One of the most enduring mysteries of Alzheimer’s disease is why women are more likely to develop it and other forms of dementia than men. Some scientists suspect part of the reason may have do with the sharp hormonal changes women experience in menopause. But exactly how or why menopause might tip the brain toward dementia in some people is unclear.
Now a pair of studies published this week suggest that when menopause kicks in and how quickly it’s treated with hormone therapy could play critical roles in cognitive decline.
In one of the studies, which was published on Wednesday in the journal Alzheimer’s & Dementia, researchers analyzed more than 180,000 postmenopausal women in the U.K. They found that those on hormone replacement therapy (HRT) had a 10 percent reduction in the risk of all kinds of dementia and a 16 percent reduction in the risk of Alzheimer’s specifically, over a 13-year follow-up period. The effect held even when correcting for factors such as ethnicity, smoking status, education, and more.
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The study represents the “most comprehensive analysis in this space to date,” says Anne-Marie Minihane, the paper’s co-senior author and a professor of nutrigenomics at the University of East Anglia in England.
Curiously, women who had undergone surgical menopause—that is, menopause arising from a hysterectomy or an oophorectomy, the removal of the uterus or the ovaries, respectively—saw even more profound effects on HRT. The risk of dementia in this group fell by 26 percent. And women who started HRT at younger ages—between 46 and 56 years old—had a lower risk of developing dementia than those who started treatment later in life.
The study isn’t a clinical trial, Minihane notes, and it isn’t enough to say HRT protects against dementia or Alzheimer’s disease. Instead it identifies a striking correlation between menopause treatment and dementia risk. And it is part of a growing body of evidence pointing to a connection between the role of menopause in cognitive decline.
The second study, which was published on Tuesday in the journal JAMA Network Open, offers more clues to that role. It found that the earlier menopause set in, the more likely it was that women would experience cognitive decline later in life. Earlier menopause was also associated with earlier diagnosis of Alzheimer’s disease. Like the Alzheimer’s & Dementia study, these results were strongest among women who had experienced surgical menopause.
“It confirms that women who’ve had surgical menopause and who’ve had menopause early are a group who really need attention,” Minihane says, referring to the JAMA Network Open study’s results.
Women with earlier menopause were also more likely to see faster accumulation of “white matter hyperintensity” volume, a marker of damage to brain tissue, the authors found. Interestingly, this effect was much more prevalent in women who had gone through nonsurgical, or spontaneous, menopause.
“There is a fairly well-established link between earlier age at menopause and risk of cognitive decline,” says Riley Bove, the JAMA Network Open paper’s senior author and a professor of neurology at the University of California, San Francisco. “What this study adds is that we detected a lasting trace of menopause on women’s brains even decades later.”
It’s not totally clear why women who had a hysterectomy or an oophorectomy were such a critical group in her study, Minihane says. It could be because they tend to have a shorter lifetime exposure to estrogen. It could also be because people who have a hysterectomy typically take estrogen-only HRT rather than a combined form—which often includes progesterone—and this could vary results.
Indeed, previous research that was published earlier this month and included thousands of women who donated their brains to science linked estrogen-only HRT to a lower risk of developing Alzheimer’s.
Taken together, the results support the idea that preventing Alzheimer’s may start long before advanced age—offering a “window of opportunity” to intervene, Minihane says.
But she cautions, more research is needed to confirm this hunch—and the evidence remains mixed. Other past research, for example, has shown combined hormone therapy increased the risk of dementia in people older than age 65, while other studies have found little to no effect from taking HRT.
It’s unclear how much of the conflicting results have to do with faults in study designs, the length of trials, the quirks of human biology or something else, Bove says. “I hope we can continue to see large and well-designed studies such as the current one [in Alzheimer’s & Dementia] add much needed evidence to the field of women's health.”
For her part, Minihane hopes to conduct a clinical trial look at how HRT might influence Alzheimer’s features. She also hopes to do further studies to understand the exact mechanism of how menopause affects the brain, as well as whether certain foods that are high in phytoestrogens, such as soybeans, may help in supporting cognition.
“We have a long way to go,” Minihane says. “Potentially, at some time in the future, [HRT] may be recommended as a treatment for reducing lifetime risk of dementia. But I think a lot more research needs to be done before we’re even close to getting to that point.”