Our objective is to thoroughly evaluate the diagnostic performance of pTau isoforms—pTau-181, pTau-217, and pTau-231—in cerebrospinal fluid (CSF) and plasma in differentiating Alzheimer's disease (AD) from non-Alzheimer's disease (non-AD) dementias and healthy controls (HC).

Alzheimer’s disease continues to be the most prevalent form of dementia globally, yet making an accurate early diagnosis remains difficult. Recent discoveries emphasize phosphorylated tau (pTau) isoforms—pTau-181, pTau-217, and pTau-231—in CSF and plasma as valuable biomarkers capable of differentiating AD from non-AD dementias and HC.

Adhering to PRISMA recommendations and PROSPERO registration (CRD42025632278), we systematically searched PubMed, Scopus, Web of Science, and Ovid databases through September 2025. Eligible investigations measured pTau-181, pTau-217, or pTau-231 in CSF or plasma using recognized AD reference standards. Pooled sensitivity, specificity, diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristic curve (AUC) were computed through random-effects models. Clinical relevance was examined by Fagan’s nomogram for post-test probabilities, while publication bias was assessed with Deeks’ funnel plot asymmetry test. 

Overall, forty-eight studies involving various global populations were included. Comparing AD versus HC, CSF pTau-217 achieved the greatest diagnostic accuracy, with pooled sensitivity of 0.95 and specificity of 0.91, surpassing all other isoforms. CSF pTau-181 and pTau-231 also demonstrated strong accuracy (AUC = 0.90). Plasma-based biomarkers showed considerable potential: plasma pTau-181 yielded sensitivity of 0.88, specificity of 0.81, and AUC of 0.91, while plasma pTau-231 exhibited sensitivity of 0.84, specificity of 0.87, and AUC of 0.86, showing minimal heterogeneity among studies. Comparative assessments revealed significantly elevated pTau levels in AD compared with both non-AD and HC. Certainty of evidence was graded moderate-to-high, ensuring strong credibility of the findings.

This meta-analysis highlights pTau isoforms—particularly CSF pTau-217—as highly reliable biomarkers for Alzheimer’s disease diagnosis. Plasma pTau-181 and pTau-231 appear to be robust, minimally invasive, and scalable options demonstrating strong diagnostic validity.