Abstract
ObjectiveTo 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.MethodsWe 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).ResultsAll 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-amyloid1-42 (Aβ1-42) 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 Aβ1-42 (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 Aβ1-42, 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.ConclusionElecsys-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 EvidenceThis study provides Class II evidence that fully automated CSF t-tau and p-tau181 measurements discriminate between autopsy-confirmed AD and other dementias.
Highlights
We studied antemortem Elecsys-derived CSF biomarkers in 45 individuals who underwent standardized postmortem assessments of Alzheimer disease (AD) and non-AD neuropathologic changes at autopsy
In pathology-specific analyses, intermediate to high Thal amyloid phases were best detected by CSF Aβ1-42 (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-tau[181] (AUC 0.89 [0.79–0.99] and 0.88 [0.77–0.99], respectively)
Discriminative Accuracy of Fluid Biomarkers for Distinguishing Those With PathologyConfirmed AD Dementia From Healthy Controls and Those With Non-AD Dementia In the full sample, all Elecsys CSF biomarkers were significantly different between patients with pathologyconfirmed AD dementia (n = 27) and Aβ-PET–negative healthy controls (n = 146; all p < 0.001; Figure 1) and differentiated between these groups with very high Areas under the curve (AUC) values ranging from 0.86 (t-tau) to 1.00 (p-tau181/Aβ1-42 ratio) (Figure 2)
Summary
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 analyzed antemortem levels of plasma p-tau[181] and neurofilament light (NfL). Reference biomarker values were obtained from 146 amyloidPET–negative healthy controls (HC). Data Source Data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The ADNI is a public-private partnership that was launched in 2003 with the primary goal of testing whether e1230 Neurology | Volume 97, Number 12 | September 21, 2021 Neurology.org/N CSF sample No. Age at DOD, y 82.5 ± 7.6 M/F, n CN/aMCI/ADD, n 4/6/35 A (0/1/2/3), n 3/4/5/33
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