Predicting amyloid PET positivity using plasma p-tau181 and other blood-based biomarkers

Abstract

Introduction: This study aimed to determine the efficacy of combining plasma phosphorylated tau (p-tau)181, amyloid beta (Aβ)42/Aβ40, neurofilament light (NfL), and apolipoprotein E (APOE) genotypes for detecting positive amyloid positron emission tomography (PET), which is little known in the Asian population, in two independent cohorts.

Methods: Biomarkers were measured using a single-molecule array (Simoa) in a cohort study (Asan). All participants underwent amyloid PET. Significant changes in the area under the curve (AUC) and Akaike Information Criterion values were considered to determine the best model. The generalizability of this model was tested using another cohort (KBASE-V).

Results: In the Asan cohort, after adjusting for age and sex, p-tau181 (AUC = 0.854) or APOE ε4 status (AUC = 0.769) distinguished Aβ status with high accuracy. Combining them or adding NfL and Aβ42/40 improved model fitness. The best-fit model included the plasma p-tau181, APOE ε4, NfL and Aβ42/40. The models established from the Asan cohort were tested in the KBASE-V cohort. Additionally, in the KBASE-V cohort, these three biomarker models had similar AUC in cognitively unimpaired (AUC = 0.768) and mild cognitive impairment (MCI) (AUC = 0.997) participants.

Conclusions: Plasma p-tau181 showed a high performance in determining Aβ-PET positivity. Adding plasma NfL and APOE ε4 status improved the model fit without significant improvement in AUC.

Keywords: APOE; Alzheimer's disease; amyloid beta; amyloid positron emission tomography; neurofilament light; p‐tau181.

FIGURE 1

ROC curve using blood biomarkers in Asan cohort. ROC curve analysis of each (A–C) and combined (D–F) biomarkers for predicting Aβ status using PET in the derivation cohort (Asan). ROC curves are shown for plasma p‐tau181, APOE status, plasma NfL, plasma Aβ42/40, a combination of plasma p‐tau181 and APOE status, a combination of plasma p‐tau181, APOE status, and plasma NfL, and the model including all four biomarkers. Aβ, amyloid beta; APOE, apolipoprotein E; NfL, neurofilament light; PET, positron emission tomography; ROC, receiver operating characteristic

FIGURE 2

Comparison of p‐tau181 level in Aβ status. Dot plots comparing plasma p‐tau181 level between participants with amyloid PET negative and positive in the Asan cohort. The solid line represents the mean with 95% confidence interval. The dotted line at 2.81 pg/mL of p‐tau181 level represents the suggested threshold for Aβ‐positivity. Aβ, amyloid beta; p‐tau181, phosphorylated tau‐181; PET, positron emission tomography

FIGURE 3

ROC curve using blood biomarkers in KBASE‐V cohort. ROC curve analysis of biomarkers for predicting Aβ status using PET in the validation cohort (KBASE‐V). ROC curves are shown for plasma p‐tau181, a combination of plasma p‐tau181 and APOE status, and a combination of plasma p‐tau181, APOE status, and serum NfL in total (A), CU (B), and MCI (C) participants. Logistic regression models established in MCI patients of Asan cohort were tested in KBASE‐V cohort (D). Continuous plasma p‐tau181 and NfL (pg/mL) were used in Asan cohort, and continuous plasma p‐tau181 and serum NfL (pg/mL) in validation cohort (KBASE‐V). Aβ, amyloid beta; APOE, apolipoprotein E; CU, cognitively unimpaired; KBASE‐V, Korea Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease; MCI, mild cognitive impairment; NfL, neurofilament light; PET, positron emission tomography; ROC, receiver operating characteristic