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 (pTau181, pTau217) and amyloid-beta ratios (Aβ42/40), 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 (pTau181, Aβ42/40), and plasma biomarker measurements (pTau181, pTau217, Aβ42/40, pTau217/Aβ42 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 pTau217 and the pTau217/Aβ42 ratio demonstrated the highest accuracy (both AUC=0.95), outperforming plasma pTau181 (AUC=0.88) and Aβ42/40 ratio (AUC=0.73). At optimal thresholds, plasma pTau217 showed 87.5 % sensitivity and 93.4 % specificity, whereas the pTau217/Aβ42 ratio showed higher sensitivity (95.8 %) but lower specificity (85.2 %). Using the three-zone model, plasma pTau217 enabled definitive classification in 80.7 % of patients, increasing to 84.4 % with the pTau217/Aβ42 ratio. Among patients with mild cognitive impairment, plasma pTau217 achieved excellent accuracy (AUC=0.98). Plasma pTau217, alone or combined with Aβ42, provides highly accurate and scalable identification of AD pathology, substantially reducing the need for invasive diagnostic procedures.