Lifetime Exposure to Endogenous Estradiol and Markers of Dementia Risk: Associations with Later Life Cognitive,...

Background/Objectives: Longer lifetime exposure to endogenous estradiol (L_EE2) has been associated with lower risk of age-related cognitive decline and dementia. Complementary to cognitive decline, behavioral and functional decline are also predictive of dementia risk; however, the association between L_EE2 and these domains is underexplored. We investigated whether L_EE2 is correlated with later-life changes in behavior and function. Methods: Baseline data from 1156 females enrolled in the CAN-PROTECT study were analyzed. L_EE2 was estimated based on the length of the reproductive period (menopause age-menarche age) plus years pregnant and scaled in 5-year increments. Objective cognition was measured using the CAN-PROTECT neuropsychological battery, while subjective cognition, behavior, and function were measured using the Revised Everyday Cognition (ECog-II) scale, Mild Behavioral Impairment Checklist (MBI-C), and Standard Assessment of Global Everyday Activities (SAGEA) scale, respectively. Linear regressions modeled the association between L_EE2 and neuropsychological performance. Three separate negative binomial regression models examined the association between L_EE2 and ECog-II, MBI-C, and SAGEA total scores. All models adjusted for menopause hormone therapy, menopause type, age at first childbirth, body mass index, age, education, and ethnocultural background. Results: Each five-year increase in L_EE2 was associated with a lower MBI-C score (count ratio [CR] = 0.89, 95% CI [0.82, 0.97]) and lower SAGEA score (CR = 0.91, 95% CI [0.84, 0.98]). L_EE2 was not significantly associated with any objective or subjective cognitive measures. Conclusions: Longer L_EE2 may associate with lower severity of later-life behavioral and functional symptoms in older women.