Menopause is the complete end of experiencing menstrual periods, and it can increase the risk for certain health problems, such as stroke. A recent study published in Neurology, the medical journal of the American Academy of Neurology, notes that estrogen levels drop during menopause, and that this could lead to a higher risk for Alzheimer’s disease.
This study found that estrogen-only menopausal hormonal therapy was associated with better Alzheimer’s disease and dementia outcomes.
In the study, women who used estrogen-only menopausal hormonal therapy were less likely to show increased Alzheimer’s disease pathology, had lower chances of memory decline symptoms, and had lower chances of having a dementia diagnosis.
However, much more research is required to fully determine the possible protective impact of estrogen-only menopausal hormonal therapy.
The data on how menopausal hormonal therapy affects dementia is mixed, with many factors at play. The current research chose to focus exclusively on estrogen-only menopausal hormonal therapy and how this relates to aspects of Alzheimer’s disease and dementia.
Researchers collected data from the National Alzheimer’s Coordinating Center (NACC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
From this first data set, they examined data from 258 participants who used estrogen-only menopausal hormone therapy and 2,701 participants who did not. From the second data set, there were 110 participants who used estrogen-only menopausal hormonal therapy and 1,948 participants who didn’t.
This definition of estrogen-only menopausal hormonal therapy did not include topical use of estrogen. Researchers excluded participants who reported taking combinations of estrogen and progestin. A majority of participants were white, and the average age was between 71 and 72 years.
For some participants, researchers were able to look at data from brain autopsies, allowing them to look at several components related to Alzheimer’s disease pathology, like amyloid deposits.
Based on autopsy data, researchers found that participants using estrogen-only menopausal hormonal therapy had a lower chance of increased scores for Alzheimer’s disease pathology.
Estrogen-only menopausal hormonal therapy was also linked to better outcomes in other brain areas, like lower chances of infarcts, which are areas of tissue death because of a lack of blood supply.
Researchers also found evidence that amyloid load was better for estrogen-only menopausal hormonal therapy users, which indicated better Alzheimer’s disease pathology compared to non-users.
Among the NACC dataset, researchers found that estrogen-only users had a lower chance of having a clinical diagnosis of dementia and a lower chance of experiencing clinical decline.
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In the ADNI group, estrogen-only menopausal hormonal therapy was linked to better immediate memory and learning. A subgroup analysis of participants in the ADNI group who did not have dementia found that estrogen-only therapy was linked to better verbal memory.
In addition to these outcomes, researchers also performed several exploratory analyses in subgroups, such as based on the type of estrogen-only menopausal hormonal therapy.
The researchers found that non-APOEe4 carriers who also used estrogen-only menopausal hormonal therapy had a lower chance of experiencing Alzheimer’s disease neuropathology.
The researchers did not observe this result in APOE e4 carriers. The APOEe4 gene can increase the risk for Alzheimer’s disease. In both carriers and non-carriers, estrogen-only use was linked to less serious clinical diagnoses and better clinical dementia rating global scores.
There were some differences when it came to the type of estrogen used. For example, conjugated estrogen users (people taking a blend of estrogen hormones) saw a lower chance of experiencing increased Alzheimer’s disease neuropathology, while the risk for those using estradiol was similar to that of non-estrogen users.
Finally, starting estrogen-only menopausal hormonal therapy prior to age sixty was linked to a lower risk for Alzheimer’s disease neuropathology, but this link didn’t reach a level of statistical significance.
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Study author Jennifer Bruno, PhD, Instructor of Psychiatry and Behavioral Sciences at the Stanford University School of Medicine, explained the following regarding the study’s findings:
“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.”
“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,” she continued.
“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,” she added.
When it comes to limitations, it’s important to note that this study doesn’t establish any causality. It only shows associations. Second, there is a reliance on participant reporting, such as the self-report of estrogen-only menopausal hormonal therapy, sex, and age.
A majority of the participants were white, limiting generalizability to other groups. There’s also limited generalizability because estrogen-only therapy is currently only appropriate for women who have had hysterectomies.
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The average age of participants also doesn’t relate to current practices of menopausal hormonal therapy, where doctors may prescribe estrogen-progesterone therapy to women in the period prior to menopause, perimenopause.
Confounding is possible from multiple factors. Researchers note that the results could have been confounded “by improved pre-existing health status of the MHT [menopausal hormonal therapy] group.”
This research also only focused on estrogen-only therapy, so it cannot speak to the use of other hormones or hormone combinations. There was only autopsy data for a subgroup of participants, and some subgroup analyses were also limited, such as looking at the different types of estrogen therapy.
Researchers were limited by the datasets they used, which included missing and sparse data. They were not able to confirm exactly when participants started hormone therapy. The authors note that the results cannot be generalized “to represent associations between life-time estrogen exposure and dementia outcomes” because they lacked data on how long estrogen-only menopausal hormonal therapy was used or on its use before the start of the study.
They also lacked data on topical estrogen use in the NACC data set. The sample size in the ADNI data was also small, so the researchers note that the findings in this group are exploratory. Other secondary outcomes were also exploratory. Finally, funding came from several sources.
This data suggests a possible protective effect of estrogen-only menopausal hormonal therapy, but there’s a major need for more research before major clinical changes can occur.
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Dung Trinh, MD, internist of MemorialCare Medical Group and Chief Medical Officer of Healthy Brain Clinic in Irvine, CA, who was not involved in the study, noted the following:
“The findings do not support prescribing menopausal hormone therapy specifically to prevent Alzheimer’s disease or dementia, since randomized trials have not established such a benefit. Instead, the study highlights the importance of taking a more individualized, life-course approach to women’s brain health.”
“Factors such as age at menopause, type and timing of hormone therapy, APOE status, vascular risk, and whether menopause was premature or surgical may eventually help clinicians better understand cognitive risk and personalize care, but more evidence is needed before these factors change routine Alzheimer’s prevention recommendations,” Trinh explained.
Additionally, despite the possible protective effects of estrogen-only therapy, it’s not something that’s always appropriate.
“Our findings are most directly relevant to women who have had a hysterectomy by age 60 (roughly 1 out of 3 women), since estrogen-only therapy is appropriate only for women without a uterus. For women with an intact uterus, combined estrogen-plus-progestin therapy is the standard approach,” Bruno noted.
“For the subset of women who have had a hysterectomy, our results suggest that estrogen-only hormone therapy may have a protective association with Alzheimer’s-related brain changes. These findings do not change current clinical recommendations, but they do add an important new line of evidence: neuropathological data from autopsied brains,” she added.
