Ante-mortem plasma phosphorylated tau (181) predicts Alzheimer's disease neuropathology and regional tau at autopsy

Abstract

Blood-based biomarkers such as tau phosphorylated at threonine 181 (phosphorylated-tau181) represent an accessible, cost-effective and scalable approach for the in vivo detection of Alzheimer's disease pathophysiology. Plasma-pathological correlation studies are needed to validate plasma phosphorylated-tau181 as an accurate and reliable biomarker of Alzheimer's disease neuropathological changes. This plasma-to-autopsy correlation study included participants from the Boston University Alzheimer's Disease Research Center who had a plasma sample analysed for phosphorylated-tau181 between 2008 and 2018 and donated their brain for neuropathological examination. Plasma phosphorelated-tau181 was measured with single molecule array technology. Of 103 participants, 62 (60.2%) had autopsy-confirmed Alzheimer's disease. Average time between blood draw and death was 5.6 years (standard deviation = 3.1 years). Multivariable analyses showed higher plasma phosphorylated-tau181 concentrations were associated with increased odds for having autopsy-confirmed Alzheimer's disease [AUC = 0.82, OR = 1.07, 95% CI = 1.03-1.11, P < 0.01; phosphorylated-tau standardized (z-transformed): OR = 2.98, 95% CI = 1.50-5.93, P < 0.01]. Higher plasma phosphorylated-tau181 levels were associated with increased odds for having a higher Braak stage (OR = 1.06, 95% CI = 1.02-1.09, P < 0.01) and more severe phosphorylated-tau across six cortical and subcortical brain regions (ORs = 1.03-1.06, P < 0.05). The association between plasma phosphorylated-tau181 and Alzheimer's disease was strongest in those who were demented at time of blood draw (OR = 1.25, 95%CI = 1.02-1.53), but an effect existed among the non-demented (OR = 1.05, 95% CI = 1.01-1.10). There was higher discrimination accuracy for Alzheimer's disease when blood draw occurred in years closer to death; however, higher plasma phosphorylated-tau181 levels were associated with Alzheimer's disease even when blood draw occurred >5 years from death. Ante-mortem plasma phosphorylated-tau181 concentrations were associated with Alzheimer's disease neuropathology and accurately differentiated brain donors with and without autopsy-confirmed Alzheimer's disease. These findings support plasma phosphorylated-tau181 as a scalable biomarker for the detection of Alzheimer's disease.

Keywords: Alzheimer’s disease; autopsy; biomarkers; plasma p-tau181; tau.

Figure 1

Distribution of plasma p-tau₁₈₁ concentrations between brain donors with and without autopsy-confirmed Alzheimer’s disease. NIA–Reagan Institute criteria were used for the neuropathological diagnosis of Alzheimer’s disease. Analyses were done in the entire sample (n = 62 Alzheimer’s disease versus 41 non-Alzheimer’s disease) and stratified by CDR score ≥1 (n = 37 Alzheimer’s disease versus n = 9 non-Alzheimer’s disease) and CDR score <1 (n = 25 Alzheimer’s disease versus n = 32 non-Alzheimer’s disease). Figure shows the median (bar) and interquartile range (whiskers) as well as the individual data points. Results of the binary logistic regression models that tested the association between plasma p-tau₁₈₁ and Alzheimer’s disease status in the entire sample and stratified by CDR are shown in Table 3. p-tau = phosphorylated-tau.

Figure 2

Accuracy of plasma p-tau₁₈₁ in discriminating brain donors with and without autopsy-confirmed Alzheimer’s disease. NIA–Reagan Institute criteria were used for the neuropathological diagnosis of Alzheimer’s disease. Analyses were done in the entire sample and stratified by CDR score ≥1 and CDR score <1. AUC statistic was calculated based on p-tau₁₈₁ alone (Model 1) and using predicted probabilities from multivariable binary logistic regression that included age at death, years between last blood draw and death, sex (1 = female, 0 = male) and APOE ε4 status (1 = ε4 carrier, 0 = non-carrier; Model 2). For the entire sample, a third model was done that included Model 2 covariates in addition to inclusion of global CDR score at the time of blood draw (Model 3). This model was not done in those stratified by CDR score. p-tau = phosphorylated-tau.

Figure 3

Distribution of plasma p-tau₁₈₁ by p-tau severity ratings at autopsy. Figure shows the median (bar) and interquartile range (whiskers) as well as the individual data points for plasma p-tau₁₈₁ levels by Braak staging of neurofibrillary tangles, as well as hyperphosphorylated tau severity across six cortical and subcortical brain regions rated at autopsy using a 0 (none) to 3 (severe) scale. As shown in Table 3, ordinal logistic regression controlling for age at death, years between last blood draw and death, sex and APOE ε4 status showed higher plasma p-tau₁₈₁ levels were associated with increased odds for more severe Braak stage and p-tau severity across all of the regions (Ps < 0.05). p-tau = phosphorylated-tau.