Alzheimer's disease and HRT: Early menopause and delayed hormone treatment may impact risk

Women at greatest risk for Alzheimer's disease were those who reported premature menopause.

ISLAMABAD, (Online) - Alzheimer’s disease is the most common type of dementia, affecting 60 to 70% of people with dementia. However, there is a major gender difference among cases. Approximately two-thirds of people diagnosed with Alzheimer’s disease are women.

Researchers say that one of the reasons for this gender disparity is likely related to hormonal changes, which play a role in the development of this neurological disorder.

According to a new study published today in JAMA Neurology, early age at menopause may be a risk factor for Alzheimer’s disease dementia, but women who received hormone replacement therapy (HRT) at the start of menopause did not show an increased risk.

Why HRT may help

The women at greatest risk for Alzheimer’s disease were those who reported premature menopause, or menopause before age 40. This supports the notion that longer exposure to estrogen throughout life is protective, according to researchers.

Researchers used positron emission tomography to look at tau deposits in the brain. Tau is a type of protein that in a person with Alzheimer’s disease can become tangled in neurons.

“This study is one of the first to report associations between tau deposition in the brain, measured with positron emission tomography, and age at menopause in women,” Rachel Buckley, PhD, a corresponding study author andan assistant professor in the department of neurology at Massachusetts General Hospital/Harvard Medical School, told Healthline.

“We found that in multiple areas of the brain that tend to be most likely to show higher tau in women relative to men, women with both earlier age at menopause combined with elevated levels of amyloid were more likely to show higher levels of tau burden than those who reported menopause onset around the average age [~50 years in the United States],” Dr. Buckley said.

Interestingly, women who had a greater risk of developing Alzheimer’s disease started HRT after 5 or 6 years of menopause rather than at the start of menopause.

“The most ground-breaking findings for me were those surrounding hormone therapy,” said Buckley. “Counterintuitively, we found that women with elevated amyloid and who reported taking hormone therapy also showed higher tau burden. One would have imagined taking hormone therapy might ameliorate the issues of lost estrogen because you are reintroducing estrogen into the body.”

But this is where it got interesting – after further investigation into this group of women who reported taking HRT, 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 than 5-6 years), Buckley stated.

Earlier age at menopause is a risk factor for Alzheimer’s disease dementia

“Estrogen and follicle-stimulating hormones, hormones that undergo major shifts around the time of menopause, have important effects on the brain, which researchers are actively working to clarify,” said Dr. Carolyn Fredericks, a neurologist at Yale New Haven Health and an assistant professor at Yale School of Medicine. “Some of those effects may help stave off neurodegeneration. Research has shown that if you compare post-menopausal women with women of the same age who are premenopausal, and with men the same age, the post-menopausal women will have higher levels of the Alzheimer’s disease proteins amyloid and tau.”

Earlier age at menopause is considered a risk factor for Alzheimer’s disease dementia, and this has been supported by previous studies, which also showed faster rates of memory decline in women who had earlier age at menopause that was induced by surgery (via removal of the ovaries), Buckley explained.

Animal studies suggest that declining levels of estrogen have a multi-faceted impact on the brain; it can affect the bioavailability of fuel, the proper working of brain vasculature, proper cellular function, and even neurogenesis.

Translating this evidence to humans, however, has been a bit more tricky given that there are so many other factors at play during menopause, Buckley added.

Why the timing of HRT matters

When it comes to HRT, timing is important.

“The largest clinical trial into hormone therapy, the Women’s Health Initiative, was a perfect example of how the timing hypothesis matters,” said Buckley. “In a very large cohort of post-menopausal women aged 65 years and older who took combined estrogen (CEE and progesterone), they found an approximately two-fold greater risk of dementia.”

The key part of that sentence is that they were aged 65 years and older. Given that the average age of menopause is 50 in the United States, that’s approximately 15 years delay before initiating HRT.

It is important to point out, however, that there are clinical trials that do not necessarily support evidence of the timing hypothesis, which highlights the complexity of hormone therapy-related research, Buckley explained.

Dr. Fredericks also shared her thoughts on the Women’s Health Initiative study.

“Hormone therapy is complex, with the Women’s Health Initiative study famously showing that hormone replacement therapy, which at that time was thought likely to reduce women’s risk of heart disease, stroke, and dementia, among other medical problems, actually increased those risks significantly. There has been some discussion in the field of the timing of hormone therapy.”

Fredericks said the research shows how timing is key in understanding risks of HRT and Alzheimer’s disease.

“I like the critical window hypothesis – which suggests that after too much time has passed since menopause, estrogen receptors in the hippocampus and other places (the hippocampus is an important structure for memory in the brain and loses volume in Alzheimer’s disease) have downregulated and so it’s ‘too late’ to get the cognitive benefit of estrogen,” said Fredericks.

Sex-specific risk factors for Alzheimer’s disease

Going through menopause starts off a range of different risk factors for women.

“Risk for metabolic syndrome increases, as well as risk for hypertension and type 2 diabetes. Part of these changes are associated with the changes in body fat distribution (particularly in abdominal fat) that occur as a consequence of menopause,” said Buckley.

Further, there are well-documented changes in sleep quality/duration and mood that occur during menopause and are also known risk factors for Alzheimer’s disease.

Studies also show compelling evidence that there are differences in the way that the APOE4 gene confers risk between the sexes, Buckley explained. Women who carry the APOE4 allele have been shown to have higher risk for dementia than men who carry the same allele.

Additionally, “women live longer, and age is the single biggest risk factor for Alzheimer’s disease,” said Fredericks. “In cultures where today’s older women had more access to factors that promote ‘cognitive reserve’ such as higher education, regular cardiovascular exercise, and intellectually challenging work, the gap between women’s risk and men’s risk is narrowing. In cultures that did not offer these opportunities to women as early, the gap is wider.”

What’s next

Researchers will be looking into sex hormones of people in midlife and tau burden in the brain.

“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,” Buckley stated. “But we don’t think the whole story is just about the reproductive side of things.”

Specifically, future studies will be examining the X chromosome in greater depth.

“We have been fortunate to receive high risk-high reward funding to explore the X chromosome in association with Alzheimer’s disease risk,” said Buckley. “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 understand 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 Alzheimer’s disease, but there might also be a very interesting story of genetic resilience out there that is yet to be aligned with the hormone findings, Buckley added.

Bottom line

Early age at menopause may be a risk factor for Alzheimer’s disease, but new research shows women who received HRT near the age of menopause onset did not show a higher risk.

One of the most surprising findings of this study was the timing of HRT and how it impacted Alzheimer’s disease dementia risk. Researchers found a greater risk of Alzheimer’s disease among women who started HRT after 5 or 6 years of menopause, rather than at the onset of menopause.

There are sex-specific risk factors for Alzheimer’s disease dementia to be aware of such as changes in sleep patterns, metabolism, and mood that are common during menopause.