In cohort 1, plasma p-tau217+Janssen and plasma p-tau217Lilly levels were higher in the MCI group than in the controls. APOEϵ4 carriers, CSF-Aβ+ subjects, and amyloid-PET+ subjects in cohort 1 were all more prevalent in the MCI group than in the control group. As expected, in cohort 2, there were also differences between the diagnostic groups in age, APOEϵ4 carriership, MMSE, and plasma p-tau217+Janssen and plasma p-tau217Lilly levels. Unfortunately, the follow-up time in cohort 2 was not consistent across the groups (Table 1 and Additional file 1: Table S2).

Table 1 Baseline demographic and clinical characteristics of the samples

Plasma p-tau217 between Aβ+ and Aβ− subjects

Cohort 1

Baseline plasma p-tau217 levels from both assays were compared between CSF-Aβ+ and CSF-Aβ− participants as well as between amyloid-PET+ and amyloid-PET− participants. Both plasma p-tau217+Janssen and plasma p-tau217Lilly were higher in CSF-Aβ+ subjects with a mean fold increase (mean CSF-Aβ+ minus mean CSF-Aβ− divided by mean CSF-Aβ−) of 2.1 (Cohen’s d [95%CI] = 1.44 [0.81–2.10]) and 0.8 (d = 1.35 [0.73–1.97]) for plasma p-tau217+Janssen and plasma p-tau217Lilly, respectively. The AUC for plasma p-tau217+Janssen to distinguish CSF-Aβ+ from CSF-Aβ− was AUC (95%CI) = 0.91 (0.84–0.99), and the corresponding AUC for plasma p-tau217Lilly was 0.89 (0.80–0.98), and these AUCs were not significantly different (z = 0.50, p = 0.620). In cohort 1, baseline plasma p-tau217 levels from both assays were also higher in amyloid-PET+ subjects (plasma p-tau217+Janssen, 2.1-fold increase, Cohen’s d [95%CI] = 1.42 [0.74–2.10], between amyloid-Aβ− and amyloid-Aβ+; plasma p-tau217Lilly, 0.8-fold increase, d = 1.36 [0.68–2.03]). The AUC for plasma p-tau217+Janssen to distinguish amyloid-PET+ from amyloid-PET− was AUC (95%CI) = 0.91(0.83–1.00), and the corresponding AUC for plasma p-tau217Lilly was 0.90 (0.81–1.00), and these were not significantly different (z = 0.34, p = 0.736; Fig. 2).

Fig. 2
figure 2

Differences in plasma p-tau217 according to amyloid status. CSF-Aβ+ was determined by CSF Aβ42/Aβ40 ratio < 0.07, and amyloid-PET+ was determined by >1.42 SUVR. AUC, area under the curve

Cohort 2

Baseline plasma p-tau217 levels from both assays were compared between CSF-Aβ+ and CSF-Aβ− participants which revealed that both plasma p-tau217+Janssen and plasma p-tau217Lilly were higher in CSF-Aβ+ subjects (plasma p-tau217+Janssen, 2.6-fold increase, Cohen’s d [95%CI] = 1.21 [0.86–1.56], between CSF-Aβ− and CSF-Aβ+; plasma p-tau217+Lilly, 1.9-fold increase, d = 1.28 [0.92–1.63]). The AUC for plasma p-tau217+Janssen to distinguish CSF-Aβ+ from CSF-Aβ− was AUC (95%CI) = 0.85(0.79–0.91), and the corresponding AUC for plasma p-tau217Lilly was 0.87 (0.82–0.93), and these were not significantly different (z = 0.70, p = 0.484; Fig. 2).

Plasma p-tau217 between the diagnostic groups

Cohort 1

Comparing plasma p-tau217 between controls and MCI subjects, we found that MCI subjects had significantly higher plasma p-tau217+Janssen (2.0 fold increase [Cohen’s d [95%CI] = 1.55 [0.91–2.19]) and plasma p-tau217Lilly (0.4 fold increase, d = 1.51 [0.88–2.14]) levels than controls. The performance of plasma p-tau217+Janssen and plasma p-tau217Lilly to distinguish MCI from controls was similar (AUC [95%CI] plasma p-tau217+Janssen = 0.91 [0.82–0.99], plasma p-tau217Lilly = 0.91 [0.82–1.00], z = 0.05, p = 0.964; Fig. 3).

Fig. 3
figure 3

Differences in plasma p-tau217 according to diagnostic groups. The groups in cohort 2 were stratified according to amyloid status (Aβ+ = CSF Aβ42/Aβ40 ratio < 0.07) and clinical diagnosis at follow-up (e.g., MCI-AD Aβ+ has AD dementia at follow-up). Brackets indicate significant differences between the groups, determined by general linear models with post hoc LSD tests, adjusted for age, sex, and [in cohort 2] total follow-up time. The y-axes represent the z-scored plasma p-tau217 levels in order to facilitate an easier visual comparison between the two assays. AUC, area under the curve

Cohort 2

Comparing plasma p-tau217 between the diagnostic groups who were stratified according to amyloid status and clinical diagnosis at follow-up, we found that MCI-AD had significantly higher plasma p-tau217+Janssen levels than all other groups except MCI-other Aβ+ (fold increase compared to MCI-other Aβ− 1.5, Cohen’s d [95%CI] = 1.17 [0.63–1.71]; stable MCI Aβ− 2.5, d [95%CI] = 1.64 [1.17–2.10]; stable MCI Aβ+ 0.8, d = 0.83 [0.26–1.41]). Plasma p-tau217Lilly was higher in MCI-AD compared to all other groups (fold increase compared to MCI-other Aβ− 1.0, Cohen’s d [95%CI] = 1.45 [0.89–2.01]; MCI-other Aβ+ 0.6, d = 1.38 [0.89–1.87]; stable MCI Aβ− 1.3, d = 1.71 [1.24–2.19]; stable MCI Aβ+ 0.5, d = 0.94 [0.36–1.52]). The AUCs for the two assays to detect future progression from MCI to AD dementia (i.e., distinguish the MCI-AD group from the other groups) were found to not be significantly different (AUC [95%CI] plasma p-tau217+Janssen = 0.88 [0.82–0.93], plasma p-tau217Lilly = 0.89 [0.83–0.95], z = − 0.51, p = 0.609; Fig. 3).

In cohort 2, we also assessed whether the similarities between AUC for plasma p-tau217+Janssen and plasma p-tau217Lilly were impacted when also considering age, sex, and APOEϵ4 carriership when detecting CSF-Aβ+ and predicting future conversion to AD dementia. We found that, as expected, AUC values increased when also considering these factors, and they became even more similar between the two assays (Additional file 1: Table S3). Additionally, we determined the optimal cut-points for plasma p-tau217+Janssen and plasma p-tau217Lilly to detect CSF-Aβ+ and future conversion to AD dementia and examined the sensitivity and specificity of the two assays at these optimal cut-points. Sensitivity and specificity to detect CSF-Aβ+ and conversion to AD dementia were 0.75/0.85 and 0.84/0.81, respectively, for plasma p-tau217+Janssen, while the corresponding sensitivity and specificity for plasma p-tau217Lilly were 0.81/0.85 and 0.85/0.84, respectively (Additional file 1: Table S4).

Longitudinal effects

Cohort 2

We found that plasma p-tau217+Janssen as well as plasma p-tau217Lilly increased with time in the whole sample, and change over time was not different between the assays (plasma p-tau217+Janssenr = 0.35, p < 0.001; plasma p-tau217Lillyr = 0.14, p < 0.001; z = 1.54, p = 0.124). We also found no differences in the change over time between the assays when assessing the MCI-AD group separately (plasma p-tau217+Janssenr = 0.50, p < 0.001; plasma p-tau217Lillyr = 0.53, p < 0.001; z = 0.14, p = 0.889) and in participants that did not convert to AD dementia (i.e., all groups combined, except MCI-AD; plasma p-tau217+Janssenr = 0.34, p < 0.001, plasma p-tau217Lillyr = 0.09, p = 0.031; z for difference = 1.58, p = 0.114).

We also assessed the differences in change over time (Δ/year) in plasma p-tau217 across the diagnostic groups. General linear models with LSD post hoc tests revealed that the MCI-AD group had a significantly higher annual increase compared to all other groups, and this was true both for plasma p-tau217+Janssen (fold increase compared to MCI-other Aβ− 2.2, Cohen’s d [95%CI] = 1.07 [0.38–1.77]; MCI-other Aβ+ 3.6, d = 1.04 [0.43 1.65]; stable MCI Aβ− 3.3, d = 1.60 [1.04–2.16]; stable MCI Aβ+ 1.4, d = 0.91 [0.20–1.62]) and plasma p-tau217Lilly (fold increase compared to MCI-other Aβ− 5.2, Cohen’s d [95%CI] = 1.21 [0.51–1.91]; MCI-other Aβ+ 2.4, d = 1.12 [0.51–1.74]; stable MCI Aβ− 43.2, d = 1.84 [1.25–2.42]; stable MCI Aβ+ 2.3, d = 0.96 [0.22–1.70]; Fig. 4). ROC analyses also revealed that annual change in plasma p-tau217+Janssen and plasma p-tau217Lilly were similarly able to distinguish converters to AD dementia from those not converting to AD dementia (Δ plasma p-tau217+Janssen AUC = 0.82 [0.71–0.93]; Δ plasma p-tau217Lilly AUC = 0.89 [0.82–0.96]; z for difference = − 1.09, p = 0.275; Fig. 4), and the difference between AUC statistics was smaller when also considering age, sex, and APOEϵ4 carriership (Δ plasma p-tau217+Janssen AUC = 0.94 [0.88–0.99]; Δ plasma p-tau217Lilly AUC = 0.95 [0.91–0.99]; z for difference = − 1.09, p = 0.275).

Fig. 4
figure 4

Differences in Δ plasma p-tau217 across the diagnostic groups, cohort 2 only. The groups were stratified according to amyloid status determined by the Aβ42/Aβ40 ratio and by clinical diagnosis at follow-up (e.g., MCI-AD Aβ+ has AD dementia at follow-up). Brackets indicate a significant difference between the groups, determined by general linear models with post hoc LSD tests, adjusted for age, sex, and total follow-up time. Plasma p-tau217 levels were z-scored to facilitate comparison between plasma p-tau217+Janssen and plasma p-tau217Lilly assays. AUC, area under the curve

Associations between the plasma p-tau217 measures

In cohort 1, the correlation between the two plasma measures was rho = 0.69, p < 0.001. In cohort 2, the correlation between the two plasma measures was rho = 0.70, p < 0.001 (Fig. 5), and the correlation between CSF measures (CSF p-tau217+Janssen and CSF p-tau217Lilly) was rho = 0.98, p < 0.001. We also assessed the agreement between the two plasma measures using Bland-Altmann plots, which revealed good agreement between plasma p-tau217+Janssen and plasma p-tau217Lilly in both cohorts (cohort 1, 51/52 [98%] within 95%CI; cohort 2, 139/147 [95%] within 95%CI), with agreement decreasing at higher plasma p-tau217 levels (Fig. 5). In cohort 2, the correlation between CSF and plasma measurements of p-tau217 as assessed by the p-tau217+Janssen assay was rho = 0.62, p < 0.001, and the corresponding correlation for measurements with the p-tau217Lilly assay was rho = 0.68, p < 0.001. Fisher’s z-test showed that these correlation coefficients did not statistically differ (z = 1.07, p = 0.285).

Fig. 5
figure 5

Spearman correlation analyses and Bland-Altmann plots assessing the associations and agreement between plasma p-tau217 assays. The figure displays the plasma vs plasma Spearman’s (rho) correlations between plasma p-tau217+Janssen and plasma p-tau217Lilly, as well as Bland-Altmann plots that visualize the agreement between the plasma measures. In the Bland-Altmann plots, the blue line represents the mean difference, and the dotted green and red lines represent 95% confidence intervals (CI). Plasma p-tau217 levels in the scatter plots were z-scored in order to facilitate comparison between plasma p-tau217+Janssen and plasma p-tau217Lilly values

Associations with MMSE

Replication cohort

Both baseline plasma p-tau217+Janssen and plasma p-tau217Lilly were correlated to baseline MMSE (plasma p-tau217+Janssen rho = −0.39, p < 0.001; plasma p-tau217Lilly rho = −0.35, p < 0.001) and to annual change in MMSE (plasma p-tau217+Janssenr = −0.45, p < 0.001; plasma p-tau217Lillyr = −0.41, p < 0.001). There were no differences in terms of associations with baseline (z for difference = 0.44, p = 0.657) or longitudinal change in MMSE (z for difference = 0.43, p = 0.667) between the two assays (Additional file 1: Fig. S1).

Sensitivity analyses

There were a few subjects with baseline plasma p-tau217 levels that would be considered outliers according to the threshold (mean ± 3SD, Additional file 1: Fig. S2). In order to assess whether these cases affected our results, we removed 1 MCI case from cohort 1 based on the plasma p-tau217Lilly value being an outlier and 6 outlier cases (plasma p-tau217+Janssenn = 2, plasma p-tau217Lillyn = 3, and plasma p-tau217+Janssen and plasma p-tau217+Lillyn = 1; Additional file 1: Fig. S2) from cohort 2 and reran all analyses. There were no differences in the results for cohort 1. In the analyses in cohort 2 without the outliers, baseline plasma p-tau217+Janssen was significantly higher in MCI-AD than in MCI-other Aβ+, while it was not in the initial analysis. Additionally, for cohort 2 only, we also reran all analyses after removing stable MCI Aβ− and stable MCI Aβ+ participants who had less than 5 years of follow-up. In these analyses, Δ plasma p-tau217+Janssen was no longer different between MCI-AD and MCI-other Aβ+.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Disclaimer:

This article is autogenerated using RSS feeds and has not been created or edited by OA JF.

Click here for Source link (https://www.biomedcentral.com/)