Reproductive period and risk of dementia in a diverse cohort of health care members

Abstract

ObjectiveWomen have >50% greater lifetime risk of dementia than men but the role of female-specific endocrine milieu is not well-understood. This study evaluates associations between indicators of estrogen exposure from women's reproductive period and dementia risk in a large diverse population.MethodsWe evaluated 15,754 female members (29.9% nonwhite) of Kaiser Permanente with clinical examinations and health survey data from 1964 to 1973 and were members as of January 1, 1996. In midlife (mean age 51.1 years), women reported age at menarche and menopause and hysterectomy status. Reproductive span was calculated as menopause age minus menarche age. Dementia diagnoses were abstracted from January 1, 1996 to September 30, 2017 medical records (mean age at start of dementia follow-up 76.5 years). Cox proportional hazard models evaluated associations between aspects of reproductive span and dementia risk adjusting for demographics and life course health indicators.ResultsForty-two percent of women developed dementia. Compared to menarche at age 13.0 (mean menarche age), menarche at ≥16 was associated with 23% greater dementia risk (adjusted hazard ratio [HR] 1.23; 95% confidence interval [CI] 1.01–1.50) adjusting for demographics and life course health indicators. Natural menopause at age <47.4 (mean menopause age) was associated with 19% elevated dementia risk (HR 1.19; 95% CI 1.07–1.31). Reproductive spans <34.4 years (mean duration) were associated with 20% elevated dementia risk (HR 1.20; 95% CI 1.08–1.32). Hysterectomies were associated with 8% elevated dementia risk (HR 1.08; 95% CI 1.01–1.16).ConclusionIn this large prospective cohort study, endocrine events signaling less estradiol exposure (i.e., later age at menarche, younger age at menopause, shorter reproductive span, and hysterectomies) were associated with elevated risk of dementia.

Sex and gender differences in Alzheimer’s disease: current challenges and implications for clinical practice

“…[47], cumulative numbers of gestations were found to reduce the risk of incident AD. Further supporting a link between reproductive life and dementia risk, higher age at menarche, menopause before age 47 and shorter reproductive span were shown to increase the risk of incident dementia in a large prospective cohort study with 15 754 participants [48]. These results need to be confirmed in further studies.…”

Reproductive period and dementia: A 44‐year longitudinal population study of Swedish women

“…The Women's Health Initiative Memory Study reported that women assigned exogenous estrogens had an increased risk of dementia, 6 while others reported no associations 7,8 . The effect of long‐term endogenous estrogen exposures on dementia risk and Alzheimer's disease (AD) is less clear 9‐11 . There are different forms of endogenous estrogens.…”

“…The Rotterdam Study, which included women with natural menopause, reported that those with longer reproductive period had higher risk of dementia and AD, especially among apolipoprotein E ( APOE ) ε4 carriers. 9 In contrast, the Kaiser Permanente Study (KP) reported a higher risk of dementia in those with shorter reproductive span, 11 while the 10/66 study found no association between reproductive period and dementia incidence 10 . None of the studies included information on oral contraceptives, 9‐11 and the two latter did not assess HRT exposure 10,11 .…”

Sex differences in cognitive reserve: implications for Alzheimer’s Disease in women

“…Importantly, female-specific hormonal transitions including puberty, parity and menopause can help in our understanding of why women are more likely to be diagnosed with AD (see Table 2). Earlier onset of menopause, either surgical (ovarian removal) or spontaneous (gradual cessation of menses at ~51yrs), is associated with increased AD/dementia risk (Bove et al, 2014;Fox et al, 2013a;Gilsanz et al, 2019;Rocca et al, 2007). Total reproductive years (age at menarche to age at menopause) has repeatedly been shown to be negatively correlated with the rate of AD diagnosis, indicating that duration of ovarian hormone exposure protects against AD (Fox et al, 2013a;Gilsanz et al, 2019).…”

“…Earlier onset of menopause, either surgical (ovarian removal) or spontaneous (gradual cessation of menses at ~51yrs), is associated with increased AD/dementia risk (Bove et al, 2014;Fox et al, 2013a;Gilsanz et al, 2019;Rocca et al, 2007). Total reproductive years (age at menarche to age at menopause) has repeatedly been shown to be negatively correlated with the rate of AD diagnosis, indicating that duration of ovarian hormone exposure protects against AD (Fox et al, 2013a;Gilsanz et al, 2019). In fact, there is evidence that the 17-estradiol (E2) decline at menopause may contribute to cognitive decline in women at late midlife, and that estrogen replacement initiated shortly after menopause reduces the incidence of AD (Kawas et al, 1997;Merlo et al, 2017;Shao et al, 2012;Tang et al, 1996;Whitmer et al, 2011).…”