Sex-Differences in Early-Onset Alzheimer's Disease

Abstract

Background: Prior research in Alzheimer’s disease (AD) suggests female sex is associated with increased disease risk and pathology burden, but this has not been examined in Early-onset AD (EOAD; onset <65). Using data from the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS), we examined sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathological burden. Methods: Chapter 2 analyses included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 early-onset non-AD (EOnonAD) LEADS participants. Each diagnostic group was stratified by sex and then by APOE ε4 carrier status. Imaging biomarkers were compared across strata, and voxel-wise multiple linear regressions generated statistical maps of gray matter density, amyloid, and tau PET burden. Chapter 3 analyses evaluated the impact of sex and APOE ε4 on plasma and cerebrospinal fluid (CSF) AD biomarkers. We included 201 EOAD, 64 EOnonAD, and 86 CN participants with plasma data; of these, 100 EOAD, 35 EOnonAD, and 38 CN also had CSF data. Participants were stratified by sex and APOE ε4 genotype. Demographics and biomarker differences were compared using ANOVA within diagnostic groups, and ANCOVA models controlled for age and education. Results: In imaging analyses, EOAD females showed greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers exhibited greater amyloid burden and gray matter atrophy than female ε4 carriers; EOnonAD female non-carriers also showed greater atrophy. EOAD women had higher plasma NfL and GFAP, with comparable Aβ42/40 and pTau231 levels relative to men. In CSF, EOAD women had higher neurogranin, tTau, pTau181, and VILIP1. EOnonAD women had higher plasma GFAP. In CN participants, women showed higher CSF SNAP25, whereas men showed a trend toward higher plasma pTau231. APOE ε4 status did not influence plasma or CSF biomarker levels in either sex. Conclusion: These analyses show that female sex and APOE ε4 status are associated with greater pathology burden in EOAD. As specific AD fluid biomarkers emerge, understanding sex-based differences across PET, CSF, and plasma measures is critical and supports further study of sex- and APOE-ε4–related variation in biomarker expression and its relevance to EOAD diagnosis and treatment.