From Cerebrospinal Fluid to Blood Draw: Plasma p-Tau217 as a Non-Invasive Biomarker for Alzheimer's Disease: A Fagan Nomogram-Based Meta-Analytic Study.

Alzheimer's disease (AD) is the leading cause of dementia worldwide and is pathologically defined by amyloid-β and tau accumulation. Current diagnostic methods, such as PET imaging and cerebrospinal fluid (CSF) assays, are accurate but invasive, costly, and limited in accessibility. Plasma phosphorylated tau at threonine 217 (p-tau217) has emerged as a promising blood-based biomarker, but evidence from individual studies remains heterogeneous. We conducted a systematic review and meta-analysis to evaluate the diagnostic performance of plasma p-tau217 for AD. Following PRISMA guidelines, PubMed, Scopus, and Web of Science were searched up to July 2025. Eligible studies included clinical or biomarker-defined AD cohorts that reported plasma p-tau217 accuracy against amyloid or tau positivity or clinical diagnosis. Data on sensitivity, specificity, likelihood ratios, and diagnostic odds ratio (DOR) were extracted. Study quality was assessed using QUADAS-2. Pooled estimates were calculated using a Bayesian bivariate model, and heterogeneity was explored with meta-regression and subgroup analyses. Twenty-seven studies including 19,652 participants were analyzed. Plasma p-tau217 demonstrated high diagnostic accuracy for biomarker-defined AD, with pooled sensitivity of 85.4% (95% posterior intervals [PI]: 81.4-88.7), specificity of 88.0% (95% PI: 85.1-90.6), positive likelihood ratio (PLR) 7.13, negative likelihood ratio (NLR) 0.167, and DOR 42.7. Performance was consistent across amyloid PET and CSF reference standards. Subgroup analyses showed robust accuracy for amyloid positivity (sensitivity 87.3%, specificity 85.5%), tau positivity (sensitivity 84.9%, specificity 93.8%), and clinical AD diagnosis (sensitivity 72.9%, specificity 89.5%). Plasma p-tau217 consistently outperformed other blood biomarkers and correlated with cognitive decline, frailty, and behavioral impairment. Risk of bias was generally low, with no major publication bias detected. This meta-analysis indicates that plasma p-tau217 demonstrates promising diagnostic accuracy for detecting AD pathology across biomarker-defined reference standards. However, heterogeneity across assays, populations, and reference definitions, along with the use of optimized cut-offs in some studies and the limited power of publication-bias assessments, warrant cautious interpretation. Plasma p-tau217 appears well suited as a triage biomarker to guide confirmatory testing, but further large, prospectively designed studies with standardized assays and externally validated thresholds are needed before widespread clinical implementation.