Plasma pTau217/Aβ 42 and pTau217 outperform pTau181/Aβ 42 and pTau181 in predicting cerebrospinal fluid amyloid positivity: A real-world retrospective study

Abstract

Background

Alzheimer's disease (AD) diagnosis often relies on invasive cerebrospinal fluid (CSF) sampling or expensive cerebral positron emission tomography (PET) imaging. Noninvasive tests could facilitate early detection. Plasma phosphorylated-tau (pTau) isoforms are promising AD biomarkers that correlate with brain amyloid-β (Aβ) deposition.

Objective

To explore the diagnostic accuracy of pTau-based plasma biomarkers to forecast CSF amyloid-positive status in a real-world consecutive population of subjects with cognitive impairment and complete plasma and CSF biomarker profiles.

Methods

We retrospectively studied 138 consecutive patients with cognitive impairment. Plasma biomarkers (pTau217, pTau181, Aβ₄₂, Aβ₄₀) were measured by automated immunoassay. Diagnostic accuracy for CSF amyloid status was assessed using area-under-the curve (AUC) values from receiver-operating characteristic (ROC) curve analysis. A dual-threshold strategy was used to define low- and high-risk groups and estimate how many lumbar punctures could be avoided.

Results

Among 138 patients (37% CSF amyloid-positive), pTau217/Aβ₄₂ ratio had the highest AUC (0.920) for predicting amyloid positivity, followed by pTau217 (AUC 0.904). These values exceeded the accuracy of pTau181-based markers. Using dual cut-offs, a 90% sensitivity-90% specificity strategy could avoid about 93.5% of lumbar punctures using pTau217/Aβ₄₂ (10.9% misclassified), and 84.1% when using pTau217 (11.2% misclassified). Stricter thresholds (95%–95% and 97.5%–97.5%) further reduced misclassification rates but at the expense of fewer avoidable invasive procedures.

Conclusions

Plasma pTau217 (alone or combined with Aβ₄₂) shows high accuracy for detecting AD pathology and could serve as a scalable, noninvasive diagnostic tool. This approach may triage patients for confirmatory testing and substantially reduce the need for invasive CSF examination.