Here’s a striking fact about Alzheimer’s disease that deserves far more attention: about two-thirds of people living with Alzheimer’s are women.
Yes, women tend to live longer than men, and age is certainly an important risk factor. But longevity alone doesn’t tell the whole story. Increasingly, researchers are asking whether the profound hormonal changes that occur during menopause might also help explain why women are disproportionately affected.
A fascinating new study published in Neurology gives us another reason to take this possibility seriously. Researchers looked at women who had used estrogen-only menopausal hormone therapy and compared them with women who had not. They used information from two of the largest Alzheimer’s research databases in the country, the National Alzheimer’s Coordinating Center and the Alzheimer’s Disease Neuroimaging Initiative.
And they didn’t just ask whether these women developed dementia. They were able to look at Alzheimer’s-related changes in the brain, including actual brain tissue examined after death.
Here’s what the researchers discovered:
Among nearly 3,000 women with autopsy information, those who had used estrogen therapy had 35% lower odds of having greater Alzheimer’s-related brain pathology compared with women who had not used it.
The researchers also looked at what happened during life. In the much larger clinical group, women who used estrogen therapy had 39% lower odds of being diagnosed with dementia and 33% lower odds of experiencing clinical and functional decline. Some measures of memory were better as well.
So why might estrogen matter to the brain?
This is where the study connects directly with something I spend a great deal of time discussing in Brain Defenders, the brain’s immune cells called the microglia.
Microglia are the brain’s resident immune cells. I like to think of them as the brain’s gardeners and guardians. When in their M2 configuration they protect neurons, clean up debris, and even help determine which connections between brain cells (our synapses) should remain and which should be removed.
But, importantly, microglia can change. When they become chronically activated, these normally protective cells can become overly aggressive. Instead of simply protecting the brain, they participate in the destruction of perfectly functional synapses. And losing synapses matters enormously because these connections form the physical foundation of our memories and our ability to think.
Estradiol, the major form of estrogen before menopause, helps keep this inflammatory activity in check. When menopause arrives, estradiol levels fall dramatically. Research suggests that this loss can encourage inflammatory signaling and increase microglia-mediated elimination of synapses.
In other words, the loss of estrogen changes the environment in which the brain’s immune cells operate and culminates in loss of synapses
That is an important idea because as I have emphasized, Alzheimer’s doesn’t suddenly begin when someone becomes forgetful at age 70 or 75. The biological changes that ultimately lead to dementia may have been developing for decades.
Menopause, therefore, may represent an important turning point and opportunity for the female brain.
Now, this study does not mean that every woman should begin taking estrogen to prevent Alzheimer’s. This was an observational study, not a randomized treatment trial, so it cannot prove that estrogen caused the better outcomes. And importantly, the study focused primarily on estrogen-only therapy, which is generally used in women who have had a hysterectomy. The researchers themselves emphasize that more prospective research is needed.
But I believe the larger message is tremendously important. If two-thirds of Alzheimer’s patients are women, we need to understand what is happening to the female brain during menopause. And that means looking beyond amyloid plaques and considering metabolism, inflammation, hormones, and especially the behavior of our brain’s immune cells.
As I describe in Brain Defenders, our microglia can be powerful defenders of the brain. Understanding what keeps them in that protective state and what causes them to turn against the very connections they are meant to protect may ultimately become one of our most important strategies for preserving the brain for life.
