Background Recent advancements in plasma pTau217 have shown its potential as a reliable biomarker for detecting brain amyloid pathology (Aβ) in Alzheimer’s disease (AD). However, its application in real-world settings remains limited, particularly in diverse populations such as those in Asia. While plasma pTau217 has demonstrated high accuracy in research cohorts, most studies have been conducted in Western populations. We evaluated the performance of plasma pTau217 and pTau181 with longitudinal cognition in a real-world tertiary memory clinic setting.

Methods Plasma ptau217 was measured using ALZpath SIMOA assay in 291 participants [68 healthy controls (HC), 100 mild cognitive impairment (MCI), 86 AD, 37 non-AD dementia] from National Neuroscience Institute, Singapore. Performances of pTau217, derived reference ranges (low-, intermediate-, high-) for amyloid positivity and associations with cognitive decline over 4 years was evaluated.

Results Plasma pTau217 [(area under the curve (AUC) = 0.942)] outperformed pTau181 (AUC= 0.909) in differentiating AD from other disease groups. Amongst patients with known amyloid status (n=40), pTau217 identified Aβ+ with AUC= 0.961 vs pTau181 with AUC= 0.917. Using a two cut-point approach, a 95% sensitivity and specificity for Aβ+ corresponded to pTau217 >0.66 pg/ml and <0.38 pg/ml, respectively. With these two cut-points, patients in the total cohort were stratified into low-, intermediate-, and high-risk groups for Aβ+. The high-risk group exhibited the steepest annual decline in both MoCA (-2.382) and MMSE (-1.580) scores; while the low-risk group demonstrated relatively stable cognitive performance over time. By applying a k-means clustering analysis, we identified three clusters of participants representing stable, slow, and fast progressors. Fast progressors exhibit the most pronounced cognitive decline and the highest pTau217 levels.

DISCUSSION Plasma pTau217 demonstrates high diagnostic accuracy and effectively predicts cognitive decline even in individuals without known Aβ+ status, potentially reducing reliance on amyloid PET confirmation. Our findings reinforce the clinical utility of plasma pTau217 as a prognostic biomarker for AD progression, offering a practical, non-invasive tool for assessing cognitive decline in real-world Southeast Asian memory clinics.

The authors have declared no competing interest.

This study was funded by Singapore National Medical Research Council (ASLN by the Clinician-Scientist Award (MOHCSAINV210005, NMRC Centre Grant Programme Category 2 (NMRC/CG2/005a/2022NNI), and SingHealth Fund NNI Fund under its Eco-system of Dementia Care programme [SHF(U)/22/GC 5C/007(EC)] and [SHF(U)/23/GC 2C/002(EC)], SES by the NMRC Clinician Scientist Individual Research Grant New Investigator Grant (CSIRG NIG; MOHCNIG22jul0006); LCST by the Open Fund Large Collaborative Grant (MOHOFLCG18May0002).

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