Plasma P-tau217 Demonstrates Excellent Diagnostic and Prognostic Performance as a Blood-Based Biomarker for Alzheimer Disease in Older Adults

Abstract Background There has been unprecedented progress in the development of blood-based biomarkers (BBMs such as p-tau217 to detect Alzheimer Disease (AD) pathology – characterised by the accumulation of Amyloid-Beta (Aβ) and hyper-phosphorylated tau (T). However, BBM performance in “real-world” memory clinic contexts remains unclear. Methods Using high-sensitivity immunoassays, plasma p-tau217 was assessed in 554 participants. Two cohorts were studied: (i) a memory clinic validation cohort of 108 older adults (69 ± 6.5 years; 54.6% female) with early cognitive symptoms and paired plasma/cerebrospinal fluid (CSF) at time of diagnostic Lumbar Puncture (LP) and (ii) a broader replication cohort of 446 individuals ranging from cognitively-unimpaired middle-aged adults to older adults with established AD with 18-month follow-up. Plasma P-tau217 performance was examined against clinically established CSF Aβ+/T+ cut-offs using Area-Under the Curve (AUC) analysis. Plasma cut-offs were optimised vs CSF based on maximal Youden index. Results In the memory clinic cohort, plasma p-tau217 exhibited excellent performance for the detection of Aβ pathology (AUC: 0.91, 0.86-0.97). Plasma p-tau217 was nearly 4-fold higher in Aβ+ (13.89; 7.36-19.0pg/mL) vs Aβ- (3.72; 2.80-4.09pg/mL, U = 230, p0.001) participants. Plasma p-tau217 was superior in the identification of Aβ vs T pathology (p0.05, DeLong Test) and outperformed p-tau181 and other BBMs(all p0.05, DeLong Test). In the replication cohort, plasma p-tau217 maintained 90% accuracy for clinical AD and was significantly associated with clinically meaningful cognitive decline over 18 months (Odds Ratio 1.40; 1.06-1.85, p=0.02). In the initial memory clinic cohort, application of plasma p-tau217 as a diagnostic test would have reduced the need for LPs by over half (56.5%). Conclusion Plasma p-217 demonstrates excellent diagnostic and prognostic performance in older adults with AD, representing an amyloid-responsive measure which also predicts meaningful cognitive decline in established AD. Incorporation of plasma p-tau217 in memory clinic settings may substantially reduce the need for over half of diagnostic LPs.