Diagnostic performance of plasma p-Tau217, p-Tau181, and p-Tau231 across the Alzheimer’s disease continuum: a network meta-analysis

Importance Blood-based biomarkers (BBMs) are transforming the diagnostic workflow for Alzheimer’s disease (AD). However, there is no consensus on the optimal phosphorylated tau (p-tau) isoform (217, 181, or 231) or analytical platform [mass spectrometry (MS) vs. immunoassay (IA)] for clinical implementation across different disease stages. Objective To systematically compare the diagnostic accuracy and prognostic value of plasma p-tau isoforms using different technical platforms for detecting amyloid- β (Aβ) pathology, tau pathology, and predicting cognitive decline. Study selection Studies reporting diagnostic accuracy [Area Under the Curve (AUC)] of plasma p-tau against cerebrospinal fluid (CSF) or Positron Emission Tomography (PET) standards were included. To ensure statistical independence, overlapping cohorts (e.g., BioFINDER, ADNI) were rigorously screened, selecting only the most comprehensive dataset per cohort. Results A total of 18 high-quality studies comprising 24 independent datasets and 4,736 participants were included. For detecting Aβ pathology, p-tau217 measured by MS (p217_MS) demonstrated the highest diagnostic accuracy (P-score = 0.86), followed by p-tau217 ratio (p217_Ratio) (P-score = 0.78) and automated immunoassays (P-score = 0.67–0.69), all of which significantly outperformed standard p-tau181 immunoassays (P-score = 0.12). Notably, the p-tau217/Aβ 42 ratio on automated platforms provided a significant incremental AUC gain of 0.025 (95% CI: 0.005 to 0.045; I 2 = 0%) compared to single-analyte assays, effectively bridging the performance gap with MS. In disease staging, while p-tau231 showed potential in detecting early amyloidosis, p-tau217_MS was superior for identifying advanced Tau-PET pathology (P-score = 0.91) and predicting MCI-to-dementia conversion (P-score = 0.82). Subgroup analyses confirmed consistent performance of p-tau217 across Han Chinese and Western cohorts, and demonstrated the diagnostic potential of serum-based assays as a viable matrix. Conclusions and relevance Plasma p-tau217, particularly when measured by mass spectrometry or as a ratio on fully automated platforms, offers the highest accuracy for AD diagnosis and staging. While p-tau231 may serve as an early indicator of amyloidosis, p-tau217 is the most robust marker for tau pathology and disease progression. These findings support the integration of automated p-tau217 assays into routine clinical care to streamline patient stratification for disease-modifying therapies. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifier (CRD420261327845).