Lifetime estrogen exposure and cognition in late life: the Cache County Study

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 (beta = 0.03, P = 0.054). In addition, longer duration of HT use was positively associated with cognitive status (beta = 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 (beta = 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.