Rachel Buckley, PhD ​Assistant Professor Department of Neurology Massachusetts General Hospital/Harvard Medical School

Alzheimer’s Disease: Long Gap Between Menopause and Hormone Therapy Might Raise Tau Burden

MedicalResearch.com Interview with:

Rachel Buckley, PhD​Assistant Professor
Department of Neurology
Massachusetts General Hospital/Harvard Medical School

Dr. Buckley

Rachel Buckley, PhD
Assistant Professor
Department of Neurology
Massachusetts General Hospital/Harvard Medical School

MedicalResearch.com: What is the background for this study?

Response: While a fair amount of studies have focused on the effects of menopause and hormone therapy on risk of dementia, far fewer studies have tested their association with the biology of Alzheimer’s disease, namely amyloid and tau. This is critical to know given that it still remains unclear what might be the driving mechanism of the menopause transition on risk for dementia. This is what our study set out to investigate.

This study is one of the first to report a link between women’s age at menopause and tau in the brain, which we measured with positron emission tomography neuroimaging. We found that in multiple areas of the brain that tend to be most likely to show higher tau in women than men, women with earlier age at menopause and elevated levels of amyloid showed higher levels of tau than those who reported an average age at menopause (~50 years in the United States). Women who reported premature menopause (<40 years at menopause onset) exhibited a much higher risk of tau in the brain. This supports the notion that longer exposure to estrogen throughout life might be protective against Alzheimer’s disease.

MedicalResearch.com: What are the main findings?

Response:  The most ground-breaking findings for me were those surrounding hormone therapy. Counterintuitively, we found that women with elevated amyloid and who reported taking hormone therapy also showed higher tau burden. One would have imagined reintroducing estrogen into the body via hormone therapy might lower the risk that lost estrogen conferred. This is where it got interesting – after further investigation into this group of women who reported taking hormone therapy, we found that higher risk was only associated with those women who had a long gap between their menopause onset and hormone therapy initiation (i.e., greater then 5-6 years). It seems that reintroduction of exogenous estrogens after a long pause, is not a great idea. And our biological evidence strongly supports that of the initial Women’s Health Initiative clinical trial.

MedicalResearch.com: What recommendations do you have for future research as a results of this study?

Response: We’re taking a multi-pronged approach with our next studies. We’re exploring the direct impact of midlife levels of sex hormones (namely, estradiol, estrone, testosterone) on amyloid and tau burden in the brain in both men and women. But we don’t think the whole story is just about the reproductive side of things. We have been fortunate to receive high risk-high reward funding from the NIA to explore the X chromosome in association with AD risk. No one really wants to touch the X chromosome because it is so hard to measure, but we believe there are some compelling reasons to roll up our sleeves and get to work to better understanding the X. Firstly, genes on the X chromosome are associated with better immune responses in women. It is entirely possible that we’ve been thinking of women as ‘more vulnerable’ to AD, but there might also be a very interesting story of genetic resilience out there that is yet to be aligned with the hormone findings.

MedicalResearch.com: Is there anything else you would like to add? Any disclosures?

Response: A major strength of this study is the focus on reproductive factors in this large observational study. It is unfortunately extremely unusual to have such a comprehensive study of Alzheimer’s disease that also includes detailed measures of menopause, surgical history and hormone therapy use. Studies just don’t often think to ask women about their menopause. There are some limitations to this study that should be acknowledged – the participants in this study were not as representative of the general population in the United States, so we cannot extrapolate our findings to women from a range of socioeconomic, racial and ethnic backgrounds or education levels. In addition, this is an observational study and not a randomized controlled trial so we cannot be sure of causation (that is, we cannot say with any certainty that menopause or hormone therapy was the direct cause of higher tau in the brain). Finally, we only report data from one time point, which is problematic because a lot of biases and confounding factors can make it seem as if the association between menopause and AD risk is important. It is far more powerful to say that premature menopause is associated with faster rates of tau accumulation in the brain than simply saying that it is higher at a single time point. This is another next step in our investigation.


Coughlan GT, Betthauser TJ, Boyle R, et al. Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography. JAMA Neurol. Published online April 03, 2023. doi:10.1001/jamaneurol.2023.0455


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Last Updated on April 3, 2023 by Marie Benz