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 β-amyloid (Aβ) 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 Aβ (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 Aβ, 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.