A scan of the author's brain
A scan of the author's brain (Lisa Mosconi)

What Menopause Does to Women’s Brains

Two-thirds of Alzheimer’s patients are women. My foggy 53-year-old brain could help explain why.  

I’ve been keeping a Google Doc of all the words my 53-year-old brain hasn’t been able to remember. The list has grown long. It might have grown twice as long, but often I forget the word I’ve forgotten between forgetting it and rushing to the computer to write it down. Next to the missing word in question, I note the description I used instead, such as “the thing that blows” (wind) and “the kind of shirt that’s soft and plaid” (flannel). Some of these Jeopardy-ready descriptions are surprisingly––if accidentally––poetic, such as the time bugs kept smashing against my car’s windshield and I called my partner on the phone to say, “There are so many dead bugs on the … on the … on the piece of glass between me and the world.”

When I couldn’t remember grill, I called it a “cooker thing.” Reincarnation became “that word Buddhists use for the next life.” More recently, my daughter and some of her college friends saw me gussied up for a party and asked where I was going. “It’s uh, you know, a party for …” I stammered. “What is the thing when you’re trying to raise funds?”

“A fundraiser?” her friend said, laughing.

I laughed too, embarrassed by yet another brain fart. But I also worried. Are these the normal perils of a woman’s brain at the beginning of its sixth decade, or am I in full-blown cognitive decline?

It’s not like I’m that old. Alzheimer’s, the most common form of dementia, predominantly affects people 65 and older. And while 200,000 Americans under the age of 60 live with early-onset Alzheimer’s, so far I’m not one of them. I have no family history of the disease. Aside from word recall, finding my keys, and remembering a person’s name after we’ve been introduced, my brain functions relatively well. Plus, I currently hold down four writing jobs, which might be the simplest explanation for my frequently scrambled cognitive state.

Still, two lingering concerns keep me up at night. First, I can’t escape noticing that my intense workload has blessed me with four of the six major lifestyle risk factors for cognitive decline, sometimes all at once: stress, poor diet, lack of exercise, and insufficient sleep. (Social and intellectual engagement and I seem to be on good terms for now.) Second, and more worrisome: I’m entering menopause. And that alone might put my brain at greater risk for Alzheimer’s.

Despite heavy investments in understanding Alzheimer’s, the condition remains mysterious. The primary cause or causes are unknown. So far, every magic-bullet drug trial has failed. From 2000 to 2017, deaths from Alzheimer’s increased by 145 percent.

Certain ideas about Alzheimer’s, however, have progressed dramatically. The disease was long considered an inescapable result of aging, accelerated or held off by a person’s genetics. But over the past decade, the research field has shifted toward believing that a combination of lifestyle factors—such as the ones affected by my jobs—play a major role in determining risk.

In this view, not all instances of cognitive decline are the same, or even, perhaps, inevitable. Richard Isaacson, the founder of the Alzheimer’s Prevention Clinic at Weill Cornell Medicine and NewYork-Presbyterian Hospital, is one of many scientists who support the idea that Alzheimer’s can possibly be averted with lifestyle interventions, such as eating better and exercising more. “Just like you can’t prevent a heart attack or a stroke definitively, you can’t prevent Alzheimer’s definitively,” Isaacson says. “But one in three cases can be either preventable or delayed.”

I’ve been deeply mired in the idea of cognitive risk reduction for the past year and a half. One of my four writing jobs is at an Alzheimer’s-prevention start-up, Neurotrack, that is working on programs and tools to prevent cognitive decline. When I started working for the company, I was aware of the encroaching fog in my own head but blithely ignoring it. As the fog thickened, I decided to reach out to the experts around me who might be able to offer solutions.

Isaacson believes that treating Alzheimer’s before it sets in, instead of after, could be a promising strategy to stave off some instances of cognitive decline, as well as a way to push researchers to reexamine the underlying factors and mechanisms of the disease. (Isaacson took a role as a scientific adviser at Neurotrack after I initially interviewed him; Neurotrack had no involvement in this story.)

To wit: Two-thirds of all Alzheimer’s patients are women. Why?

It has often been posited that this is because women live longer than men, giving the disease more time to set in. But Lisa Mosconi, a colleague of Isaacson’s who directs Weill Cornell Medicine’s Women’s Brain Initiative, wasn’t buying it, even as audience members and some researchers at various scientific conferences she attended begged to differ. Female life expectancy in the United States, for example, is only about five years longer than that of males. The preclinical stage of Alzheimer’s, before symptoms appear, can last decades. These numbers, to her, didn’t add up.

Mosconi is in the nascent stages of a research project exploring another theory: Alzheimer’s might be triggered in women years before any signs of the disease appear, during perimenopause, the period of transition into menopause. While the effects of menopause on rodent brains have been studied for decades, Mosconi says that this possibility has received surprisingly little research in humans and almost no public recognition. “Every woman knows that as you reach menopause, your hair goes dry, your skin goes dry—that’s aging,” she says. “Few people are aware that the same thing would happen in the brain. Our brain cells start aging faster.”

Mosconi has been conducting multiple MRI scans of perimenopausal women to look at brain atrophy, vascular damage, and connectivity. She’s also running PET scans to examine brain-energy levels and the presence of Alzheimer’s plaques. Her published data thus far have shown that middle-aged women’s brains exhibit signs of a higher risk of Alzheimer’s than men’s. “Forty-to-60-year-old men are doing well,” she says, “whereas for women, there is a marked decline in brain energy and an increase in Alzheimer’s plaques as they go from premenopausal to fully menopausal.”

Mosconi’s theory for why this is so, in a nutshell, is estrogen. During menopause, estrogen dramatically decreases. “Estrogen,” Mosconi says, “is a neuroprotective hormone. When it declines, the brain is left more vulnerable. So if a woman is somehow predisposed to Alzheimer’s, that’s when the risk manifests itself in her brain.”

Roberta Diaz Brinton, the director of the Center for Innovation in Brain Science at the University of Arizona, shares this view. Thirty years ago, she was the first researcher to study estrogen depletion in the brains of rodents during their perimenopause-to-menopause transition. “Menopause is like puberty,” Brinton says. It changes the brain forever. “The loss of estrogen means that glucose metabolism in the brain, its primary fuel, is reduced by about 20 to 25 percent. That’s why women experience that they’re off their game. They still can play the game, just not as well.”

Mosconi and Brinton are not claiming causation. Rather, their work shows an association between menopause and an earlier emergence of Alzheimer’s in the female brain compared with the male brain. “Menopause is more like a trigger than a cause,” Mosconi says. And not just for Alzheimer’s, but for cognitive fog in general.

When I spoke with Brinton, I confessed my word-recall issues and told her that I’m right in the thick of menopause. She was confident that the loss of estrogen has played a major role. “It’s the whatchamacallit syndrome,” she said.

Mosconi believes that developing methods of Alzheimer’s treatment and prevention for women who are still cognitively sharp and nearing the end of their reproductive years, rather than pursuing treatment when women are older and already too far gone, is a necessary paradigm shift. She has an upcoming book that explores Alzheimer’s prevention specifically geared toward women. “The good news is that these findings give us a window of opportunity to detect signs of higher risk and intervene,” she says. The stakes are personal for her: She has a family history of Alzheimer’s.

The bad news is that barriers remain to early detection and preventative treatment, particularly the lack of public information. After my first interview with Mosconi in May, I posted the transcript on the blogging platform Medium, where it received more than 100 responses, predominantly from women shocked by the link between menopause and Alzheimer’s. As the article spread around social media, the responses ballooned into a chorus of confusion and frustration that has yet to let up five months later.

As Brinton sees it, the popular idea that women have higher rates of Alzheimer’s simply because they live longer “completely dismisses the importance of the female biology.” Misconceptions of the differences between men and women––and a dearth of studies on the female body that might uncover such differences––are a sad if recurring theme throughout the history of women’s health. In her book Invisible Women: Data Bias in a World Designed for Men, the journalist and feminist activist Caroline Criado-Perez catalogs seemingly endless examples, including how a small 2013 study accidentally discovered that Viagra relieved period cramps without any adverse side effects for up to four hours, but a panel of male reviewers said they did not see dysmenorrhea “as a priority public-health issue” and refused to fund further studies.

At one point during my interview with Mosconi, she happened to mention that women who undergo hysterectomies have a higher risk of Alzheimer’s. A chill shot up my spine. In my early 40s, I had a hysterectomy to remove a uterus beleaguered by adenomyosis. I’m certain no one ever warned me of the risk pre-op, even though the information was already out there. I couldn’t have forgone the surgery; my adenomyosis had left me fatally anemic. But I at least could have been informed. I was so upset to learn this, I had to shut off the digital recorder to catch my breath.

Rudy Tanzi, a professor of neurology at Massachusetts General Hospital and a co-director of the McCance Center for Brain Health, concedes that science is still playing catch-up when it comes to women’s brains and health. “We all are trying to correct the imbalance right now,” he says. “Whether it’s in mice or in people, we make sure there are equal numbers of males and females.”

Tanzi stresses that scientists have considered the possible link between estrogen depletion and Alzheimer’s for decades, but he sees Mosconi’s clinical work as a crucial new piece of the Alzheimer’s puzzle. “She’s certainly ramping it up on looking at how women are more prone to Alzheimer’s,” he says. (Tanzi serves on various advisory boards of the Cure Alzheimer’s Fund, which funds some of Mosconi’s research.)

Still, he says, “I’m a little bit more agnostic about the question––it’s a very important question––about why two-thirds of Alzheimer’s patients are women.” As a geneticist, Tanzi approaches the issue at the level of DNA. “I’m not thinking estrogen or any particular hypothesis. I’m just doing genetic analysis,” he says. The genes that could be linked to Alzheimer’s “have brought us all over the map. They haven’t specifically landed on metabolism or energy metabolism, but if you follow the track of a new gene enough, you might get back to it.”

Mosconi and Brinton, for their parts, have gone all-in on the estrogen theory. Recently, the two joined forces so that Mosconi could design parts of her human study based on what Brinton knows about rodents. One potential treatment they’re beginning to explore is a new type of estrogen therapy. Administering the hormone during perimenopause and menopause “can restore cognitive function,” Brinton said. But she stressed that the timing and the type of hormone therapy are crucial: “Estrogen or combined hormone therapy years after the menopause is unlikely to be beneficial, whereas introduction of therapy when symptoms occur is most likely to have benefit.”

There are many complicating factors in traditional estrogen therapy. Estrogen taken orally, according to both doctors, is not only hardly guaranteed to reach the brain, but it might increase a woman’s risk of cancer. To avoid this, Brinton is developing an estrogen supplement that can be injected straight into the human brain. Mosconi, in tandem, has been devising a new brain-imaging technique to monitor the effects of this injection. To test the new supplement, Mosconi said that before she experiments with it on any other women, “I’ll shoot it into my own brain first.”

Until a reliable form of estrogen therapy exists, I’m taking the doctors’ other preventative advice to heart and protecting my brain in whatever way I can. Call it installing a metaphoric piece of glass between my brain and the world, or a cognitive windshield. Either works. After my interview with Mosconi, I biked home instead of taking the subway. I went straight to the grocery store to buy six containers of the darkest berries I could find; blackberries are said to be the best for brain health, followed by blueberries, then raspberries. I upped my daily walk with the dog from 10 minutes to an hour, and focused on getting, well, not eight hours of sleep each night, but, okay, seven.

Still, words keep failing me. During one of my allegedly brain-boosting bike rides, a man absentmindedly stepped into the bike lane, nearly causing me to crash. “Hey, get out of the … green thing!” I shouted.

A few weeks after we spoke, Mosconi’s team invited me to take part in their Women’s Brain Initiative study. I jumped at the chance—not for the $150 honorarium I had no idea I’d be getting until the check arrived in the mail, but because I wanted to know what was going on inside my brain. I also wanted to help further the science before my 22-year-old daughter slams into menopause. So in September, I found myself in an MRI on one day and a PET scan on another. Before each scan, I had to endure cognitive challenges, such as a research assistant sadistically lobbing words at me that I would have to recall––ha!––five minutes later.

The results of my first round of scans and tests look good. My brain apparently has excellent volume, good connectivity and energy levels, and neither vascular damage nor amyloid plaques, the warning signposts of dementia. However, my hormone levels suggest that I’m probably still at the tail end of perimenopause. Once I enter menopause, it’s still anyone’s guess as to what happens next.