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

Abstract

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 Aβ42/40) 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-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aβ 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 Aβ 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 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.

Keywords: Alzheimer’s disease; amyloid-β; blood p-tau; dementia.

Figure 1

ROC curve analysis for abnormal CSF Aβ_42/40 status and progression to ADD. ROC curve analysis for differentiating (A) MCI participants with abnormal CSF Aβ_42/40 from those with normal CSF Aβ_42/40 and (B) MCI patients who progressed to ADD during follow-up from those who did not (stable MCI patients and MCI patients who progressed to other types of dementia).

Figure 2

Plasma p-tau biomarkers in amyloid-negative and -positive MCI patients. Plasma levels of p-tau217 (A–C), p-tau181 (D–E and G–J) and p-tau231 (F) measured using different assays in the A− and A+ MCI groups. Aβ status was defined based on the CSF Aβ_42/40 ratio. Data are presented as a fold change from the mean of the A− MCI group. Two p-tau217^WashU and p-tau217^Janss outliers in the A+ group and one p-tau181^ADx outlier in the A− group are not shown in A, C and D, but these data were included in the statistical analysis. F-values and P-values are from univariate general linear models adjusted for age and sex. Boxes show interquartile range, the horizontal lines are medians and the whiskers and outliers were plotted using the Tukey method.

Figure 3

Plasma p-tau biomarkers in MCI participants who progressed to ADD during follow-up and amyloid-negative and -positive non-progressors. Plasma levels of p-tau217 (A–C), p-tau181 (D–E and G–J) and p-tau231 (F) measured using different assays in patients with MCI who progressed to ADD during follow-up (MCI-ADD), A− and A+ non-progressor MCI patients. Aβ status was defined based on the CSF Aβ_42/40 ratio. Data are presented as a fold change from the mean of the A− MCI group. Two p-tau217^WashU and p-tau217^Janss outliers in the MCI-ADD group and one p-tau181^ADx outlier in the A− group are not shown in A, C and D, but these data were included in the statistical analysis. F-values and P-values are from univariate general linear models adjusted for age, sex and follow-up time. Boxes show interquartile range, the horizontal lines are medians and the whiskers and outliers were plotted using the Tukey method.

Figure 4

Correlations between CSF and plasma p-tau. Heat map showing Spearman coefficients for correlations between CSF and plasma p-tau measured using different assays (p-tau181^UGOT, n = 72; p-tau181^Splex, n = 52; all other biomarkers n = 78). Correlations between plasma and CSF p-tau measured with the same assay are highlighted in orange except plasma p-tau181^Lilly and p-tau181^Splex for which corresponding CSF assay data were not available.