Plasma Phosphorylated Tau 217 to Identify Preclinical Alzheimer Disease.
Level 3 - non-randomized controlled study
Cross-sectional multi-cohort diagnostic validation study comparing a blood biomarker against CSF and PET reference standards.
PubMed 40952756 · doi:10.1001/jamaneurol.2025.3217
What was done
A cross-sectional study pooled data from 2,916 cognitively unimpaired participants across 12 independent cohorts in the US, Europe, Australia, and Canada (collected June 2009 to March 2024). Investigators evaluated the diagnostic performance of immunoassay-measured plasma phosphorylated tau 217 (p-tau217) against cerebrospinal fluid (CSF) or amyloid positron emission tomography (PET) reference standards for amyloid-β (Aβ) status. Performance was evaluated both as a stand-alone test and in a 2-step workflow where positive blood tests were confirmed with PET or CSF. A subgroup analysis (n = 964) compared immunoassay-based measurements to mass spectrometry.
What was found
Participants had a mean age of 66.9 years, 57.2% were female, and 33.3% (n = 971) were Aβ-positive. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74–84) and an overall accuracy of 81% (95% CI, 80–82). In the 2-step workflow, PPV and accuracy both increased to 91% (95% CI, 86–95). This 2-step strategy required initial screening of 677 individuals to identify 100 Aβ-positive individuals (compared to 536 for PET alone) while reducing required confirmatory PET scans to 124. Compared to mass spectrometry, immunoassays showed similar PPV (80% vs 85%; P = .12) but significantly lower overall accuracy (82% vs 88%; P < .001) and lower true Aβ-positive detection rates (49% vs 69%; P < .001).
Why it matters
Plasma p-tau217 offers a scalable, minimally invasive screening tool to identify cognitively unimpaired individuals with early amyloid pathology. Incorporating it as the first step in a sequential workflow can reduce the need for confirmatory PET scans by more than 75% in preclinical Alzheimer disease clinical trials and diagnostic workflows.
Limits
The cross-sectional design cannot determine longitudinal risk of progression to cognitive impairment. Immunoassay testing demonstrated a low true Aβ-positive detection rate (49%), meaning over half of Aβ-positive individuals were missed in that subgroup. The reference standard combined two different modalities (CSF and PET) rather than a single uniform standard across all cohorts.
Cited by
- supports Blood levels of phosphorylated tau-217 (p-tau217) serve as a biomarker that can detect Alzheimer's disease pathology decades before symptom onset.