Validation of the plasma phosphorylated tau quantified using NUcleic acid Linked Immuno‐Sandwich Assay (NULISA) for the detection of Alzheimer’s disease pathology

Abstract Background Blood‐based biomarkers have been revolutionizing the detection, diagnosis and screening of Alzheimer’s disease (AD). Antibody‐based immunoassays are powerful tools to investigate pathological changes indicated by blood‐based biomarkers and have been studied extensively in AD research. A novel proteomic technology ‐ NUcleic acid Linked Immuno‐Sandwich Assay (NULISA) – was developed to improve the sensitivity of traditional proximity ligation assays and offer a comprehensive outlook for protein biomarkers in neurodegenerative diseases. Due to the relative novelty of the NULISA technology in quantifying AD plasma biomarkers, validation through comparisons with more established methods is required. Method In this present study, we assessed 397 participants from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort where participants had plasma measurements of p‐tau 181 , p‐tau 217 and p‐tau 231 from both NULISA and other established immunoassays. Participants also underwent neuroimaging assessments including MRI, amyloid and tau positron emission tomography (PET). Result Our findings suggest an excellent agreement between plasma p‐tau variants quantified using different immunoassays and strong associations with PET signals in the brain (Fig. 1). As shown in Figure 2, similar to p‐tau 217 quantified using Janssen and ALZpath immunoassays, plasma p‐tau 217 NULISA shows excellent discriminative accuracy for abnormal amyloid‐PET (AUC = 0.918, 95%CI: 0.883 to 0.953, P < 0.0001) and abnormal tau‐PET status (AUC = 0.939; 95%CI: 0.909 to 0.969, P < 0.0001). It also presents the capability for differentiating tau‐PET staging (Table 1). Conclusion Validation of the NULISA CNS panel adds to the current analytical methods for AD diagnosis, screening, and staging, and could potentially expedite the development of a blood‐based biomarker panel.