Performance of plasma p-tau217 for the detection of amyloid-[beta] positivity in a memory clinic cohort using an electrochemiluminescence immunoassay

Background Plasma p-tau217 has emerged as the most promising blood-based marker (BBM) for the detection of Alzheimer Disease (AD) pathology, yet few studies have evaluated plasma p-tau217 performance in memory clinic settings. We examined the performance of plasma p-tau217 for the detection of AD using a high-sensitivity immunoassay in individuals undergoing diagnostic lumbar puncture (LP). Methods Paired plasma and cerebrospinal fluid (CSF) samples were analysed from the TIMC-BRAiN cohort. Amyloid (A[beta]) and Tau (T) pathology were classified based on established cut-offs for CSF A[beta].sub.42 and CSF p-tau181 respectively. High-sensitivity electrochemiluminescence (ECL) immunoassays were performed on paired plasma/CSF samples for p-tau217, p-tau181, Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light (NfL) and total tau (t-tau). Biomarker performance was evaluated using Receiver-Operating Curve (ROC) and Area-Under-the-Curve (AUC) analysis. Results Of 108 participants (age: 69 [+ or -] 6.5 years; 54.6% female) with paired samples obtained at time of LP, 64.8% (n = 70/108) had A[beta] pathology detected (35 with Mild Cognitive Impairment and 35 with mild dementia). Plasma p-tau217 was over three-fold higher in A[beta] + (12.4 pg/mL; 7.3--19.2 pg/mL) vs. A[beta]- participants (3.7 pg/mL; 2.8--4.1 pg/mL; Mann-Whitney U = 230, p < 0.001). Plasma p-tau217 exhibited excellent performance for the detection of A[beta] pathology (AUC: 0.91; 95% Confidence Interval [95% CI]: 0.86-0.97)--greater than for T pathology (AUC: 0.83; 95% CI: 0.75-0.90; z = 1.75, p = 0.04). Plasma p-tau217 outperformed plasma p-tau181 for the detection of A[beta] pathology (z = 3.24, p < 0.001). Of the other BBMs, only plasma GFAP significantly differed by A[beta] status which significantly correlated with plasma p-tau217 in A[beta] + (but not in A[beta]-) individuals. Application of a two-point threshold at 95% and 97.5% sensitivities & specificities may have enabled avoidance of LP in 58-68% of cases. Conclusions Plasma p-tau217 measured using a high-sensitivity ECL immunoassay demonstrated excellent performance for detection of A[beta] pathology in a real-world memory clinic cohort. Moving forward, clinical use of plasma p-tau217 to detect AD pathology may substantially reduce need for confirmatory diagnostic testing for AD pathology with diagnostic LP in specialist memory services. Keywords: Alzheimer disease, Cerebrospinal fluid, Blood-based markers, Amyloid, P-tau217, Cer