Associations of Fully Automated CSF and Novel Plasma Biomarkers With Alzheimer Disease Neuropathology at Autopsy

Objective To study CSF biomarkers of Alzheimer disease (AD) analyzed by fully automated Elecsys immunoassays compared to neuropathologic gold standards and to compare their accuracy to plasma phosphorylated tau (p-tau181) measured with a novel single molecule array method. Methods We studied antemortem Elecsys-derived CSF biomarkers in 45 individuals who underwent standardized postmortem assessments of AD and non-AD neuropathologic changes at autopsy. In a subset of 26 participants, we also analyzed antemortem levels of plasma p-tau181 and neurofilament light (NfL). Reference biomarker values were obtained from 146 amyloid-PET-negative healthy controls (HC). Results All CSF biomarkers clearly distinguished pathology-confirmed AD dementia (n = 27) from HC (area under the curve [AUC] 0.86-1.00). CSF total tau (t-tau), p-tau181, and their ratios with beta-amyloid(1-42) (A beta(1-42)) also accurately distinguished pathology-confirmed AD from non-AD dementia (n = 8; AUC 0.94-0.97). In pathology-specific analyses, intermediate to high Thal amyloid phases were best detected by CSF A beta(1-42) (AUC [95% confidence interval] 0.91 [0.81-1]), while intermediate to high scores for Consortium to Establish a Registry for Alzheimer's Disease neuritic plaques and Braak tau stages were best detected by CSF p-tau181 (AUC 0.89 [0.79-0.99] and 0.88 [0.77-0.99], respectively). Optimal Elecsys biomarker cutoffs were derived at 1,097, 229, and 19 pg/mL for A beta(1-42), t-tau, and p-tau181. In the plasma subsample, both plasma p-tau181 (AUC 0.91 [0.86-0.96]) and NfL (AUC 0.93 [0.87-0.99]) accurately distinguished those with pathology-confirmed AD (n = 14) from HC. However, only p-tau181 distinguished AD from non-AD dementia cases (n = 4; AUC 0.96 [0.88-1.00]) and showed a similar, although weaker, pathologic specificity for neuritic plaques (AUC 0.75 [0.52-0.98]) and Braak stage (AUC 0.71 [0.44-0.98]) as CSF p-tau181. Conclusion Elecsys-derived CSF biomarkers detect AD neuropathologic changes with very high discriminative accuracy in vivo. Preliminary findings support the use of plasma p-tau181 as an easily accessible and scalable biomarker of AD pathology. Classification of Evidence This study provides Class II evidence that fully automated CSF t-tau and p-tau181 measurements discriminate between autopsy-confirmed AD and other dementias.