Diagnostic Value of Serum p-tau217 in Alzheimer Disease: Equal to Plasma in Levels and Clinical Utility?

Abstract Background Phosphorylated tau 217 (p-tau217) has emerged as a leading blood-based biomarker for Alzheimer disease (AD). While typically measured in plasma, serum is a widely used matrix in clinical laboratories, yet few p-tau217 assays have been validated for serum. Evaluating serum p-tau217 performance is essential for expanding its use in clinical and research settings, particularly for cohorts with only serum samples available. Methods We quantified p-tau217 in plasma and serum from individuals within the AD continuum (n = 100; mean age 72.5 ± 5.0 years; 54% female) using 6 assays across 4 platforms. Spearman correlation, Passing–Bablok regression, and receiver operating characteristics analysis were used to assess intermatrix agreement and diagnostic performance. Specific validation parameters (e.g., precision, parallelism, dilution linearity, stability) were evaluated in both matrices. Results High correlations between plasma and serum were observed for most assays (ρ > 0.8), though plasma often yielded higher concentrations. Notably, the Lumipulse assay showed near-perfect correlation (ρ = 0.98) and minimal bias. Fold changes in p-tau217 levels across the AD continuum were comparable between matrices, though cutoffs for detecting AD pathology differed. Applying plasma-derived cutoffs to serum resulted in misclassification rates ranging from 16% to 47%, except for Lumipulse (10% in serum vs 5% in plasma). Not all assays performed equally in serum, as reflected in validation metrics. Conclusions Serum p-tau217, across multiple platforms, shows strong correlations with plasma p-tau217 and reflected comparable patterns across the AD continuum. However, absolute concentrations differed for most assays, thus requiring differing disease specific cutoffs. Most of the evaluated platforms demonstrated reliable quantification of p-tau217 in serum, yielding satisfactory validation performance. These findings support serum as a viable alternative to plasma for p-tau217 quantification in both research and clinical settings, provided matrix-specific validation is ensured.