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By Alice Park
July 23, 2018

In the U.S., two-thirds of people with Alzheimer’s disease are women, according to the Alzheimer’s Association. For decades, experts have explained the gender divide by the fact that women also tend to live longer than men, and the biggest risk factor for Alzheimer’s is age.

“Everyone brushed it off to the fact that women were living longer,” says Rachel Whitmer, professor of epidemiology at University of California Davis. “Now science is saying, wait, that’s not the end of the story.”

Pregnancy, according to two of the latest studies on the issue, may have something to do with it.

The new studies come to opposite conclusions about pregnancy and the risk of dementia. One study found that the more children a woman had, the lower her risk of developing dementia, while another found that having five or more children was tied to a higher risk of Alzheimer’s. Both studies—though their findings conflict—point to the need for more studies investigating the under-researched area.

Whitmer and her colleague Paola Gilsanz, a staff scientist from the Kaiser Permanente Division of Research, presented data on their study at the annual meeting of the Alzheimer’s Association. They analyzed health information from more than 14,500 women who were members of Kaiser Permanente from the 1960s to 2017. They tracked the women’s reproductive milestones, including their first period, the number of children and miscarriages they had, and when they began menopause. They then correlated this information with records of dementia diagnoses.

After adjusting for factors that could affect dementia (including Alzheimer’s dementia), such as obesity, smoking, education and race, they found that women who had three or more children had a 12% lower risk of developing dementia compared to women with one child. And women who had miscarriages were at higher risk of developing dementia compared to women who did not; each miscarriage was linked to an 8% increased risk. When women began menstruating also seemed to influence dementia risk. Those whose first periods occurred at 16 years or later had a 22% greater risk of developing dementia compared to women who got their first period between ages 10 years and 13 years.

“These findings are really exciting, especially in the context of life course research,” says Gilsanz. “We hope doctors and researchers will really start to think about brain health and dementia risk across the life course and identify places for intervention, and understand that changes that happen that can eventually lead to dementia really begin much, much earlier in life.”

The other recent study on pregnancies and the risk of Alzheimer’s appeared in the journal Neurology. Researchers from Korea analyzed nearly 3,500 women from Korea and Greece—and they found the opposite trend. They reported that women who had five or more children had nearly twice the risk of showing signs of Alzheimer’s, as measured on standard cognitive tests, compared to women with one to four children. They also found that women with incomplete pregnancies, due to miscarriage or abortion, performed better on the cognitive tests compared to women who never experienced a miscarriage or abortion.

“Our results may provide one possible mechanism why Alzheimer’s disease is more prevalent in women than in men,” says Dr. Ki Woong Kim, from the department of brain and cognitive sciences at Seoul National University College of Natural Sciences and senior author of the study. Kim says that “because pregnancy and childbirth induce dramatic changes of sex hormone levels, we hypothesized that pregnancy and its outcomes affect the risk of Alzheimer’s disease in late life.”

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Kim notes that levels of certain estrogens can rise up to 40 times the normal level during pregnancy, and that previous studies have suggested that at certain levels, the hormone can be protective of the brain, while at extremely high levels, it might be harmful. Estrogen-based contraceptives, for example, have been linked to improved cognitive function in women both before and after menopause. Theoretically, says Kim, it’s possible that women who have more children may be exposed to more extreme levels of estrogen that might be detrimental to cognitive functions over time.

Whitmer and Gilsanz point out, however, that the estrogens that spike during pregnancy “are not the same ones that women are exposed to when they are fertile and ovulating,” says Whitmer. “They are two different things, and there could potentially be two different mechanisms modulating dementia risk and brain health,” she says.

It’s the latter group of hormones that fluctuate with a woman’s monthly cycle that Whitmer and Gilsanz’s study, and most studies on reproductive history, measure. The researchers found that the longer a woman’s reproductive years—from when her period begins to menopause—the lower her risk of developing dementia, including Alzheimer’s dementia. They found that women who began menopause earlier saw an uptick in their risk of dementia.

That correlates with studies looking at hormone replacement therapy, which some women may take at menopause to replace declining levels of estrogen and address symptoms of hot flashes and night sweats. Some studies suggest that taking hormone replacement therapy, including estrogen, may lower the risk of dementia if taken at menopause for a short period, but may not be as beneficial if taken years after menopause, when changes in brain neurons affecting memory and thinking may have already occurred.

The contrary findings on the relationship between miscarriages may also be attributed to other health factors that the studies did not consider. It’s possible, for example, that women experiencing more miscarriages may have other health issues that contribute both to their difficulty in carrying a pregnancy to term as well as dementia.

It’s also possible that the conflicting results have to do with other, non-biological factors that could affect how many children women have. While the researchers accounted for the effect of things like education and socioeconomic status, which can impact access to health care, there may be other effects that the scientists didn’t consider. “It’s important to keep in mind that while there is a very real possibility that there is a biological connection between reproductive history and dementia risk, there is a bigger picture of other pathways that could be associating with the number of children born and dementia risk,” says Gilsanz.

For now, the scientists say the findings should not be interpreted as a guide for determining the ideal number of pregnancies women should target for optimal brain health. All of the study authors note that it’s not yet clear how women’s changing exposure to hormones, as a result of puberty, childbearing and menopause, can affect the brain.

“We wouldn’t be ready to say, ‘yes, for brain health, ladies, go out and have three or more kids,’” says Whitmer. “What these results are is a clue and a window into what is happening mechanistically. It’s a call to action for the field to take seriously why women specifically are at higher risk of developing dementia, and what it is about the female brain and the hormonal milieu over the life course that sets the brain up for higher or lower risk.”

Contact us at editors@time.com.

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