Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer's disease.

Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-ß (Aß) status and predict future progression to Alzheimer's dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aß-status (i.e. abnormal CSF Aß42/40) at baseline; and 45 of these Aß-positive participants progressed to Alzheimer's dementia during follow-up. P-tau concentrations were determined in baseline plasma and CSF. P-tau217 and p-tau181 were both measured using immunoassays developed by Lilly Research Laboratories (Lilly) and mass spectrometry assays developed at Washington University (WashU). P-tau217 was also analysed using Simoa immunoassay developed by Janssen Research and Development (Janss). P-tau181 was measured using Simoa immunoassay from ADxNeurosciences (ADx), Lumipulse immunoassay from Fujirebio (Fuji) and Splex immunoassay from Mesoscale Discovery (Splex). Both p-tau181 and p-tau231 were quantified using Simoa immunoassay developed at the University of Gothenburg (UGOT). We found that the mass spectrometry-based p-tau217 (p-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aß status [area under curve (AUC) = 0.947; Pdiff < 0.015] or progression to Alzheimer's dementia (AUC = 0.932; Pdiff < 0.027). Among immunoassays, p-tau217Lilly had the highest AUCs (0.886-0.889), which was not significantly different from the AUCs of p-tau217Janss, p-tau181ADx and p-tau181WashU (AUCrange 0.835-0.872; Pdiff > 0.09), but higher compared with AUC of p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji and p-tau181Splex (AUCrange 0.642-0.813; Pdiff ≤ 0.029). Correlations between plasma and CSF values were strongest for p-tau217WashU (R = 0.891) followed by p-tau217Lilly (R = 0.755; Pdiff = 0.003 versus p-tau217WashU) and weak to moderate for the rest of the p-tau biomarkers (Rrange 0.320-0.669). In conclusion, our findings suggest that among all tested plasma p-tau assays, mass spectrometry-based measures of p-tau217 perform best when identifying mild cognitive impairment patients with abnormal brain Aß or those who will subsequently progress to Alzheimer's dementia. Several other assays (p-tau217Lilly, p-tau217Janss, p-tau181ADx and p-tau181WashU) showed relatively high and consistent accuracy across both outcomes. The results further indicate that the highest performing assays have performance metrics that rival the gold standards of Aß-PET and CSF. If further validated, our findings will have significant impacts in diagnosis, screening and treatment for Alzheimer's dementia in the future.

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-ß (Aß)-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 p-tau217 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/Aß42 Elecsys and p-tau181 Elecsys . All plasma p-tau217 tests exhibited high ability to detect abnormal Aß-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 Aß-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 Aß-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 Aß-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 Aß-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 Aß-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 Aß-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.