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BackgroundThe last few years have seen major advances in blood biomarkers for Alzheimer’s Disease (AD) with the development of ultrasensitive immunoassays, promising to transform how we diagnose, prognose, and track progression of neurodegenerative dementias.MethodsWe evaluated a panel of four novel ultrasensitive electrochemiluminescence (ECL) immunoassays against presumed CNS derived proteins of interest in AD in plasma [phosphorylated-Tau181 (pTau181), total Tau (tTau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)]. 366 plasma samples from the Massachusetts Alzheimer’s Disease Research Center’s longitudinal cohort study were examined to differentiate definite AD, other neurodegenerative diseases (OND), and cognitively normal (CN) individuals. A subset of samples were selected to have longitudinal follow up to also determine the utility of this plasma biomarker panel in predicting 4-year risk for cognitive decline in individuals with different levels of cognitive impairment.ResultspTau181, tTau and GFAP were higher in AD compared to CN and OND, while NfL was elevated in AD and further increased in OND. pTau181 performed the best (AD vs CN: AUC=0.88, 2-fold increase; AD vs OND: AUC=0.78, 1.5-fold increase) but tTau also showed excellent discrimination (AD vs CN: AUC=0.79, 1.5-fold increase; AD vs OND: AUC=0.72, 1.3-fold increase). Participants with MCI who progressed to AD dementia had higher baseline plasma concentrations of pTau181, NfL, and GFAP compared to non-progressors with the best discrimination for pTau181 (AUC=0.82, 1.7-fold increase) and GFAP (AUC=0.81, 1.6-fold increase).ConclusionsThese new ultrasensitive ECL plasma assays for pTau181, tTau, NfL, and GFAP detect CNS disease with high specificity and accuracy. Moreover, the absolute baseline plasma levels of pTau and GFAP reflect clinical disease aggressiveness over the next 4 years, providing diagnostic and prognostic information that may have utility in both clinical and clinical trial populations.Classification of EvidenceThis study provides Class II evidence that plasma levels of pTau181, tTau, NfL, and GFAP are associated with AD and that pTau181 and GFAP are associated with progression from MCI to AD dementia.