Women make up some 60% of Alzheimer’s disease patients in the United States, and over her lifetime, a woman is almost twice as likely than a man to develop the memory-robbing condition.
New research offers tantalizing clues as to why that might be, suggesting that either hormonal influences or pregnancy-related changes in the immune system – or both -- may nudge a woman’s risk for dementia in one direction or the other.
In a comprehensive study that tracked almost 15,000 U.S. women from middle age into their senior years, researchers found that women who gave birth to three or more children were less likely than those who had a single child to develop dementia.
Reporting their findings Monday, the authors of the new research said also that women whose lifetime span of fertility was shorter appeared more likely to develop dementia than were those who began menstruating earlier.
The new findings, reported at the Alzheimer’s Assn.'s International Conference in Chicago, offer an early clue that hormones, specifically estrogen, may exert some influence on a woman’s risk of dementia. They emerged from the first study to explore women’s lifetime dementia prospects by tracking a very large group of women over a long period – for some, as long as 53 years.
In other research presented Monday, a pilot study that captured the pregnancy histories of 133 British women offered evidence that a female’s likelihood of developing dementia declined as the number of months she had spent pregnant rose.
In many ways, those findings are consistent with the study suggesting a hormonal influence on dementia risk in women. But the author of the pilot study, UCLA anthropologist Molly Fox, said her findings suggest another influence on a woman’s dementia risk – the profound changes in the immune system wrought by pregnancy.
Collectively, the new research marks a first-ever effort to explore the underpinnings of gender differences in dementia. That effort is certain to uncover insights into the factors that influence the risk of cognitive decline as we age, and possibly ways to counter that risk in both men and women.
For decades, researchers presumed that women were more likely than men to develop dementia because they are more likely than men to survive into old age. As a disease of aging, their reasoning went, dementia is more likely to affect the longer-lived sex.
By suggesting possible roles for hormones and the immune system, the new research has offered some intriguing alternative hypotheses: that women, who evolved to spend much of their fertile years in pregnancy, might long have accrued protections against dementia equal to a man’s. But as families have become smaller, women have lived longer, and their reproductive years have come to account for a smaller share of their lives, it’s possible that women’s dementia risk has risen.
That the female hormone estrogen is at work is suggested by several of the large study’s findings. From 1964 to 1973, the undertaking enrolled female members of Kaiser Permanente ages 40 to 55. Researchers initially collected data on the number of children the women had birthed, how many miscarriages they had suffered, and the ages at which they began and ceased to menstruate. In addition to recording the women’s race and educational levels, they tracked other midlife health conditions, including smoking, high blood pressure and obesity, which are known to influence dementia risk.
Between 1996 and 2017, the researchers combed the women’s health records for evidence of dementia.
Compared to women with one child, women who had three or more children had a 12% lower risk of dementia. And that effect was still seen after accounting for the other factors collected by researchers. In addition, with each additional pregnancy miscarriage a woman reported, her average risk of dementia rose by 8%. Women who had suffered three or more miscarried pregnancies were 47% more likely to develop dementia than were women who reported no miscarriages.
Finally, women whose first menstrual period occurred between the ages of 10 and 13 were 22% less likely to develop dementia later in life than were women who did not begin to menstruate until age 16.
Paola Gilsanz, a Kaiser Permanente researcher in Oakland and co-author of the new study, acknowledged that the new findings will do little to help women stave off dementia. Many sex-related hormones are involved in reproduction, and they wax and wane in complex patterns. “And you can’t really change when you get your first period or whether you have a miscarriage,” she added, uncovering a link between pregnancies, periods and miscarriages.
“It’s more that these provide a window into sex-specific modes of action” that may underlie dementia, Gilsanz said. If researchers can get a better handle on what factors contribute to dementia, or to its prevention, they are a few steps closer to identifying drugs, dietary influences or behavioral changes that might mimic those effects.
The smaller of the two studies suggests that pregnancy-related changes in a woman’s immune function may be at work. During pregnancy, particularly in the first trimester of pregnancy, a woman’s immune system undergoes dramatic reorganization. To allow the implantation and development of a fetus that could be construed as a foreign invader, the immune system needs to selectively ease its normal level of vigilance.
This retrenchment helps explain why for some disorders linked to the immune system’s hypervigilance — auto-immune disorders such as allergies and multiple sclerosis -- pregnancy reduces risk or eases symptoms, said Molly Fox, the author of the second study. And there’s evidence that some pregnancy-related changes in “immunoregulation” persist over a woman’s lifetime.
If immune system overreaction is a feature of dementias such as Alzheimer’s disease (and there is strong evidence that it is), then there might be some protective value to getting the immune system to “stand down” during early pregnancy, Fox added.
Fox found that for each additional month of pregnancy a woman experienced, her average probability of developing Alzheimer’s disease declined by 5.5%.
Fox said the results of her pilot study “would hopefully...expand the conversation beyond just one hormone — estrogen -- and encourage larger studies and future research” to tease out women’s dementia risk.
Other research presented Monday expands the picture of women’s dementia risk in ways that offer other insights. One study uncovered a curious difference between men and women whose brains have begun to show the hallmarks of Alzheimer’s disease: that even as physiological evidence of Alzheimer’s mounts, women tend to perform better at verbal memory tasks, such as recalling words and names.
That advantage may act as a “cognitive reserve” for women, serving them well as they navigate the earliest stages of Alzheimer’s disease, the authors of the new research said. But because families often seek help when they first detect a loved one’s “searching for words,” a woman’s verbal resilience may also delay recognition of the onset of dementia.
By measuring the effects of a female’s reproductive span and her childbearing history on her risk for dementia, the new research is also likely to refine efforts to identify women early who are at higher risk of the disease.
No medication has been found effective in altering the course of Alzheimer’s disease. But mounting evidence suggests that the processes leading to memory loss start decades before behavioral symptoms are evident, and that with widespread early interventions, some cases can be delayed or prevented. That has put a premium on early identification of those at risk.
In an interview, Suzanne Craft, a professor of geriatric medicine at Wake Forest University, called the new studies an important first step in understanding dementia risk in women. Studies that look at women’s life courses can generate hypotheses about the mechanisms that drive dementia – or that protect a woman’s brain from its ravages, said Craft, who moderated a panel on the new research Monday morning in Chicago.
Craft said that researchers now should explore these hypotheses in animal studies, clinical trials and in populations of women whose life courses and childbearing patterns are different than those explored here.
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