, it does not prove causation. The findings align with growing research suggesting that hormone therapy initiated early in menopause may offer cognitive benefits, though further clinical trials are needed to confirm these effects.
The study’s senior author, Hadi Hosseini, PhD, stated: “Our study is unique in that we looked at all the standards of Alzheimer’s diagnosis, including the gold-standard outcome: Alzheimer’s-associated hallmarks in autopsied brains.” No prior study had examined such a large number of postmortem Alzheimer’s outcomes.
Background on hormone therapy and dementia risk:
Menopausal hormone therapy, once widely prescribed, saw a sharp decline in use in the U.S. after the Women’s Health Initiative (WHI) study in 2002 linked combined estrogen-progestin therapy to increased risks of heart disease, stroke, and breast cancer. The WHI findings led to widespread caution around hormone therapy, though subsequent research has suggested that risks may vary by age, formulation, and timing of initiation.
This Stanford study adds to a growing body of evidence exploring estrogen’s potential cognitive benefits, particularly when administered early in menopause. Researchers noted that the women in this study were older on average when they began therapy, which may mean the observed benefits are understated compared to what could be achieved with earlier treatment.
Next steps:
The study’s authors call for randomized controlled trials to directly test whether estrogen-only therapy can prevent or delay Alzheimer’s disease in postmenopausal women. They also stress the need for personalized risk-benefit assessments, as hormone therapy is not suitable for all women due to varying health profiles and potential side effects.
For now, the findings offer hope for a potential protective effect against Alzheimer’s, particularly for women who have undergone hysterectomies and are considering hormone therapy. However, experts urge caution, noting that individual medical advice should guide treatment decisions rather than broad recommendations.