Plasma p-tau217, quantified by the fully automated LUMIPULSE G platform, outperforms p-tau181 in predicting amyloid pathology in cognitive complaints patients

Plasma phosphorylated tau (p-tau) biomarkers offer a minimally invasive alternative for detecting Alzheimer’s disease (AD) pathology. We evaluated the diagnostic performance of plasma p-tau217 relative to p-tau181 using the fully automated LUMIPULSE platform. A total of 494 consecutively recruited patients with cognitive complaints from the Coimbra cohort were divided into exploratory and internal validation sets, and an external set of 100 well-characterized patients with mild cognitive impairment was obtained from Lisbon. Plasma biomarkers were assessed in relation to cerebrospinal fluid (CSF) AD biomarkers and evaluated their ability to detect amyloid pathology, defined by the CSF Aβ42/40 ratio. In the exploratory dataset, plasma p-tau217 showed stronger correlations with CSF biomarkers and higher accuracy in identifying amyloid positivity than p-tau181 (AUC = 0.90 vs. 0.81, p < 0.001). Age and blood urea nitrogen had minimal influence on p-tau217’s performance. Applying the Youden-derived single p-tau217 cutoff achieved an overall agreement of 88% with CSF-defined amyloid status across both validation sets. In addition, we evaluated a two-cutoff framework (95% sensitivity/specificity), which reduced misclassification and confined fewer than 30% of individuals to an intermediate, confirmatory-testing zone. These findings support the potential of plasma p-tau217 as a scalable blood-based biomarker that can aid triage and diagnostic decision-making in AD.