Abstract Body: Introduction: Women are disproportionately likely to develop dementia, but there is an incomplete understanding of sex-specific risk factors for cognitive impairment. Whether postmenopausal levels of endogenous sex hormones are associated with later-life brain health is unclear and warrants further investigation.

Hypothesis: Among postmenopausal women, lower levels of estradiol (E2) and sex hormone binding globulin (SHBG) are associated with a greater risk of incident mild cognitive impairment (MCI) or probable dementia (PD).

Methods: We conducted a nested cohort study of women who were enrolled in the Women’s Health Initiative (WHI) hormone therapy (HT) trials and were part of separate ancillary studies that measured sex hormones in baseline blood samples and that annually assessed women for incident MCI and PD, adjudicated by study clinicians. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between log-transformed baseline E2 and SHBG levels and a combined endpoint of MCI or PD, adjusted for relevant confounders, right-censoring at death or loss to follow-up. The Cox stratification procedure was used to account for trial arm participation (HT vs. placebo).

Results: The analysis included 2,081 participants with a median follow-up time of 7 years. The mean baseline age was 71 years (SD 4.0). There were 567 women who developed MCI/PD. In base models (adjusted for age, age at menopause, baseline BMI), higher baseline E2 and SHBG levels were associated with greater MCI/PD risk (per 1 SD change in hormone level: HR for E2: 1.12 [95% CI 1.02-1.23], HR for SHBG, 1.18 [95% CI 1.07-1.30]. In models additionally adjusted for baseline physical activity, alcohol use, smoking, education, cardiovascular comorbidities, and time-varying occurrence of stroke during follow-up, the association between E2 levels and MCI/PD was no longer significant (HR 1.08, 95% CI 0.98-1.19), but remained significant for SHBG (HR 1.26, 95% CI 1.14-1.39).

Conclusions: Among postmenopausal women, our findings suggest a significant association between higher baseline SHBG levels and risk of MCI/PD, in the direction opposite to our hypothesis. Future work is planned to examine the role of other hormones (testosterone) and of postmenopausal E2, SHBG, and testosterone levels in relation to cognitive trajectories over time.