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

Background/Objectives: Longer lifetime exposure to endogenous estradiol (LEE2) 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 LEE2 and these domains is underexplored. We investigated whether LEE2 is correlated with later-life changes in behavior and function. Methods: Baseline data from 1156 females enrolled in the CAN-PROTECT study were analyzed. LEE2 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 LEE2 and neuropsychological performance. Three separate negative binomial regression models examined the association between LEE2 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 LEE2 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]). LEE2 was not significantly associated with any objective or subjective cognitive measures. Conclusions: Longer LEE2 may associate with lower severity of later-life behavioral and functional symptoms in older women.