Associations between serum estradiol and estrone and Alzheimer's disease biomarkers: An analysis in female participants from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS).

INTRODUCTION: Postmenopausal estrogen decline may contribute to Alzheimer's disease (AD), but evidence linking circulating estrogens to cerebrospinal fluid (CSF) AD biomarkers remains limited. METHODS: We analyzed 854 female participants from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study with baseline serum estradiol and estrone measured by liquid chromatography-tandem mass spectrometry and repeated CSF amyloid-beta 42 (Aβ42), phosphorylated tau 181 (pTau181), and total tau (tTau). Models used regression for cross-sectional analyses and mixed-effects models restricted to the 187 participants with follow-up, adjusted for age, body mass index, waist circumference, and hormone replacement therapy (HRT) use. We also tested apolipoprotein E ε4 (APOEε4) and amyloid moderation and conducted sensitivity analyses excluding current HRT users. RESULTS: Neither hormone was associated with Aβ42. Higher estradiol was associated with lower baseline tau, especially among APOEε4 carriers, but not with tau change. In exploratory longitudinal analyses, estrone showed a modest association with slower pTau181 increase. DISCUSSION: Findings suggest more consistent cross-sectional associations of estradiol with tau than with Aβ42; longitudinal findings were limited by attrition and should be interpreted as exploratory.