A Comprehensive Head-to-Head Comparison of Key Plasma Phosphorylated Tau 217 Biomarker Tests

Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarkers for reliable detection of Alzheimer's disease (AD) pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-β (Aβ)-PET, tau-PET, and cognition as outcomes, and benchmarked them against cerebrospinal fluid (CSF) biomarker tests. Samples from 998 individuals (mean[range] age 68.5[20.0-92.5], 53% female) from the Swedish BioFINDER-2 cohort were analyzed. Plasma p-tau217 was measured with mass spectrometry (MS) assays (the ratio between phosphorylated and non-phosphorylated [%p-tau217_WashU]and ptau217_WashU) as well as with immunoassays (p-tau217_Lilly, p-tau217_Janssen, p-tau217_ALZpath). CSF biomarkers included p-tau217_Lilly, and the FDA-approved p-tau181/Aβ42_Elecsys and p-tau181_Elecsys. All plasma p-tau217 tests exhibited high ability to detect abnormal Aβ-PET (AUC range: 0.91-0.96) and tau-PET (AUC range: 0.94-0.97). Plasma %p-tau217_WashU had the highest performance, with significantly higher AUCs than all the immunoassays (P _diff<0.007). For detecting Aβ-PET status, %p-tau217_WashU had an accuracy of 0.93 (immunoassays: 0.83-0.88), sensitivity of 91% (immunoassays: 84-87%), and a specificity of 94% (immunoassays: 85-89%). Among immunoassays, p-tau217_Lilly and plasma p-tau217_ALZpath had higher AUCs than plasma p-tau217_Janssen for Aβ-PET status (P _diff<0.006), and p-tau217_Lilly outperformed plasma p-tau217_ALZpath for tau-PET status (P _diff=0.025). Plasma %p-tau217_WashU exhibited higher associations with all PET load outcomes compared to immunoassays; baseline Aβ-PET load (R²: 0.72; immunoassays: 0.47-0.58; P_diff<0.001), baseline tau-PET load (R²: 0.51; immunoassays: 0.38-0.45; P_diff<0.001), longitudinal Aβ-PET load (R²: 0.53; immunoassays: 0.31-0.38; P_diff<0.001) and longitudinal tau-PET load (R²: 0.50; immunoassays: 0.35-0.43; P_diff<0.014). Among immunoassays, plasma p-tau217_Lilly was more strongly associated with Aβ-PET load than plasma p-tau217_Janssen (P _diff<0.020) and with tau-PET load than both plasma p-tau217_Janssen and plasma p-tau217_ALZpath (all P _diff<0.010). Plasma %p-tau217 also correlated more strongly with baseline cognition (Mini-Mental State Examination[MMSE]) than all immunoassays (R² %p-tau217_WashU: 0.33; immunoassays: 0.27-0.30; P _diff<0.024). The main results were replicated in an external cohort from Washington University in St Louis (n =219). Finally, p-tau217_Nulisa showed similar performance to other immunoassays in subsets of both cohorts. In summary, both MS- and immunoassay-based p-tau217 tests generally perform well in identifying Aβ-PET, tau-PET, and cognitive abnormalities, but %p-tau217_WashU performed significantly better than all the examined immunoassays. Plasma %p-tau217 may be considered as a stand-alone confirmatory test for AD pathology, while some immunoassays might be better suited as triage tests where positive results are confirmed with a second test.