Stanford Study Links Estrogen-Only Hormone Therapy To 35% Lower Alzheimer's Disease Risk

A large study led by Stanford Medicine researchers has found that women who used estrogen-only menopausal hormone therapy showed significantly less brain evidence of Alzheimer's disease at autopsy, along with lower odds of receiving a dementia diagnosis during their lifetimes, offering new pathological evidence in a research area that has produced conflicting findings for decades.

The study, published August 12 in Neurology, the medical journal of the American Academy of Neurology, analyzed data from 21,462 women, drawing on two existing research datasets: the National Alzheimer's Coordinating Center's autopsy cohort and the Alzheimer's Disease Neuroimaging Initiative's living cohort. Within that population, researchers compared 258 women who reported using estrogen-only hormone therapy against roughly 2,701 women who reported no hormone therapy use.

Women who had used estrogen-only therapy showed 35% lower odds of Alzheimer's disease pathology in their autopsied brain tissue and 39% lower odds of having ever received a clinical dementia diagnosis, according to the study's findings. Researchers examined brain tissue directly for amyloid plaques, neurofibrillary tangles and amyloid-plaque density, three hallmark physical changes associated with Alzheimer's disease, rather than relying solely on cognitive test scores or clinical symptom assessments used in many earlier studies on the topic.

Jennifer Bruno, the study's lead author and an instructor in psychiatry and behavioral sciences at Stanford, said the direct examination of brain tissue set the research apart from prior work in the field. "Women who had used estrogen-only hormone therapy had 35% lower odds," Bruno said, describing the reduced presence of the disease's defining brain changes compared with women who had not used the therapy.

Because estrogen-only hormone therapy is generally prescribed to women who have undergone a hysterectomy, given that estrogen alone can raise the risk of endometrial cancer in women who still have a uterus, most participants in the estrogen-only group likely fell into that category, according to the study's authors, though the datasets used did not include confirmed hysterectomy records.

Senior author Hadi Hosseini, an associate professor of psychiatry and behavioral sciences at Stanford, said examining actual brain tissue offered a more definitive picture than symptom-based measures alone. "By looking where the actual damage is done, the brain, you can see where the Alzheimer's-associated defining features are," Hosseini said, describing the approach as a way to more directly locate and quantify disease-related changes rather than inferring them indirectly.

The findings arrive in an area of medical research that has produced notably inconsistent results over the years. Earlier studies, including large trials from the Women's Health Initiative, had previously linked menopausal hormone therapy, particularly combined estrogen-progesterone regimens, to an increased risk of dementia, guidance that shaped clinical recommendations discouraging hormone therapy use specifically for memory-related concerns. The new findings run counter to that established guidance, at least with respect to estrogen-only regimens.

Researchers cautioned that the study's observational design means it can demonstrate an association between estrogen-only therapy and reduced Alzheimer's pathology, but cannot prove that the therapy directly causes that reduction. Hosseini told Fox News Digital that other factors could help explain the pattern, noting it remains possible that women who used hormone therapy differed from non-users in ways researchers could not fully measure, including overall baseline health or general engagement with the health care system.

Timing also complicates how directly the findings apply to women considering hormone therapy today. Participants in the study who used hormone therapy generally began treatment around age 70, according to reporting on the study, whereas current clinical practice typically involves starting therapy in the late 40s or early 50s and discontinuing it before age 60. Because more recent research suggests menopausal hormone therapy may offer greater benefits when started during or shortly after menopause, researchers said the study's findings, based on a group that started therapy considerably later in life, may actually understate the potential benefit of earlier initiation.

Alzheimer's disease remains the leading cause of dementia among older adults, with women accounting for roughly two-thirds of all diagnoses. Some research has pointed to the sharp decline in estrogen levels during menopause as a possible contributing factor to increased Alzheimer's risk among women, a hypothesis the new findings offer additional, though still preliminary, support for.

Despite the notable findings, the study's authors were clear that the results should not be interpreted as a basis for changing current medical guidance. Bruno said the findings represent meaningful, first-of-their-kind pathological evidence in a genuinely contested area of research, but stressed they serve as a signal calling for further study rather than a reason for women to start or stop hormone therapy specifically for brain health. Both Bruno and Hosseini said the field now needs prospective, biomarker-based clinical trials following women before, during and after menopause to determine more conclusively whether menopausal hormone therapy offers a genuine protective effect against Alzheimer's disease.

The study was funded by the National Institutes of Health. Researchers said the findings underscore the continued need for well-designed clinical trials capable of establishing a clearer, causal relationship between hormone therapy and long-term brain health outcomes in women.