Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

Abstract

ImportancePhosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests.ObjectiveTo determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid β (Aβ) and longitudinal change across 3 selected cohorts.Design, Setting, and ParticipantsThis cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017–August 2021) and Wisconsin Registry for Alzheimer’s Prevention (WRAP) cohort (visits February 2007–November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009–November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023.ExposuresMagnetic resonance imaging, Aβ positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (Aβ42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay).Main Outcomes and MeasuresAccuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status.ResultsThe study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated Aβ (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal Aβ pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in Aβ-positive individuals, with the highest increase observed in those with tau positivity.Conclusions and RelevanceThis study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.

Plasma p-tau217 in Alzheimer’s disease: Lumipulse and ALZpath SIMOA head-to-head comparison

“…These results are consistent with the greater fold change of p-tau217 compared to other p-tau species, namely p-tau231 and p-tau181 recently demonstrated. 4,5,[10][11][12][13][14][15][16] Of note, the cutoffs resulting in the highest Youden index in the ROC analyses for discriminating AD versus NDD and controls resulted in very similar cutoff values across assays, suggesting the possible adoption of a single value for AD diagnosis, ideally to be established by multi-centre validation studies. The head-to-head comparison with ALZpath p-tau217 showed a slightly higher fold-change for Lumipulse with a comparable discrimination accuracy compared to SIMOA, even in the subcohort of MCI subjects at earlier stages of the disease.…”

“…These results are consistent with the greater fold change of p-tau217 compared to other p-tau species, namely p-tau231 and p-tau181 recently demonstrated. 4,5,10–16…”

“…The commercial ALZpath p-tau217 assay uses a proprietary monoclonal p-tau217 specific capture antibody, an N-terminal detector antibody, and a peptide calibrator. 5 It has been validated as a fit-for-purpose assay 24 with a limit of detection of 0.0052 to 0.0074 pg/mL, a functional lower limit of quantification of 0.06 pg/mL, and a dynamic range of 0.007 to 30 pg/mL. The spike recovery for the endogenous analyte was 80%, and intrarun and interrun precision was 0.5% to 13% and 9.2% to 15.7%, respectively.…”

“…3,4 Phosphorylated tau species (p-tau) stand at the forefront of emerging AD blood tests, exhibiting superior accuracy in diagnosis and specificity for the disease compared to the Aβ42/40 ratio or other suggested biomarkers. 5–9…”

Peripheral inflammatory markers relate to central inflammation and survival in syndromes associated with frontotemporal lobar degeneration

“…Calibrators (neat) and samples (plasma: 1:4 dilution) were measured in duplicates. The plasma assays measured were the Quanterix Simoa Human Neurology 4-Plex E assay (measuring Aβ40, Aβ42, GFAP and NfL, Quanterix, Billerica, MA) and the pTau217 ALZPath assay measuring p-tau217 of the human tau protein associated with Alzheimer's disease, as previously described 55 . Plasma samples were analysed at the same time using the same batch of reagents.…”