Diagnostic accuracy of the plasma ALZpath pTau217 immunoassay to identify Alzheimers disease pathology

ImportancePhosphorylated tau (pTau) is a specific blood biomarker for Alzheimers disease (AD) pathology, with pTau217 considered to have the most utility. However, availability of pTau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests. ObjectiveTo determine the utility of a novel and commercially available Single molecule array (Simoa) for plasma pTau217 (ALZpath) to detect AD pathology. To evaluate references ranges for abnormal A{beta} across three selected cohorts. Design, Setting, ParticipantsThree single-centre observational cohorts were involved in the study: Translational Biomarkers in Aging and Dementia (TRIAD), Wisconsin Registry for Alzheimers Prevention (WRAP), and Sant Pau Initiative on Neurodegeneration (SPIN). MRI, A{beta}-PET, and tau-PET data were available for TRIAD and WRAP, while CSF biomarkers were additionally measured in a subset of TRIAD and SPIN. Plasma measurements of pTau181, pTau217 (ALZpath), pTau231, A{beta}42/40, GFAP, and NfL, were available for all cohorts. Longitudinal blood biomarker data spanning 3 years for TRIAD and 8 years for WRAP were included. ExposuresMRI, A{beta}-PET, tau-PET, CSF biomarkers (A{beta}42/40 and pTau immunoassays) and plasma pTau217 (ALZpath Simoa). Main Outcomes and MeasuresThe accuracy of plasma pTau217 for detecting abnormal amyloid and tau pathology. Longitudinal pTau217 change according to baseline pathology status. ResultsThe study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%]) were included in the study. High accuracy was observed in identifying elevated A{beta} (AUC, 0.92-0.96; 95%CI 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95%CI 0.84-0.99) across all cohorts. These accuracies were significantly higher than other plasma biomarker combinations and comparable to CSF biomarkers. The detection of abnormal A{beta} pathology using binary or three-range references yielded reproducible results. Longitudinally, plasma pTau217 showed an annual increase only in A{beta}-positive individuals, with the highest increase observed in those with tau-positivity. Conclusions and RelevanceThe ALZpath plasma pTau217 Simoa assay accurately identifies biological AD, comparable to CSF biomarkers, with reproducible cut-offs across cohorts. It detects longitudinal changes, including at the preclinical stage, and is the first widely available, accessible, and scalable blood test for pTau217 detection. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the capabilities of the ALZpath plasma pTau217 Single molecule array (Simoa) to identify Alzheimers disease (AD) pathophysiology? FindingsALZpath pTau217 showed similar accuracies to cerebrospinal fluid biomarkers in identifying abnormal A{beta} and tau pathologies. Calculated reference ranges for detecting abnormal A{beta} were consistent across three cohorts. Over 8 years, the largest change of pTau217 was in individuals positive for both A{beta} and tau. MeaningThese results demonstrate the high-performance of the ALZpath plasma pTau217 Simoa in identifying AD-type pathophysiology. The wider availability of high-performing assays will expedite the use of blood biomarkers in clinical settings and benefit the research community.