Abstract
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.