Exploring the Utility of Biofluid‐Based Biomarkers in Early‐Onset Alzheimer’s Disease

Abstract

AbstractBackgroundOne goal of the longitudinal early onset Alzheimer’s disease study (LEADS) is to define fluid biomarker characteristics of early‐onset Alzheimer’s disease (EOAD). In this mid‐study cross sectional analysis, participants have undergone clinical and cognitive assessments, magnetic resonance imaging (MRI), positron emission tomography (PET), lumbar puncture, and blood draws. There is limited data available concerning comprehensive analysis of fluid biomarkers in an EOAD population and this study represents first results from the mid‐study analysis of a large multi‐site cohort.MethodLEADS is an observational study with N = 371 subjects included in the mid‐study analysis (N = 165 with CSF and N = 324 with plasma biomarker data). CSF levels of Aβ1‐40, Aβ1‐42, tTau, pTau181, VILIP‐1, SNAP‐25, neurogranin (Ng), neurofilament light chain (NfL), and YKL‐40 were measured by immunoassay. Plasma levels of Aβ1‐40, Aβ1‐42, NfL, pTau231, and glial fibrillary acid protein (GFAP) were measured by immunoassay. Differences by diagnostic group and Spearman’s correlations with cognitive measures (MOCA, CDR‐SB, ADAS‐Cog) were evaluated for each fluid biomarker. Diagnostic accuracies were determined using area under the curve of receiver operating characteristics curve analysis which included APOE4 carrier status, age and sex in logistic regression models.ResultLevels of CSF Aβ42/40, pTau181, tTau, SNAP25, and Ng in the EOAD group were significantly different from both cognitively normal and early‐onset non‐AD dementia groups; CSF NfL, YKL‐40 and VILIP‐1 did not vary by diagnosis. The combination of APOE ε4 carrier status, age, sex and CSF Aβ42/40 and pTau181 (Figure 1A) or plasma Aβ42/40 and pTau231 (Figure 1B) separated the EOAD group from CN and EOnonAD with Area Under the ROC curves of 0.99 and 0.89 respectively. The diagnostic accuracies of plasma Aβ42/40 or pTau231 were 0.80 and 0.86 respectively. In the pooled analysis, all CSF biomarkers except SNAP25 were correlated with cognition (Figure 2A). Within the EOAD group only CSF Aβ42/40, NfL, Ng, and SNAP25 were correlated with at least one cognitive measure (Figure 2B).ConclusionThis study provides the first comprehensive analysis of fluid biomarkers in sporadic EOAD and will inform clinical trial designs that incorporate fluid biomarkers in patient selection, or as biomarker endpoints.