Women with shorter-than-average reproductive periods are at a markedly increased risk for dementia, according to a paper published March 27 in Neurology. Researchers led by Paola Gilsanz at Kaiser Permanente Division of Research in Oakland and Rachel Whitmer at the University of California, Davis, reported that among more than 6,000 women in a diverse prospective cohort study, those who started menstruation at a later age, and/or entered menopause early, had more than 20 percent greater risk of developing dementia later on. The researchers attribute this reduced exposure to the neuroprotective effects of estradiol, the predominant estrogen secreted by the ovaries during the reproductive years. Women who have shorter lifetime exposure to the hormone miss out on its full benefits, they proposed.
- Shorter reproductive span linked to increased dementia risk.
- Late menarche and early menopause each correlated with dementia risk.
- Hysterectomies linked to 8 percent higher dementia risk.
Gilsanz presented the gist of the findings at AAIC last year (Aug 2018 conference news). In her talk, she also reported that women who had more children had less risk of dementia, potentially owing to the surge in estrogen that occurs during pregnancy. Gilsanz told Alzforum that the pregnancy data will be published separately.
Two-thirds of people with AD are women (Mar 2014 news). While the reasons women shoulder more of the AD burden are complex, a drop off in neuroprotective estradiol at menopause is one potential factor.
To test the idea that shorter lifetime exposure to the hormone could be important, Gilsanz and colleagues analyzed data from female members of Kaiser Permanente Northern California (KPNC), an integrated health care system that now has 4 million members. Between 1964 and 1973, Kaiser offered optional evaluations called multiphasic health checkups. Women filled out questionnaires about menarche, menopause, and whether they had had a hysterectomy. Gilsanz’s study included women who were 40–55 years of age during that time. In 1996, when electronic health records became available and the women were an average of 76.5 years old, 6,137 who completed the questionnaire in midlife were still members of Kaiser, and had not been diagnosed with dementia. They were tracked until 2017, by which time 2,577 of them—42 percent—had been diagnosed with dementia.
Among the 6,137 women, the average ages at menarche and menopause were 13 and 45, respectively, meaning an average reproductive period of 32 years. A third of the women reported undergoing a hysterectomy. Those who didn’t began menopause at 47, on average, and their reproductive span was 34 years.
Menarche before age 13 was not associated with dementia risk. However, women who started menstruating at age 16 or 17 had a 23 percent greater risk of dementia than those who started at 13. Women who entered menopause between 41 and 46 years of age had a 29 percent greater risk of dementia than those who hit menopause between 51 and 55. All told, women with reproductive spans of between 14–20 and 21–34 years had a 55 and 26 percent higher dementia risk, respectively, than those with spans of 34 years or more. Findings were similar across racial and ethnic groups, and remained significant when controlling for midlife health factors such as hypertension and smoking, as well as late-life health problems such as stroke, diabetes, and heart disease.
Women who reported undergoing a hysterectomy had an 8 percent higher risk of dementia. However, the researchers did not have data on the ages women underwent their hysterectomies, or whether the procedures included removal of the ovaries, which are the primary source of estradiol.
The findings support the idea that longer lifetime exposure to estradiol protects against dementia. However, Gilsanz acknowledged that other hormones, such as progesterone, as well as social and lifestyle factors, could play a role too. While the data does not provide direct evidence that using hormone replacement therapy to extend estradiol exposure will protect against dementia, it is consistent with that idea, Gilsanz said. Studies on the effects of hormone replacement therapy have been controversial, some suggesting that starting therapy too late, or in women with health problems, might damage the brain instead (Jun 2013 news; Sep 2015 news).
“While there is some level of controversy surrounding the efficacy of hormone replacement therapy as a therapeutic intervention for Alzheimer’s disease dementia, this large epidemiological study supports the notion that estrogen may be one potential biological mechanism moderating the AD pathological trajectory,” commented Rachel Buckley of Massachusetts General Hospital in Boston. Buckley recently reported that women have more tau deposition in the entorhinal cortex than men, and wondered whether lifetime estrogen exposure played a role in that phenomenon, too (Feb 2019 news).
“A really fantastic component of this study is the racial diversity of the cohort,” she added. “With this rich dataset, the authors were able to conclude that estrogen-related resilience may not be mediated by race.”
Roberta Brinton of the University of Arizona in Tucson noted that paper dovetails with numerous studies describing how loss of estrogen at menopause negatively impacts the brain. “The findings of Whitmer and colleagues are consistent with a loss of estrogenic mechanisms of action in brain, which can activate a cascade of events leading to the hallmark pathologies of Alzheimer’s disease, decline in brain glucose metabolism, white matter degeneration, and β-amyloid deposition,” she wrote.—Jessica Shugart
- Gilsanz P, Lee C, Corrada MM, Kawas CH, Quesenberry CP Jr, Whitmer RA. Reproductive period and risk of dementia in a diverse cohort of health care members. Neurology. 2019 Mar 28; PubMed.