Diagnostic performance of plasma pTau217/Aβ42 ratio and a three-zone threshold model for Alzheimer’s disease

Early and accurate diagnosis of Alzheimer’s disease (AD) typically relies on invasive or expensive methods like cerebrospinal fluid (CSF) biomarkers and amyloid PET imaging. Blood-based biomarkers, particularly plasma phosphorylated tau (pTau 181 , pTau 217 ) and amyloid-beta ratios (Aβ 42 / 40 ), offer a more accessible diagnostic alternative. This study assessed the diagnostic accuracy of plasma biomarkers and developed a three-zone classification model to reduce reliance on invasive confirmatory tests. We retrospectively evaluated 109 participants referred to a tertiary memory clinic. Participants underwent cognitive assessments, brain MRI, CSF biomarker analyses (pTau 181 , Aβ 42 / 40 ), and plasma biomarker measurements (pTau 181 , pTau 217 , Aβ 42 / 40 , pTau 217 /Aβ 42 ratio). Diagnostic performance was evaluated using ROC analyses, and thresholds achieving ≥95% sensitivity and specificity were used to define low, intermediate and high-risk zones. Plasma biomarkers correlated significantly with CSF biomarkers. For identifying AD pathology (A+/T+ vs. others), plasma pTau 217 and the pTau 217 /Aβ 42 ratio demonstrated the highest accuracy (both AUC=0.95), outperforming plasma pTau 181 (AUC=0.88) and Aβ 42 / 40 ratio (AUC=0.73). At optimal thresholds, plasma pTau 217 showed 87.5% sensitivity and 93.4% specificity, whereas the pTau 217 /Aβ 42 ratio showed higher sensitivity (95.8%) but lower specificity (85.2%). Using the three-zone model, plasma pTau 217 enabled definitive classification in 80.7% of patients, increasing to 84.4% with the pTau 217 /Aβ 42 ratio. Among patients with mild cognitive impairment, plasma pTau 217 achieved excellent accuracy (AUC=0.98). Plasma pTau 217 , alone or combined with Aβ 42 , provides highly accurate and scalable identification of AD pathology, substantially reducing the need for invasive diagnostic procedures. • Plasma pTau 217 accurately detects CSF-defined Alzheimer’s pathology. • pTau 217 /Aβ 42 ratio reduces intermediate grey-zone classifications. • Three-zone model classifies over 80% of patients without CSF or amyloid PET. • Plasma biomarkers show strong correlations with CSF Aβ 42 / 40 and pTau 181 . • Plasma pTau 217 performs excellently in mild cognitive impairment (CDR 0.5).