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)

Abstract INTRODUCTION Postmenopausal estrogen decline may contribute to Alzheimer’s disease (AD) risk, but longitudinal evidence linking circulating estrogens to cerebrospinal fluid (CSF) biomarkers is lacking. METHODS We analyzed 866 female participants from the European Prevention of AD Longitudinal Cohort Study with baseline serum estradiol and estrone measured by liquid chromatography tandem mass spectrometry and repeated CSF measurements of amyloid-beta (Aβ) 42 , phosphorylated (p) Tau 181 , and total (t) Tau. RESULTS Neither estradiol nor estrone was associated with longitudinal Aβ 42 . Higher estradiol was associated with lower baseline tau and slower tau increases over time. Baseline estradiol-tau associations were stronger in apolipoprotein E ( APOE ) ε4 carriers, though APOEε4 did not modify longitudinal associations. Amyloid positivity did not moderate hormone-tau associations but was associated with steeper tau increases over time. Estrone showed no significant associations. DISCUSSION These findings suggest a more consistent relationship between estradiol and tau-related rather than amyloid-related pathology.