Lifetime Estrogen Exposure and Cognition in Late Life

The Cache County Study

Joshua M. Matyi, MS; Gail B. Rattinger, PharmD, PhD; Sarah Schwartz, PhD; Mona Buhusi, MD, PhD; JoAnn T. Tschanz, PhD


Menopause. 2019;26(12):1366-1374. 

In This Article

Abstract and Introduction


Objective: Prevalence of Alzheimer's disease (AD) is higher for women, possibly influenced by sex-dependent effects of the estrogen. We examined the association between estrogen and cognitive decline in over 2,000 older adult women in a 12-year population-based study in Cache County, Utah.

Methods: The baseline sample included 2,114 women (mean age = 74.94 y, SD = 6.71) who were dementia-free at baseline and completed a women's health questionnaire, asking questions regarding reproductive history and hormone therapy (HT). Endogenous estrogen exposure (EEE) was calculated taking the reproductive window (age at menarche to age at menopause), adjusted for pregnancy and breastfeeding. HT variables included duration of use, HT type (unopposed; opposed), and time of HT initiation. A modified version of the Mini-Mental State Examination (3MS) was administered at four triennial waves to assess cognitive status. Linear mixed-effects models examined the relationship between estrogen exposure and 3MS score over time.

Results: EEE was positively associated with cognitive status (β = 0.03, P = 0.054). In addition, longer duration of HT use was positively associated with cognitive status (β = 0.02, P = 0.046) and interacted with age; older women had greater benefit compared with younger women. The timing of HT initiation was significantly associated with 3MS (β = 0.55, P = 0.048), with higher scores for women who initiated HT within 5 years of menopause compared with those initiating HT 6-or-more years later.

Conclusions: Our results suggest that longer EEE and HT use, especially in older women, are associated with higher cognitive status in late life.


Approximately two-thirds of the 5.5 million cases of Alzheimer's disease (AD) in the United States[1] are female, suggesting that sex-specific factors may contribute to greater risk of the disease.[2] Sex-dependent differences in gonadal hormone development and synthesis have been implicated as a potential factor underlying the higher prevalence of AD in females.[3]

Endogenous Estrogen Exposure

Estrogen has a significant role in overall brain health and cognitive function. A review of human and animal studies suggests a role for estrogen in promoting memory and learning and in dendritic spine growth in the hippocampus and medial prefrontal cortex.[4] A study of adult female rats found that as cycling estrogen levels increased, so did the density of dendritic spines in the CA1 region of the hippocampus.[5] Synaptic growth peaked during proestrus (the period during the estrous cycle that immediately precedes estrus) and decreased when estrogen levels dropped.

Estrogen levels in women vary throughout the lifespan in relation to a woman's reproductive history, including the length of the reproductive window (time between the onset of menarche to menopause), number of pregnancies, and postpartum breastfeeding. Several studies suggest that the duration of the reproductive window can affect later cognitive health and risk for neurodegenerative disease. One study found that a longer reproductive window was associated with higher scores on a verbal fluency task in a community-based sample of 996 older adult French women.[6] Age at first menses was, however, negatively associated with scores on tasks of visual memory and psychomotor speed, and length of the reproductive window was not significantly associated with cognitive decline measured at 4-year follow-up. Other cross-sectional research found no association between length of the reproductive window on cognitive functioning in 760 postmenopausal Australian women aged 60 to 64 years.[7] In the Epidemiologic Catchment Area (ECA) study that included women aged 31 to 94 years, lower age at the onset of menopause (hence a shorter reproductive window) was associated with a 0.03-point per year decline in the Mini-Mental State Examination (MMSE) over a 12-year period.[8] In addition, women who experienced menopause between the ages of 16 to 40 years had the largest declines in MMSE scores from baseline to follow-up, with mean differences between 2.2 points in those aged 41 to 50 years and 1.6 points for those aged 51 to 63 years.

Pregnancy and breastfeeding affect estradiol levels[9] and research has suggested an association with cognitive decline. In a sample of 89 parous British women aged 70 to 98 years, women with a cumulative history greater than the median of 27 months pregnant (and presumably higher cumulative levels of circulating estrogen over the lifespan) had a 37% reduction in AD risk compared with those below the median.[10] In the ECA study, nulliparous women, however, had significantly higher MMSE scores (0.83 [95% CI = 0.11–1.54]) compared with parous women.[8] The latter is consistent with a study examining risk of AD and number of pregnancies in an Italian sample,[11] where women who had had three or more pregnancies had a 3.2-fold higher risk of AD than nulliparous women. With respect to duration of breastfeeding, women with longer duration of breastfeeding have showed a 23% reduced risk of AD compared with those with shorter duration.[12] Other research has, however, found a significant negative association (r = −0.599) between duration of breastfeeding and performance on a planning task in a sample of 50 older adult postmenopausal women.[13]

Hormone Therapy

Use of hormone therapy (HT) further impacts lifetime estrogen exposure. Several observational studies report protective benefits of HT regarding AD[14,15] and cognitive decline,[16] with strongest effects in those above age 85 years in the latter study.[16] The randomized-controlled trial (RCT) of the Women's Health Initiative (WHI) Women's Health Initiative Memory Study (WHIMS), however, concluded that in a group of 4,532 postmenopausal women, HT not only failed to reduce the risk of mild-cognitive impairment (MCI), but doubled the risk of all-cause dementia.[17] Conversely, in the randomized-controlled Kronos Early Estrogen Prevention Study (KEEPS) authors found no change in cognitive outcomes over 4 years comparing HT with placebo for 662 healthy, postmenopausal women.[18]

Discrepancies between observational studies and the above RCTs have led to hypotheses related to the initiation of HT within a "critical window" promoting cognitive benefit.[19,20] A review of the critical window of HT suggests that women who begin HT shortly after the onset of menopause in the perimenopausal stage may experience benefits of reduced cognitive decline as compared with those who wait a substantial period of time before starting HT.[20] Furthermore, in a group of healthy postmenopausal women, a 17-beta estradiol patch initiated close to the onset of menopause was predictive of better executive functioning compared with placebo, although this interaction was at trend-level significance.[19] In the Cache County Study, a sample of 1,769 women (mean age = 75.3 y [SD = 6.6 y]) showed those who used HT within 5 years of menopause had a 30% reduced risk of AD.[15] In addition, those women who did not start HT until 5 or more years after menopause showed no reduction in risk and those who initiated opposed (ie estrogen that includes progesterone) HT within 3 years of study baseline showed a trend for an increase in AD risk (adjusted HR = 1.93 [95% CI, 0.94–3.96]).

One study of a British sample of older adult women examined both endogenous and exogenous estrogen exposure over the lifespan.[10] The authors calculated lifetime estrogen exposure by taking menopausal age, minus age at menarche, and subtracting the number of months spent breastfeeding after pregnancy to account for the lack of cycling estrogen during this time. The results suggested that for each additional month of endogenous estrogen exposure, there was a 0.5% decrease in AD risk. Also, for each additional month of extended HT exposure, there was an overall 0.56% decrease in AD risk. Limitations included the small sample size and inclusion of only parous women.

Our current study examined cumulative lifetime estrogen exposure and late-life cognitive decline in a population-based sample of over 2,000 older adult women in the Cache County (Utah, USA) Study. Lifetime estrogen exposure was based on endogenous exposure (time of menarche to menopause), number of pregnancies, duration of breastfeeding, and HT use. The role of potential confounding factors such as overall health predicting cognitive outcomes was also examined.