Plasma pTau217: single vs multiple phospho‐site assays.

Abstract Background Blood biomarkers have gained much attention in recent years given their increasing ability to indicate amyloid pathology and excellent performance in distinguishing diagnostic groups in the context of Alzheimer’s disease (AD). Plasma pTau217 has been considered the best candidate biomarker to serve as diagnostic and prognostic tool for clinical trials. However, biomarker assays targeting tau phosphorylation on Thr217 may differ because of their composition (e.g., targeting multiple or single phosphorylation sites) which may lead to distinct associations with pathology. Thus, we aimed to compare two plasma pTau217 immunoassays that differ in regard to their target specificity. Method Participants from the TRIAD cohort with available cross‐sectional plasma and imaging data, incorporating within the AD spectrum, were included in this study (Young = 25;CU‐ = 107;CU+ = 32;MCI+ = 42;AD+ = 47;MCI‐ = 19). Plasma pTau was quantified using the assays from Janssen (pTau217+; which exhibits enhanced signal with co‐phosphorylation of pTau212) and from ALZpath (single phosphorylation on pTau217), both performed on the Simoa platform. Amyloid and tau pathologies were indexed by PET using [ 18 F]AZD4694 and [ 18 F]MK6240, respectively. ANCOVA compared biomarker values across groups, Spearman rank tested the correlations between them. Linear regression models (LM) evaluated the association between plasma and PET biomarkers globally and at the voxel level. Result Biomarker levels (fold mean of CU‐) were comparable across diagnostic groups, showing the expected increases in amyloid positive groups. Both plasma assays were highly correlated with amyloid (Fig.1), which was also observed on the LM adjusted by age and sex, and on the voxel‐wise analysis (Fig.2). Associations with tau PET SUVR (medial temporal) were also significant and showed similar distribution between the two pTau assays. When neocortical tau was evaluated, however, pTau217+ had a better association as well as higher correlation coefficients within amyloid+ (Fig.3) and neocortical tau+ groups than did ALZpath pTau217. Conclusion In general, pTau217 assays with different antibody specificity showed very similar associations with PET. However, pTau217+ achieved a better association with neocortical tau as compared to ALZpath pTau217. A biomarker targeting multiple phosphorylation sites might be a better proxy of advanced tau, therefore may offer improved ability to detect and exclude participants with advanced AD pathology for clinical trials.