Nemes : Sex-Associated Differences in Cerebrospinal Fluid and Plasma Biomarkers in Early-Onset Alzheimer’s Disease
Sex-associated differences in plasma and cerebrospinal fluid biomarkers in Early-onset Alzheimer’s disease
Sára Nemes, Paige E. Logan, Jeffrey L. Dage, Dustin B. Hammers, Anne M. Fagan, Mohit K. Manchella, Ani Eloyan,Tatiana M. Foroud, Henrik Zetterberg, Robert A. Koeppe, Paul S. Aisen, Kaj Blennow, Julia D. Gray, Suzanne E. Schindler, Maria C. Carrillo, Gil D. Rabinovici, Bradford C. Dickerson, Liana G. Apostolova
Female-sex is associated with greater atrophy, amyloid and tau burden in Early-onset Alzheimer’s Disease (EOAD) in the Longitudinal EOAD Study (LEADS). APOE-ε4-non-carrier-status was found to be a further predictor of EOAD pathology. We expanded the analyses by examining the impact of sex and APOE-ε4 on plasma and cerebrospinal fluid (CSF) biomarkers of AD. Plasma markers included: neurofilament light chain (NfL), plasma glial fibrillary acidic protein (GFAP), Aβ 42/40, and pTau231. CSF markers included: Aβ 42/40, neurogranin, tTau, pTau181, SNAP25, YKL-40, and VILIP1.
We included 201 amyloid-positive EOAD, 64 amyloid-negative EO cognitively impaired (EOnonAD), and 86 Cognitively-normal (CN) LEADS participants with plasma biomarker data. Of these 100 EOAD, 35 EOnonAD, and 38 CN participants also had CSF data. Participants were stratified by sex and APOE-ε4-genotype. Demographics (age, education, APOE-ε4, MMSE) and biomarker differences were compared using ANOVA within each diagnostic group. ANCOVAs were run to control for effects of age and education on biomarkers.
Compared to men, EOAD women showed greater levels of plasma NfL (p=.03), and GFAP (p<.001) while Aβ 42/40, and pTau231 were comparable. In CSF, EOAD women showed higher levels of neurogranin (p=.01), tTau (p=.01), pTau181 (p=.01) and VILIP1 (p=.02). EOnonAD women showed significantly greater plasma GFAP levels (p=.02). In the CN cohort, women had greater CSF SNAP25 levels (p=.03) while men showed a trend for higher plasma pTau231 levels (p=.05).
APOE-ε4-carrier-status was not associated with differences in levels of plasma or CSF biomarkers in either sex.
As new AD fluid biomarkers and treatments emerge, understanding sex-based differences in CSF and plasma is imperative. Female sex is associated with higher levels of neurodegeneration in EOAD and astrogliosis in both EOAD and EOnonAD. This paves the way for further examination of sex and APOE-ε4-genotype-based differences in imaging and fluid biomarkers, their associations, and utility in early diagnosis and treatment.