Streamlining Alzheimer's disease diagnosis: real-world validation of two-cut-off diagnostic models based on plasma p-tau/Aβ42 ratios.

INTRODUCTION

Anti-amyloid monoclonal antibodies have increased the need for scalable, minimally invasive biomarkers for Alzheimer's disease (AD). In this single-center cohort study, we evaluated plasma biomarkers performance in detecting biologically defined AD, assessing diagnostic accuracy and generalizability outside dedicated laboratory settings and exploring suitability for clinical implementation.

METHODS

We enrolled 204 outpatients referred to the memory clinic of Policlinico "Rome Tor Vergata" who underwent standard work-up, lumbar puncture for cerebrospinal fluid (CSF) biomarkers and paired blood sampling. Among plasma biomarkers, phosphorylated tau (p-tau) 181, p-tau217, and their ratios adjusted for Aβ42 were measured on the Lumipulse platform. AD pathology was defined by CSF p-tau181/Aβ42 ≥ 0.069. ROC analyses estimated AUCs, and a two-cut-off approach targeting 90% sensitivity and specificity classified individuals as low, intermediate, or high AD risk. Subgroup analyses examined the impact of sex, age (< 75, ≥ 75 years), chronic kidney disease, and cognitive impairment (MMSE ≥ 26/30, < 26/30) on plasma biomarker levels.

RESULTS

Among single analytes, plasma p-tau217 showed the highest discriminative capacity (AUC 0.883). Combined ratios improved overall performance (p-tau181/Aβ42, AUC 0.928; p-tau217/Aβ42, AUC 0.894) and reduced intermediate-risk classifications to < 15%, with slightly better performance in women, patients < 75 and cognitively unimpaired. The two-cut-off model improved accuracy and rule-in ability.

DISCUSSION: Plasma p-tau/Aβ42 ratios show high and robust accuracy for detecting CSF-defined AD pathology. A two-step approach based on p-tau181/Aβ42 or p-tau217/Aβ42 could streamline diagnostic workflows in memory clinics, reserving second-line assessments to indeterminate cases and supporting selection of candidates for disease-modifying anti-amyloid therapies.