Women who utilized estrogen-only menopausal hormone therapy (MHT) exhibited a significantly lower likelihood of developing Alzheimer's-related brain changes or dementia, according to a large study from Stanford University published in the journal Neurology.
The research analyzed post-mortem brain data from 21,462 participants, comparing 258 women who reported using estrogen-only MHT with approximately 2,701 women who did not.
Scientists examined the brains for hallmarks of Alzheimer's disease, including amyloid plaques and neurofibrillary tangles. The findings indicated that women who took estrogen-only therapy showed a 35% lower chance of Alzheimer's pathology and 39% lower odds of dementia over their lifetime. These women had most likely undergone hysterectomies, the study noted.
Among some living participants, those using estrogen-only therapy also performed better on memory tests and maintained independent functioning, with supporting evidence from blood and cerebrospinal fluid biomarkers. The average age of participants in the study was 70.
Researchers pointed out that recent findings suggest MHT may offer greater benefits when initiated during or shortly after menopause. Because the study participants were generally older when they began treatment, the observed benefits might actually underestimate the potential advantages of earlier therapy.
These results appear to diverge from some prior studies that had linked menopausal hormone therapy to an increased risk of dementia.
"Estrogen has well-described neuroprotective effects in animal models," stated co-author Jennifer Bruno, PhD, an instructor in psychiatry and behavioral sciences. "Estrogen plays a role in shifting amyloid toward the non-amyloidogenic pathway and promoting tau dephosphorylation — both amyloid and tau are hallmarks of Alzheimer’s disease."
Bruno added that estrogen supports synaptic plasticity, reduces neuroinflammation, and maintains blood-brain barrier integrity, which is consistent with the observed lower Alzheimer's pathology in estrogen-only users.
The study authors acknowledged limitations, noting that as an observational study, it could only establish an association and not definitively prove that hormone therapy reduced Alzheimer's risk. Senior author Hadi Hosseini, Ph.D., an associate professor of psychiatry and behavioral sciences at Stanford, explained that while biomarkers offer insights, examining the brain directly provides a clearer picture of damage.
"By looking where the actual damage is done — the brain — you can see where the Alzheimer’s-associated defining features are and how many of them are there," Hosseini said.
Hosseini also noted potential confounding factors, such as baseline health status or healthcare engagement, which are difficult to fully measure in observational data. "We worked hard to adjust for known confounders and to account for who does and doesn't come to autopsy, but observational data can only take you so far."
Alzheimer's disease is the primary cause of dementia in older adults, with women accounting for approximately two-thirds of diagnoses.
While the study's findings do not alter current clinical recommendations, Hosseini emphasized the need for well-designed clinical trials to confirm these observations and to determine if MHT offers a protective cognitive effect. Bruno concluded, "These results add meaningful, first-of-their-kind pathological evidence to a genuinely controversial area — but they are a signal for further study, not a reason to start or stop MHT for brain health."