A new study suggests that estrogen-only menopausal hormone therapy may offer protection against Alzheimer's disease pathology and cognitive decline in women. Researchers analyzing data from two large brain imaging and autopsy databases found that women who used estrogen-only therapy had significantly lower levels of amyloid plaques, tau tangles, and other hallmark brain changes associated with Alzheimer's disease compared to women who never used hormone therapy.

What Did the Study Actually Show?

Researchers examined data from 258 estrogen-only therapy users and 2,701 non-users in one dataset, plus 110 users and 1,948 non-users in a second dataset. The findings were striking: women who had used estrogen-only hormone therapy showed 35% lower odds of displaying the hallmark brain changes of Alzheimer's disease on autopsy, including amyloid plaques, tau tangles, and neuritic plaques.

Beyond autopsy findings, the protective association held up in living patients too. Blood and spinal fluid biomarkers collected while women were still alive also pointed to lower levels of amyloid accumulation in the brain among estrogen-only users. Additionally, estrogen-only therapy users had lower odds of receiving a clinical dementia diagnosis and showed better performance on memory tests.

"We found that, on autopsy, women who had used estrogen-only hormone therapy had 35% lower odds of showing the hallmark brain changes of Alzheimer's disease: amyloid plaques, tau tangles, and neuritic plaques, compared to women who had not used hormone therapy," explained Jennifer Bruno, PhD, Instructor of Psychiatry and Behavioral Sciences at the Stanford University School of Medicine.

Jennifer Bruno, PhD, Instructor of Psychiatry and Behavioral Sciences at Stanford University School of Medicine

The study also found that estrogen-only therapy was linked to better outcomes in other brain areas, including lower chances of infarcts, which are areas of tissue death due to lack of blood supply.

How Does Estrogen Protect the Brain?

Estrogen levels naturally decline during menopause, and this drop may increase the risk for Alzheimer's disease. The exact mechanism by which estrogen-only therapy protects against cognitive decline remains an area of active research, but the findings suggest that maintaining adequate estrogen levels during and after menopause may help preserve brain health and reduce the accumulation of disease-related proteins.

Interestingly, the type of estrogen used appeared to matter. Women taking conjugated estrogen, a blend of estrogen hormones, saw a lower chance of experiencing increased Alzheimer's disease neuropathology. However, those using estradiol showed similar risk levels to non-estrogen users. Additionally, starting estrogen-only therapy before age 60 was linked to a lower risk for Alzheimer's disease neuropathology, though this finding did not reach statistical significance.

Important Limitations and What Experts Want You to Know

While the findings are promising, researchers emphasize that this study shows association, not causation. Several important limitations should be considered before drawing firm conclusions:

• Study Design: The research relied on participant self-reporting of hormone therapy use, age, and sex, which can introduce inaccuracies.
• Demographic Limitations: A majority of participants were white, which limits how well the findings apply to other racial and ethnic groups.
• Current Practice Mismatch: Estrogen-only therapy is currently appropriate only for women who have had hysterectomies, and modern practice often involves estrogen-progesterone combinations prescribed during perimenopause, not after menopause.
• Missing Data: Researchers could not confirm exactly when participants started hormone therapy or how long they used it, making it difficult to determine lifetime estrogen exposure.
• Autopsy Data Gaps: Only a subgroup of participants had autopsy data available, and some analyses were limited by small sample sizes.

The researchers also noted that results could have been confounded by improved pre-existing health status among women who used menopausal hormone therapy, meaning healthier women may have been more likely to use the treatment in the first place.

What Should Women Consider About Hormone Therapy?

This study adds to a growing body of research exploring how menopausal hormone therapy affects dementia risk. However, the data on this topic remains mixed, with many factors at play. The current research focused exclusively on estrogen-only therapy and did not examine other hormone combinations or topical estrogen use.

"These autopsy findings were supported by blood and spinal fluid biomarkers collected while women were still living, which also pointed to lower levels of amyloid accumulation in the brain," Bruno added. "In addition, estrogen-only hormone therapy users had lower odds of receiving a clinical dementia diagnosis and showed better performance on memory tests. Importantly, these associations held after we accounted for key risk factors including age, genetics, education, race, and hypertension."

Jennifer Bruno, PhD, Instructor of Psychiatry and Behavioral Sciences at Stanford University School of Medicine

Women considering hormone therapy should discuss the potential benefits and risks with their healthcare provider, taking into account their individual health history, family history of dementia, and personal preferences. This study suggests that estrogen-only therapy may offer cognitive benefits, but more research is needed to fully understand the protective impact and to determine which women might benefit most from this approach.

The findings were published in Neurology, the medical journal of the American Academy of Neurology, and represent an important step toward understanding how hormonal changes during menopause influence brain health and dementia risk in women.