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).

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)