A comprehensive head-to-head comparison of key plasma phosphorylated tau 217 biomarker tests
Authors: Warmenhoven Noëlle , Salvadó Gemma , Janelidze Shorena , Mattsson-Carlgren Niklas , Bali Divya , Orduña Dolado Anna , Kolb Hartmuth , Triana-Baltzer Gallen , Barthélemy Nicolas R , Schindler Suzanne E , Aschenbrenner Andrew J , Raji Cyrus A , Benzinger Tammie L S , Morris John C , Ibanez Laura , Timsina Jigyasha , Cruchaga Carlos , Bateman Randall J , Ashton Nicholas , Arslan Burak , Zetterberg Henrik , Blennow Kaj , Pichet Binette Alexa , Hansson Oskar 
Published: October 2024

Abstract
Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarker for reliable detection of Alzheimer’s disease 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 CSF biomarker tests.
Samples from 998 individuals [mean (range) age 68.5 (20.0–92.5) years, 53% female] from the Swedish BioFINDER-2 cohort, including both cognitively unimpaired and cognitively impaired individuals, were analysed. Plasma p-tau217 was measured with mass spectrometry assays [the ratio between phosphorylated and non-phosphorylated (%p-tau217WashU) and p-tau217WashU] and with immunoassays (p-tau217Lilly, p-tau217Janssen and p-tau217ALZpath). CSF biomarkers included p-tau217Lilly, the US Food and Drug Administration-approved p-tau181/Aβ42Elecsys, and p-tau181Elecsys.
All plasma p-tau217 tests exhibited a high ability to detect abnormal Aβ-PET [area under the curve (AUC) range: 0.91–0.96] and tau-PET (AUC range: 0.94–0.97). Plasma %p-tau217WashU had the highest performance, with significantly higher AUCs than all the immunoassays (Pdiff &lt; 0.007). For detecting Aβ-PET status, %p-tau217WashU had an accuracy of 0.93 (immunoassays: 0.83–0.88), sensitivity of 0.91 (immunoassays: 0.84–0.87) and a specificity of 0.94 (immunoassays: 0.85–0.89). Among immunoassays, p-tau217Lilly and plasma p-tau217ALZpath had higher AUCs than plasma p-tau217Janssen for Aβ-PET status (Pdiff &lt; 0.006), and p-tau217Lilly outperformed plasma p-tau217ALZpath for tau-PET status (Pdiff = 0.025). Plasma %p-tau217WashU exhibited stronger associations with all PET load outcomes compared with immunoassays; baseline Aβ-PET load (R2: 0.72; immunoassays: 0.47–0.58; Pdiff &lt; 0.001), baseline tau-PET load (R2: 0.51; immunoassays: 0.38–0.45; Pdiff &lt; 0.001), longitudinal Aβ-PET load (R2: 0.53; immunoassays: 0.31–0.38; Pdiff &lt; 0.001) and longitudinal tau-PET load (R2: 0.50; immunoassays: 0.35–0.43; Pdiff &lt; 0.014). Among immunoassays, plasma p-tau217Lilly was more associated with Aβ-PET load than plasma p-tau217Janssen (Pdiff &lt; 0.020) and with tau-PET load than both plasma p-tau217Janssen and plasma p-tau217ALZpath (all Pdiff &lt; 0.010). Plasma %p-tau217 also correlated more strongly with baseline cognition (Mini-Mental State Examination) than all immunoassays (R2: %p-tau217WashU: 0.33; immunoassays: 0.27–0.30; Pdiff &lt; 0.024). The main results were replicated in an external cohort from Washington University in St Louis (n = 219). Finally, p-tau217NULISA showed similar performance to other immunoassays in subsets of both cohorts.
In summary, both mass spectrometry- and immunoassay-based p-tau217 tests generally perform well in identifying Aβ-PET, tau-PET and cognitive abnormalities, but %p-tau217WashU performed significantly better than all the examined immunoassays. Plasma %p-tau217 may be considered as a stand-alone confirmatory test for Alzheimer’s disease pathology, whereas some immunoassays might be better suited as triage tests where positive results are confirmed with a second test, which needs to be determined by future reviews incorporating results from multiple cohorts.