Women who used estrogen-only menopausal hormone therapy had significantly less evidence of Alzheimer's disease in their brains than women who never used it, according to a large observational study published Aug. 12 in Neurology, the medical journal of the American Academy of Neurology. The analysis, led by researchers at Stanford Medicine, drew on data from 21,462 women, making it one of the largest studies to examine hormone therapy and dementia risk using direct brain evidence rather than self-reported diagnoses alone.
Roughly 2,959 participants had their brains examined after death, at an average age of 82, while a further 728 underwent brain scans or biomarker testing while still living. Among the full cohort, 1,953 women had used estrogen-only hormone therapy and 19,509 had not; researchers followed participants for three to five years starting at an average age of 71. Estrogen-only formulations are prescribed specifically to women who have had a hysterectomy, since estrogen taken without progesterone raises the risk of endometrial cancer in women who still have a uterus.
Fewer amyloid plaques, lower dementia odds
At autopsy, hormone therapy users had 35% lower odds of showing the plaques and tangles characteristic of Alzheimer's pathology. Eighteen percent of users had no detectable Alzheimer's signs at all, compared with 10% of non-users, while 40% of users carried all three recognized hallmarks of the disease compared with 51% of non-users. Living participants who had used hormone therapy also showed lower amyloid buildup on biomarker testing. Across the study, hormone therapy use was associated with 39% lower odds of receiving a clinical dementia diagnosis during participants' lifetimes.
While these findings help us better understand the relationship between hormone therapy use and various markers of dementia, more research needs to be done.
— Jennifer Bruno, Stanford Medicine
The results arrive more than two decades after the Women's Health Initiative trials led many clinicians to scale back hormone therapy prescriptions over concerns it raised dementia and stroke risk in older women. Researchers on the new study caution that its design cannot establish that estrogen therapy prevents Alzheimer's disease — it is an observational analysis, not a randomized trial, and cannot rule out that healthier women were simply more likely to have been prescribed and to have stayed on hormone therapy in the first place.
The study population also used hormone therapy under older prescribing patterns, often starting treatment well past age 70, whereas current guidance favors starting therapy, when used, closer to the onset of menopause in a woman's late 40s or early 50s. That mismatch means the findings may not directly translate to how hormone therapy is prescribed today. The authors say the results justify further investigation, including trials that could test whether the timing of estrogen therapy relative to menopause affects long-term brain outcomes, rather than any immediate change to clinical recommendations.
