The timing of menopause, menarche, along with the duration of a woman's reproductive span, was associated with the risk for dementia, according to a new analysis in the March 28 online edition of Neurology.
Previous research has suggested that women have as much as a 50 percent greater lifetime risk of developing dementia than men. But the new analysis proposes that a woman's reproductive history is significantly associated with that risk.
In the prospective study, researchers found later age at menarche, younger age at menopause, shorter reproductive span, and hysterectomies appeared to elevate dementia risk.
Endocrine events that signal less estradiol exposure may play a role in modulating disease risk, according to the researchers, led by Paola Gilsanz, ScD, staff scientist at Kaiser Permanente Division of Research, Oakland, California.
"Our epidemiologic findings support prior basic science work suggesting neuroprotective effects of estrogen," the researchers wrote.
Previous studies have shown estradiol boosts neuronal resilience and repair. For example, estradiol has been shown to reduce inflammation, apoptosis, and tau hyperphosphorylation. However, research on estradiol exposure and women's reproductive history across life has yielded inconsistent findings.
To better understand the associations between estradiol lifetime exposure and dementia risk, the team analyzed data from 15,574 female members of Kaiser Permanente Northern California, an integrated health care system.
The members filled out questionnaires about menarche, menopause, and whether they had a hysterectomy, between 1964 and 1973. The average age was 40 to 55 years during this time.
In 1996, when electronic health records became available, the average age was 76.5 years old. A total of 6,137 who completed the questionnaire in midlife were still members of Kaiser and had not been diagnosed with dementia.
The researchers calculated the reproductive span (menopause age minus menarche age) for each participant and used medical records to determine which participants developed dementia, which included Alzheimer's disease, vascular dementia, and non-specified forms of dementia, later in life.
They adjusted for demographics and midlife health indicators (hypertension, BMI, smoking status) and late-life health indicators (stroke, diabetes, and heart failure).
Participants were followed until 2017, by which that time 42 percent had been diagnosed with dementia.
Of 6,137 women, the average ages at menarche and menopause were 13 and 45.1 years, respectively, resulting in a reproductive span of 32.2 years. A total of 34 percent of participants reported undergoing a hysterectomy. Among those who didn't report a hysterectomy, the average age at menarche was 13 years, the average age at menopause was 47.4 years, and the average reproductive span was 34.4 years.
The findings revealed that women who experienced menarche at age 16 years or older were at a 23 percent greater risk for dementia than those who experienced menarche at age 13 years.
Those with reproductive spans of less than 34.4 years were at a 20 percent elevated risk for dementia. Compared to the longest reproductive span (39 to 44 years), spans of 14 to 20 years were tied to a 55 percent higher risk for dementia; spans of 20 to 30 years had a 26 percent higher risk; and spans of 31 to 34 years were associated with a 26 percent higher risk.
Going through menopause before age 47.4 years was tied to a 19 percent greater risk of dementia than those who went through menopause at age 47 or later.
Hysterectomies were associated with an 8 percent elevated risk for dementia.
"Studies suggest that timing of surgical menopause influences dementia risk, with younger age associated with greater risk of dementia or cognitive impairment and AD pathology," the researchers wrote, about the potential influence of hysterectomies on dementia risk.
Overall, they concluded that later age at menarche or earlier age at menopause, along with the duration of a woman's reproductive span, was associated with an increased risk for dementia.
Although the study was diverse and large, the researchers did not have enough data to account for other factors that could affect estrogen levels, including pregnancies, hormone replacement therapy, or birth control.
Therefore, the researchers concluded, the findings warrant further research into how loss of estrogen at menopause can influence brain health.
The researchers report no relevant financial disclosures.
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Gilsanz P, Lee Catherine, Corrada MM, et al. Reproductive period and risk of dementia in a diverse cohort of health care members. Neurology 2019; Epub 2019 Mar 28.