Associations of fully-automated CSF and novel plasma biomarkers with Alzheimer's disease neuropathology at autopsy

<p>The objective of this study was to study cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) analyzed by fully automated Elecsys immunoassays in comparison to neuropathologic gold standards, and compare their accuracy to plasma phosphorylated tau (p-tau181) measured using a novel Simoa method. We studied <i>ante-mortem</i> Elecsys-derived CSF biomarkers in 45 individuals who underwent standardized <i>post-mortem</i> assessments of AD and non-AD neuropathologic changes at autopsy. In a subset of 26 participants, we also analysed <i>ante-mortem</i> levels of plasma p-tau181 and neurofilament light (NfL). Reference biomarker values were obtained from 146 amyloid-PET-negative healthy controls (HC). All CSF biomarkers clearly distinguished pathology-confirmed AD dementia (N=27) from HC (AUCs=0.86-1.00). CSF total-tau (t-tau), p-tau181, and their ratios with Aβ_1-42, also accurately distinguished pathology-confirmed AD from non-AD dementia (N=8; AUCs=0.94-0.97). In pathology-specific analyses, intermediate-to-high Thal amyloid phases were best detected by CSF Aβ_1-42 (AUC[95% CI]=0.91[0.81-1]), while intermediate-to-high CERAD 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 cut-offs were derived at 1097/229/19 pg/ml for Aβ_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 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, though 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. Elecsys-derived CSF biomarkers detect AD neuropathologic changes with very high discriminative accuracy<i> in-vivo</i>. Preliminary findings support the use of plasma p-tau181 as an easily accessible and scalable biomarker of AD pathology. This study provides Class II evidence that fully-automated CSF t-tau and p-tau181measurements discriminate between autopsy-confirmed Alzheimer's disease and other dementias.</p>