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 (R 2 : 0.72; immunoassays: 0.47-0.58; P diff <0.001), baseline tau-PET load (R 2 : 0.51; immunoassays: 0.38-0.45; P diff <0.001), longitudinal Aβ-PET load (R 2 : 0.53; immunoassays: 0.31-0.38; P diff <0.001) and longitudinal tau-PET load (R 2 : 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 (R 2 %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.