Head‐to‐Head Comparison of Four Plasma Phosphorylated Tau 217 Biomarkers

Abstract Background We assessed the efficacy of four plasma phospho‐tau217 (p‐tau217) biomarkers in a head‐to‐head comparison, and against two clinically available CSF biomarkers for Alzheimer’s disease (AD). Method Samples were analyzed from 1009 individuals from the Swedish BioFINDER‐2 cohort (Table 1). We included the following biomarkers: %p‐tau217 WashU , p‐tau217 WashU (both mass‐spectrometry), p‐tau217 Lilly , p‐tau217 Janssen (both immunoassays), CSF p‐tau181 and p‐tau181/Aβ42 (Elecsys). Biomarker correlations were assessed using linear regression models. Their discriminative accuracy for global Aβ‐ and temporal meta‐ROI tau‐PET status was evaluated with receiver operating characteristic (ROC) curves. Area under the curve (AUC) values from two ROC curves were compared with DeLong tests. Linear regression models with continuous Aβ‐ and tau‐PET measures were performed. Participants were grouped into PET‐positive quartiles, which were compared with t‐tests. Effect sizes (Cohen’s D (CD)) were calculated between PET‐positive/negative groups, and between neighboring quantiles. Result All plasma biomarkers were correlated (0.62≥R adj 2 ≥0.92, Figure 1). %p‐tau217 WashU showed the significantly largest effect size for both Aβ‐PET status and tau‐PET status (CD Aβ‐PET =1.635 ; CD Tau‐PET =1.828) compared to the other biomarkers (all p FDR <0.05). p‐tau217 Janssen had a lower plasma effect size (CD Aβ‐PET =1.313; CD Tau‐PET =1.590), but not significantly different from p‐tau217 Lilly . Although all plasma biomarkers showed high AUCs (0.90‐0.95) for Aβ‐PET positivity, %p‐tau217 WashU was the highest, performing significantly better than all other biomarkers including CSF p‐tau181/Aβ42 Elecsys (all p FDR <0.01) (Figure 2A). A similar pattern was observed for tau‐PET where %p‐tau217 WashU also performed significantly better than all other biomarkers except for p‐tau217 WashU (all p FDR< 0.01) (Figure 2A). With continuous PET measures, %p‐tau217 WashU showed the highest R adj 2 compared to the other biomarkers for Aβ‐PET and tau‐PET (Figure 2B). In this context, all plasma ptau217 markers performed better that CSF ptau181 Elecsys . Compared to CSF p‐tau181/Aβ42 Elecsys , p‐tau217 Lilly and p‐tau217 WashU performed similarly whereas %p‐tau217 WashU performed significantly better. Quantile grouping revealed that all biomarkers showed significant differences when distinguishing between negatives and early‐stage positives for both Aβ‐PET and tau‐PET, with %p‐tau217 WashU consistently having the significantly largest effect size (Figure 2C). For tau‐PET, plasma biomarkers distinguished better between disease stages compared to CSF. Conclusion When predicting Aβ‐ and tau‐PET load, both mass‐spectrometry and immunoassay methods detecting plasma p‐tau217 perform similarly to an FDA‐approved CSF test, with %p‐tau217 WashU performing even better.