Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology: pilot case-control studies including patients with Alzheimer's disease and down syndrome

Abstract

Background: There is still a substantial unmet need for less invasive and lower-cost blood-based biomarkers to detect brain Alzheimer's disease (AD) pathology. This study is aimed to determine whether quantification of plasma tau phosphorylated at threonine 181 (p-tau181) is informative in the diagnosis of AD.

Methods: We have developed a novel ultrasensitive immunoassay to quantify plasma p-tau181, and measured the levels of plasma p-tau181 in three cohorts.

Results: In the first cohort composed of 20 AD patients and 15 age-matched controls, the plasma levels of p-tau181 were significantly higher in the AD patients than those in the controls (0.171 ± 0.166 pg/ml in AD versus 0.0405 ± 0.0756 pg/ml in controls, p = 0.0039). The percentage of the subjects whose levels of plasma p-tau181 exceeded the cut-off value (0.0921 pg/ml) was significantly higher in the AD group compared with the control group (60% in AD versus 16.7% in controls, p = 0.0090). In the second cohort composed of 20 patients with Down syndrome (DS) and 22 age-matched controls, the plasma concentrations of p-tau181 were significantly higher in the DS group (0.767 ± 1.26 pg/ml in DS versus 0.0415 ± 0.0710 pg/ml in controls, p = 0.0313). There was a significant correlation between the plasma levels of p-tau181 and age in the DS group (R2 = 0.4451, p = 0.0013). All of the DS individuals showing an extremely high concentration of plasma p-tau181 (> 1.0 pg/ml) were older than the age of 40. In the third cohort composed of 8 AD patients and 3 patients with other neurological diseases, the levels of plasma p-tau181 significantly correlated with those of CSF p-tau181 (R2 = 0.4525, p = 0.023).

Conclusions: We report for the first time quantitative data on the plasma levels of p-tau181 in controls and patients with AD and DS, and these data suggest that the plasma p-tau181 is a promising blood biomarker for brain AD pathology. This exploratory pilot study warrants further large-scale and well-controlled studies to validate the usefulness of plasma p-tau181 as an urgently needed surrogate marker for the diagnosis and disease progression of AD.

Keywords: Alzheimer’s disease; Down syndrome; Plasma biomarker; Simoa; Tau phosphorylated at threonine 181 (p-tau181).

Conflict of interest statement

Competing interest

Drs Kishi and Kakeya are employees of SCRUM Inc. Drs Tatebe, Kasai, Omichi, Waragai, Kondo, Allsop and Tokuda declare that they have no competing interests.

Ethics approval and consent to participate

All subjects including patients with DS provided written informed consent to participate in the study, which was approved by the University Ethics Committee (Kyoto Prefectural University of Medicine, Kyoto, Japan; the reference number RBMR-C-1027-2). The study procedures were designed and performed in accordance with the Declaration of Helsinki.

Consent for publication

Not applicable

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Standard curve for the plasma p-tau181 immunoassay (ultrasensitive digital array technology, Simoa™ system, Quanterix). Data represent the mean ± SD of duplicate readings. The goodness of fit was 0.9999. The limit of detection of the assay is 0.0090 pg/ml

Fig. 2

a Plots for the concentrations of plasma p-tau181 in the control patients (n = 15) and the clinically diagnosed patients with AD (n = 20) of Cohort 1. The solid lines represent the mean value ± standard errors (SE) of the concentrations of each group. The concentration of plasma p-tau181 in the AD group was significantly higher than that in the age-matched control subjects (p = 0.0039, Mann–Whitney U test). The dashed line corresponds to the cut-off value of the plasma p-tau181 to discriminate those two groups (0.0921 pg/ml). b ROC analysis of the levels of plasma p-tau181 for the discrimination between AD and control groups (AUC = 0.786, sensitivity = 60.0%, specificity = 85.7%)

Fig. 3

a Plots for the concentrations of plasma p-tau181 in the control patients (n = 22) and the clinically diagnosed patients with DS (n = 20) of Cohort 2. The solid lines represent the mean value ± standard errors (SE) of the concentrations of each group. The concentration of plasma p-tau181 in the DS group was significantly higher than that in the age-matched controls (p = 0.0313, Mann–Whitney U test). The dashed line corresponds to the cut-off value of the plasma p-tau181 to discriminate AD from control (0.0921 pg/ml) derived from the ROC analysis of AD and control groups in Cohort 1 (Fig. 2a). b A scatter plot of the levels of plasma p-tau181 versus the patient age of the DS patients (n = 20) and a linear regression line for the correlation of those two parameters. There is a significant correlation between the levels of plasma p-tau181 and the age of the DS patients (R2 = 0.4451, p = 0.0013, Pearson correlation). c A scatter plot of the levels of plasma p-tau181 versus the social ages of the DS patients (n = 18) indexed by social maturity scale developed for the Japanese (S-M) [18] that represents the intellectual ability of each DS patient. The solid lines represent the linear regression line between those two parameters. The levels of plasma p-tau181 were weakly correlated negatively with the social ages of DS patients, but the correlation was not significant (p = 0.0563, n = 18). d A scatter plot of the levels of plasma p-tau181 versus the Δsocial ages of the DS patients (n = 6), which indicates the changes of the social ages of the patient during the ~1-year follow-up period. The larger negative values of Δsocial ages means the more cognitive decline the patient had. e A scatter plot of the levels of plasma p-tau181 versus the mean cortical SUVR in PiB-PET study of the DS patients (n = 6), which represents the severity of cerebral Aβ-amyloid burden

Fig. 4

A scatter plot of the levels of plasma p-tau181 versus those of CSF p-tau181 in the patients of Cohort 3 (n = 11) and a linear regression line for the correlation of those two parameters. There is a significant correlation between the levels of plasma and CSF p-tau181 in this small cohort (R2 = 0.4525, p = 0.023, n = 11, Pearson correlation)