When asking why more women than men have Alzheimer’s disease or dementia — nearly two thirds of Americans with the disease are women — the prevailing explanation has been that women live longer and that it is a disease associated with aging.
But scientists at the Alzheimer’s Association International Conference in Chicago on Monday said it is important to look at how women’s reproductive history relates to their risk of developing the disease. Their latest research has found associations between a woman’s dementia risk and her number of children, miscarriages, cumulative months of pregnancy and years between first menstrual period and menopause.
In a study of 14,595 long-term Kaiser Permanente members, researchers looked at the reproductive history of women who were 40 to 55 between 1964 and 1973 and were still members between 1996 and 2017.
They found that women who had had three or more children had a 12 percent lower risk of dementia in later life than those with fewer children. The study also showed that women who didn’t get their first period until age 16 or 17 had a 31 percent higher risk of dementia than those who began menstruating at 13, and that women who stopped menstruating at age 45 or earlier had a 28 percent higher risk of dementia than women who stopped menstruating after age 45.
“One hypothesized reason is that it is cumulative exposure to estrogen across the life course,” which may protect against the disease, said Paula Gilsanz, a staff scientist at the division of research at Kaiser Permanente Northern California and an author of the study.
The study, the largest of its kind in the United States, spanned a range of education levels and included 32 percent nonwhite subjects, making it more diverse than many.
It found that those who had reported miscarriages had an 8 percent higher risk of dementia with each report of a miscarriage.
Rachel Whitmer, a professor of epidemiology at the University of California at Davis’s school of medicine and the study’s other author, cautioned against seeing miscarriages themselves as contributing to Alzheimer’s. Whatever conditions caused the miscarriages could also have put women at higher risk for the disease, she said.
“We don’t know why they had miscarriages,” she said. “A plausible explanation is they had some pregnancy-related health issues” such as hypertension or gestational diabetes. “In the ’60s and ’70s, we knew much less about pregnancy, about medical conditions that might be manifest.”
But estrogen may not be the only reason pregnancy seems to protect against Alzheimer’s. Another may lie in immune function, according to a University of California at Los Angeles study presented at the conference. It found that women who spend more cumulative months pregnant — especially in the first trimester — have a lower risk of developing dementia. For each additional month pregnant, the risk went down by 5.5 percent.
Although the dominant theory for the lower risk associated with pregnancies has credited the estrogen boosts that happen largely in the third trimester, the UCLA study suggests the benefit may lie in the immune system changes that take place in the first trimester. It found that the lower risk was associated with the cumulative number of first trimesters, but that the number of third trimesters had no significant effect.
That could be because early in the first trimester a woman experiences increases in a special type of immune cell that suppresses inflammation, which help prevent her body from rejecting the fetus as a “foreign” entity. Those cells, known as regulatory T-cells or Tregs, continue to rise even after pregnancy. Alzheimer’s patients have fewer Tregs and more of the type of immune cells that cause inflammation.
The UCLA study looked at the reproductive history — births, miscarriages and abortions — of 133 women between 70 and 100 living in Southern England. Half had Alzheimer’s, and half did not. It found that a woman who spent 3 percent more time pregnant than another otherwise identical woman had around a 5.5 percent lower Alzheimer’s risk, and a woman who spent 12.5 percent more time pregnant had around a 20 percent lower risk.
But not all months of pregnancy gave equal protection. A woman who had 20 percent more first trimesters than another otherwise identical woman had around 30 percent lower risk of the disease, while the amount of third semester accumulated had no apparent effect on Alzheimer’s risk.
Pregnancy provides relief from certain autoimmune diseases that cause inflammation similar to that seen in Alzheimer’s. That prompted the idea that the immune system changes in the first trimester might be more protective than the estrogen surges later in pregnancy, said Molly Fox, the study’s author and an assistant professor in UCLA’s departments of anthropology and psychiatry and behavioral sciences.
“If estrogen were explaining the relationship, the most potent predictor would be how many times you experienced that late surge in hormone level,” she said. “We hope that it will spark a little bit more of a comprehensive conversation . . . beyond the one topic that has dominated the debate so far.”
Research at the conference also included updates to the associations between hormone therapy and Alzheimer’s risk. Previous studies had suggested that women who start taking hormones in their late 60s and 70s have a higher rate of cognitive decline, a paper out of the University of Wisconsin school of medicine and public health found that risk to be elevated specifically for women with diabetes.
For non-diabetic women and for women who started the therapy in their early 50s, there was no cognitive harm or benefit associated with taking the hormones, the new research found. And women receiving an oral form of the therapy demonstrated improved mood and reductions in anxiety and depression.
Previous findings had sometimes contradicted each other, leading women to swing between embracing or avoiding hormone therapy based on fears of cognitive effects, said Carey Gleason, an associate professor of medicine at Wisconsin.
The new findings should reassure “women who are worried they are hurting their brains either in the moment or down the road,” Gleason said. Women need to talk with their doctors about their personal risk profiles, but for a woman using hormone therapy to help with menopause-related issues related to sleep, sexual function, mood and bone health, “at least she can put into the algorithm the information that she’s not hurting her cognition if she opts to use it.”
Another gender-related presentation at the conference offered an explanation of sex differences in the diagnosis of Alzheimer’s. Women tend to decline more quickly after a diagnosis than men do, and men are more often diagnosed with amnestic mild cognitive impairment (aMCI), a precursor to Alzheimer’s.
The study, out of the University of Illinois at Chicago, used the Alzheimer’s Disease Neuroimaging Initiative, a large longitudinal study in the United States, to look at brain imaging of 764 women and 941 men at different stages of diagnosis.
Among women and men who showed similar moderate disease levels in neuroimaging, women had better verbal memory performance in clinical tests, though this advantage disappeared as the disease advanced.
Women perform better on such verbal tests throughout their life span. But while the standard measures for diagnosing aMCI account for age and education, they do not account for gender. So doctors might miss diagnosing women in early stages of dementia because their better verbal memory can mask the disease, according to the study. They might also over-diagnose aMCI in men, since the assessment standards are based on average performance by both women and men.
“It interferes with the staging of Alzheimer’s disease, when you’re asking, ‘How many good years does mom have left,’ ” said Pauline Maki, a professor of psychiatry and psychology at the University of Illinois at Chicago, the study’s author.
If the standards were adjusted to account for gender, some men could avoid the stress of being wrongly diagnosed with aMCI, Maki said. And some women could benefit from knowing sooner, both in terms of planning and in being able to benefit from FDA-approved medications that work best in the early stages of dementia.