Sorting Out the Links Between Menopause and Memory Decline

During my last annual Well Woman exam, my gynecologist unceremoniously handed me a short booklet outlining the symptoms of perimenopause, the period of time prior to menopause when the ovaries start gradually making less estrogen. I must have made an unpleasant face in response because she immediately smiled and informed me, “That’s standard operating procedure for patients in their 40s. Menopause isn’t something that just happens overnight, you know.”

She’s right: The process of leaving fertility is one that can take years. The pamphlet discussed the hormonal changes that pave the way towards the “great change of life,” as well as the most common menopausal symptoms like irregular menstrual cycles, hot flashes, mood changes, and weight gain. What it did not mention were things like distractability or forgetfulness—problems that many women also report as they move both towards and through menopause. But while memory issues are often touted as part and parcel of the aging process, a new study out of Brigham and Women’s Hospital demonstrates that these issues may be tied not to a woman’s chronological age, but rather to her hormone levels and reproductive status.

Estrogen and the hippocampus

It’s long been known that there are distinct sex differences in the prevalence of certain psychiatric disorders. For example, women are more likely to develop mental health conditions like anxiety and depression. There is also a sex difference in the prevalence of Alzheimer’s disease—according to the Alzheimer’s Association, two-thirds of Alzheimer’s patients are women.

Jill Goldstein, director of research at the Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital, says that this difference in disease prevalence reflects, at least in part, sex differences in the brain.

“Memory circuitry actually develops differently in boys and in girls. This includes sex differences in the pace of the development of connections with prefrontal cortex. Dorsolateral prefrontal cortex, a key brain region of the memory circuitry, is not fully connected to other memory circuitry regions until one’s early 20’s, and these connections develop about two years earlier in the female than the male brain. So we already see sex differences in both the timing of adult memory circuitry development, in volumetric size of these regions, and in connectivity,” she says. “These sex differences in the development of memory circuitry have important implications for aging of the circuitry. So one question is, ‘What happens over the life course that differs by sex to change one’s trajectory as we age?’ as well as ‘Why are women at almost twice the risk for Alzheimer’s than men, when women actually begin with advantages in memory circuitry development and verbal memory performance?’”

One thing that could help shed light on both those questions is the sex steroid estrogen. Julie Dumas, a neuroscientist at the University of Vermont, says that the hippocampus, the brain’s memory center, has a very dense population of estrogen receptors, so it would make sense that changes in hormonal status may affect its function.

“While women are fertile, they have had regularly cycling hormones every month. But all of a sudden, around age 45 or 50, that all changes. Your periods aren’t so regular. The ovaries are at the end of their estrogen-producing phase so they are trying to spit out a ton of estrogen in attempts to get things working again—but, of course, it doesn’t work that way,” she says. “The brain has basically been bathing in estrogen for 40 or so years and now that estrogen isn’t there anymore, at least not in the way it was. So the brain now has to operate in a different environment. And it makes sense, because of what estrogen does and where those receptors are, that such a significant change may affect memory and other cognitive functions.”

Memory and reproductive status

Talk to many women of my age and you’ll hear us confess that we do struggle with subtle changes in memory function. Even those of us with strong memories now find ourselves relying more and more on to-do lists and smartphone reminders—and far too often misplacing our keys and glasses right before we’re called to run out the door.

What might be behind these changes? To help characterize what’s happening in the brain’s memory circuitry as women approach menopause, Goldstein and colleagues did fMRI scans on the brains of 200 healthy men and women between the ages of 45 and 55 as they were asked to create sentences using two words and then later asked to recall those two words. The researchers also took reproductive histories and measured the hormone levels of female participants, including those that diminish during menopause like 17β-estradiol. The researchers found that chronological age did not impact memory—but reproductive status did. Women with lower 17β-estradiol levels not only showed poorer performance on the memory task but also more pronounced changes in hippocampal circuitry. In addition, the researchers also saw that women who performed strongly on the memory task showed connectivity patterns that were similar to those seen in premenopausal women. The results were published in the Journal of Neuroscience on Sept. 28, 2016.

“We were able to detect changes in memory circuitry decades before scientists have historically studied aging populations by taking a sex differences approach,” says Emily Jacobs, first author of the study, now at the University of California Santa Barbara. “This is a first step in characterizing the normative changes that occur in this critical midlife window in women and how it may influence cognition. And it’s something that can help give us some new insights into divergent trajectories of aging and why so many more women go on to develop dementia and Alzheimer’s disease.”

Investigating early changes

Other research in the Alzheimer’s field now promotes studying the so-called “pre-clinical” stage, or younger, at-risk populations so that we can better understand the variety of pathological processes that may contribute to disease. Jacobs says this study supports the idea that research into aging needs to begin long before retirement age.

“Most cognitive neuroscience studies on aging have traditionally taken a sample of 65-year-olds and then compare them to a convenient sample of 20-year-olds. It’s likely that age was yoked to the average retirement age in the United States. But 65 doesn’t make sense from a women’s health perspective, since we know that women go through one of the most profound hormonal changes in life, that menopausal transition, a decade or more before that,” says Jacobs. “We’re learning that if you wait until people are 65, you’ve missed the boat on understanding what’s happening because even if they are asymptomatic at the behavioral level, there are a lot of changes happening in the brain that will eventually bubble up to the level of behavior. To understand some of these vulnerabilities, you really do need to go back and look at the very earliest stages.”

Goldstein and Jacobs plan to continue this line of research to better understand how hormones may affect memory status—and susceptibility for dementia and Alzheimer’s later in life. “It’s the $64,000 question,” says Jacobs. “What is the difference between women who perform well on memory tasks and those who don’t?  Because we see some women who just breeze through the transition without any deficits to speak of. Then others have a lot of trouble. I can tell you that the difference is nothing as obvious as years of education, or years since she went through the menopausal transition, or body-mass index. It’s going to require some digging.”

Goldstein says a better understanding of how the brain functions under different hormonal contexts is going to be a critical part of our understanding of the aging brain. “Of course, everyone wants to maintain intact memory function as we age. This is going to be one of the biggest, if not the biggest, public health challenges of my generation. And this study could help us develop clinical risk tools for identifying who may be at the highest risk in early midlife for developing Alzheimer’s later in life,” she says. “This is just the beginning of this line of research which will help us understand the risk factors very early on. We know that early intervention has more successful results across a number of different disorders. The more we understand about early biomarkers for memory decline, the more likely we have the possibility of prevention or at least the attenuation of cognitive disabilities.”