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-β (Aβ) 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 Aβ-status (i.e. abnormal CSF Aβ(42/40)) at baseline; and 45 of these Aβ-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-tau217(WashU)) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aβ status [area under curve (AUC) = 0.947; P(diff) < 0.015] or progression to Alzheimer's dementia (AUC = 0.932; P(diff) < 0.027). Among immunoassays, p-tau217(Lilly) had the highest AUCs (0.886–0.889), which was not significantly different from the AUCs of p-tau217(Janss), p-tau181(ADx) and p-tau181(WashU) (AUC(range) 0.835–0.872; P(diff) > 0.09), but higher compared with AUC of p-tau231(UGOT), p-tau181(Lilly), p-tau181(UGOT), p-tau181(Fuji) and p-tau181(Splex) (AUC(range) 0.642–0.813; P(diff) ≤ 0.029). Correlations between plasma and CSF values were strongest for p-tau217(WashU) (R = 0.891) followed by p-tau217(Lilly) (R = 0.755; P(diff) = 0.003 versus p-tau217(WashU)) and weak to moderate for the rest of the p-tau biomarkers (R(range) 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 Aβ or those who will subsequently progress to Alzheimer's dementia. Several other assays (p-tau217(Lilly), p-tau217(Janss), p-tau181(ADx) and p-tau181(WashU)) 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 Aβ-PET and CSF. If further validated, our findings will have significant impacts in diagnosis, screening and treatment for Alzheimer's dementia in the future.