Plasma p-tau as a biomarker for the differential diagnosis of Alzheimer’s disease: a systematic review and meta-analysis

BACKGROUND: With the clinical implementation of amyloid-targeting therapies, accurately differentiating Alzheimer's disease (AD) from other neurodegenerative dementias is imperative. This systematic review and meta-analysis synthesized data on the diagnostic performance of three plasma phosphorylated tau (p-tau) isoforms identified through a comprehensive literature search, namely p-tau181, p-tau217, and p-tau231. METHODS: We searched major databases up to November 30, 2025, for studies comparing blood p-tau levels in AD versus biologically confirmed non-AD neurodegenerative disorders. Data were synthesized using bivariate random-effects models to calculate pooled sensitivity, specificity, area under the curve (AUC), and diagnostic odds ratio (DOR). RESULTS: Thirty-three studies comprising 6,138 participants were included. Blood p-tau biomarkers demonstrated robust overall accuracy (AUC 0.90) and a high positive likelihood ratio (PLR 3.77). Comparison of isoforms revealed that plasma p-tau217 exhibited superior performance (AUC 0.95; Sensitivity 0.93) with a remarkable DOR of 57.98, which was nearly six-fold higher than that of p-tau231 (DOR 9.83). Subgroup analyses showed exceptional specificity for differentiating AD from behavioral variant frontotemporal dementia (bvFTD) (0.91) and vascular dementia (0.83), but discriminative ability against dementia with Lewy bodies (DLB) was significantly lower (Specificity 0.69; DOR 7.54). Furthermore, plasma-based assays (AUC 0.92, 95% CI 0.88-0.96) significantly outperformed serum-based methods (AUC 0.76, 95% CI 0.74-0.78), as evidenced by non-overlapping confidence intervals. CONCLUSIONS: Plasma p-tau217 is the superior biomarker for the differential diagnosis of AD, particularly for ruling out FTD, though distinguishing AD from DLB remains challenging due to mixed pathology. The distinct superiority of plasma over serum supports the exclusive use of plasma-based protocols for clinical implementation.