Head‐to‐Head Comparison of Four Plasma Phospho‐Tau Immunoassays in the Neuropathological Diagnosis of Alzheimer’s Disease

Background Plasma ptau is a promising indicator of amyloid‐β (Aβ) mediated tau pathophysiology. We previously characterized the ability of Lilly’s MesoScale Discovery (MSD)‐based plasma ptau217 and ptau181 assays to discriminate between those with and without the neuropathological diagnosis of Alzheimer’s disease (AD) in Banner research participants with near‐end‐of‐life blood samples and extensive postmortem neuropathological assessments. We now extend this work in a head‐to‐head comparison of those assays to the University of Gothenburg’s Single molecule array (Simoa)‐based plasma ptau181 and 231 assays. Method Assays were performed blindly in plasma samples acquired 1.0±0.7 years before death from up to 106 Banner research participants with and without cognitive impairment and different neuropathological diagnoses. ROC analyses were used to discriminate between those with and without the neuropathological diagnosis of AD and presence or absence of neuritic Aβ plaques. Spearman correlations were used to characterize their associations with mean cortical neuritic plaque counts and with mean cortical tau tangle counts in those with and without the diagnosis of AD or neuritic plaques. Result Lilly’s ptau217 assay was better than Lilly’s ptau181 and Gothenburg’s ptau231 and ptau181 assays in discriminating between the neuropathological diagnosis of Intermediate/High Likelihood versus Low Likelihood/No AD (respective AUCs=0.86, 0.67, 0.62 and 0.61), the diagnosis of High Likelihood versus Low Likelihood/No AD (AUCs=0.95, 0.83, 0.67 and 0.67), and presence or absence of neuritic Aβ plaques (AUCs=0.86, 0.70, 0.61 and 0.62). It also provided better indicators of mean cortical neuritic plaque (r’s=0.69, 0.35, 0.26 and 0.29) and tangle counts (r’s=0.73, 0.60, 0.19, ‐0.04) in those with the neuropathological diagnosis of AD or at least moderately frequent neuritic plaques (r’s=0.71, 0.59, 0.22, 0.01). The assays were not correlated with tangle counts in those without AD or neuritic plaques. Conclusion Lilly’s MSD‐based plasma ptau217 assay performed better than the other three ptau assays in the neuropathological diagnosis of AD, discriminating between those with and without neuritic Aβ plaques, and providing an indicator of Aβ‐related tau tangle burden. Banner Sun Health Research Institute's growing brain donation program resources could help characterize and compare blood‐based biomarkers in the neuropathological diagnosis of AD, Parkinson’s disease and related diseases.