Comparison of two plasma p-tau217 assays to detect and monitor Alzheimer's pathology

Abstract

Background: Blood-based biomarkers of Alzheimer's disease (AD) have become increasingly important as scalable tools for diagnosis and determining clinical trial eligibility. P-tau217 is the most promising due to its excellent sensitivity and specificity for AD-related pathological changes.

Methods: We compared the performance of two commercially available plasma p-tau217 assays (ALZpath p-tau217 and Janssen p-tau217+) in 294 individuals cross-sectionally. Correlations with amyloid PET and tau PET were assessed, and Receiver Operating Characteristic (ROC) analyses evaluated both p-tau217 assays for identifying AD pathology.

Findings: Both plasma p-tau217 assays were strongly associated with amyloid and tau PET. Furthermore, both plasma p-tau217 assays identified individuals with AD vs other neurodegenerative diseases (ALZpath AUC = 0.95; Janssen AUC = 0.96). Additionally, plasma p-tau217 concentrations rose with AD severity and their annual changes correlated with tau PET annual change.

Interpretation: Both p-tau217 assays had excellent diagnostic performance for AD. Our study supports the future clinical use of commercially-available assays for p-tau217.

Funding: This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR), Canadian Consortium on Neurodegeneration in Aging, the Alzheimer's Association, Brain Canada Foundation, the Fonds de Recherche du Québec - Santé and the Colin J. Adair Charitable Foundation.

Keywords: Alzheimer’s disease; Blood biomarker; Comparison; Diagnosis; p-tau217.

Fig. 1

Association of two plasma p-tau217 assays with amyloid PET and tau PET. a: Plasma p-tau217 ALZpath and p-tau217+ Janssen in across diagnostic groups and amyloid PET status. The boxplots depict the median (horizontal bar), 25th to 75th percentiles (hinges) and whiskers indicate 10th and 90th percentiles. Group comparisons (presented in the Supplementary material) were computed with a one-way ANCOVA adjusting for age and sex. Tukey honest significant difference (HSD) test was used for the post hoc pairwise comparisons. The ∗ indicates, for each biomarker, the groups that are significantly different from CU- group. b: Correlation between plasma p-tau217 ALZpath and p-tau217+ Janssen with neocortical composite amyloid PET SUVR. The line represents the locally estimated scatterplot smoothing (LOESS; span = 1) regression and the shaded area shows the 95% confidence interval. c: Voxelwise association between plasma p-tau217 ALZpath and p-tau217+ Janssen with amyloid PET SUVR. d: Brain regions used for medial temporal (red) and neocortical (purple) tau PET ROI analyses. Brain regions were taken from Ossenkoppele et al. e: Correlation between plasma p-tau217 assays with medial temporal tau PET SUVR. The line represents the LOESS regression (span = 1) and the shaded area shows the 95% confidence interval. f: Correlation between plasma p-tau217 assays with neocortical temporal tau PET SUVR. The line represents the LOESS regression (span = 1) and the shaded area shows the 95% confidence interval. g: Voxelwise association between plasma p-tau217 assays with tau PET SUVR. N = 294.

Fig. 2

Head-to-head comparison of plasma p-tau217 and p-tau217+. a: Linear regression between plasma p-tau217 ALZpath and p-tau217+ Janssen (z-scored); the grey line represents the linear regression between the biomarkers with its 95% confidence interval (shaded area) whereas in black is the identity line. b: Bland–Altman comparison of plasma p-tau217 and p-tau217+ concentrations indicating high levels of agreement between both assays and few individuals with biomarker concentrations outside the limits of agreement. c: Excellent (92%) within-subject agreement between plasma p-tau217+ (Janssen) and plasma p-tau217 (ALZpath) statuses. The Scatter plot shows the distribution of plasma p-tau217 concentrations across assays and cut-offs. The dashed lines indicate the cut-off values for of each of the plasma p-tau217 assays to indicate amyloid PET status (A+). The shaded areas represent the range of values in which individuals would be classified as amyloid PET negative (green), amyloid PET positive (orange) based on the plasma assays cut-offs. The values displayed within the plot show the percentage (%) agreement between plasma assays. The dots are coloured according to the individual status on the PET imaging classification, as presented in the legend in the figure. N = 294.

Fig. 3

Plasma p-tau217 assays identify biological AD in vivo, track AD severity and correlate with tau PET progression. a: ROC curves for plasma p-tau217 ALZpath and p-tau217+ Janssen differentiating among amyloid PET positive and negative individuals without cognitive impairment (AUC_ALZpath: 0.84, 95% CI = 0.76–0.92; AUC_Janssen: 0.86, 95% CI = 0.79–0.93; Delong’s comparison test unveiled a P = 0.58, 95% CI = −0.04 to 0.08, S = 0.78). b: ROC curves for plasma p-tau217 ALZpath and p-tau217+ Janssen for the identification of biological AD (amyloid PET and tau PET positivity) in individuals with cognitive impairment (AUC_ALZpath: 0.91, 95% CI = 0.86–0.96; AUC_Janssen: 0.92, 95% CI = 0.88–0.96; Delong’s comparison test unveiled a P = 0.50, 95% CI = −0.02 to 0.04, S = 1). c: Plasma p-tau217 ALZpath and p-tau217+ Janssen rise with AD severity measured using PET-based Braak staging. The line represents the locally estimated scatterplot smoothing (LOESS) regression and the shaded area shows the 95% confidence interval. d and e: Correlation of annual change in plasma p-tau217 assays with annual change in tau PET (meta-ROI). The line represents the LOESS regression (span = 1) and the shaded area shows the 95% confidence interval. Using the PET status, amyloid-negative participants are here labelled as A−; individuals amyloid-positive and neocortical tau-negative are labelled as A + T(neo)−; and individuals amyloid-positive and neocortical tau-positive are labelled as A + T(neo)+. N = 294.