Plasma phosphorylated-tau181 as a predictive biomarker for Alzheimer's amyloid, tau and FDG PET status

Abstract

Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer's diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer's pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET were included from ADNI. Cross-sectional relationships of plasma p-tau181 with PET biomarkers were tested. Longitudinally, we further investigated whether different p-tau181 levels at baseline predicted different progression of Alzheimer's pathological changes in the brain. We found plasma p-tau181 significantly correlated with brain amyloid (Spearman ρ = 0.45, P < 0.0001), tau (0.25, P = 0.0003), and FDG PET uptakes (-0.37, P < 0.0001), and increased along the Alzheimer's continuum. Individually, plasma p-tau181 could detect abnormal amyloid, tau pathologies and hypometabolism in the brain, similar with or even better than clinical indicators. The diagnostic accuracy of plasma p-tau181 elevated significantly when combined with clinical information (AUC = 0.814 for amyloid PET, 0.773 for tau PET, and 0.708 for FDG PET). Relationships of plasma p-tau181 with brain pathologies were partly or entirely mediated by the corresponding CSF biomarkers. Besides, individuals with abnormal plasma p-tau181 level (>18.85 pg/ml) at baseline had a higher risk of pathological progression in brain amyloid (HR: 2.32, 95%CI 1.32-4.08) and FDG PET (3.21, 95%CI 2.06-5.01) status. Plasma p-tau181 may be a sensitive screening test for detecting brain pathologies, and serve as a predictive biomarker for Alzheimer's pathophysiology.

Fig. 1. Plasma p-tau181 plots for PET and clinical classification groups.

Box plots of plasma p-tau181 concentration between amyloid PET groups (A), tau PET groups (B), FDG PET groups (C), clinical diagnostic groups (D), or clinical classification combined with Aβ status (E). Raw data are presented on the box-and-whisker plot background. The middle line represents the median, and the upper and lower lines represent the first and third quartiles, respectively. Patients with mild cognitive impairment were excluded if they had a follow-up time less than 2 years. CN cognitively normal control, sMCI stable mild cognitive impairment, pMCI progressive mild cognitive impairment, AD Alzheimer’s disease.

Fig. 2. Relationships of plasma p-tau181 concentration with brain PET uptakes.

Scatter fitting curves (A–C) plot the associations of plasma p-tau181 concentration with brain amyloid (A), tau (B), and FDG (C) PET uptakes. Statistical results were generated by the Spearman correlation analyses, and the corresponding curves were roughly smoothed to show directionality. Blue points represent plasma p-tau181 levels of individuals with normal PET uptakes, whereas red points represent those of individuals with abnormal PET uptakes. ROC curves (D–F) illustrate the performance of plasma p-tau181 in discriminating brain pathological changes (D for detecting the abnormal amyloid PET, E for detecting the abnormal tau PET, and F for detecting the abnormal FDG PET). The blue line represents the performance of the clinical model, consisting of age, gender, years of education, and APOE ɛ4 carriage. The red line represents the performance of the adjusted model which combined plasma p-tau181 and the clinical indicators including age, gender, years of education, and APOE ɛ4 carriage. ROC receiver operating characteristic; AUC area under the curve.

Fig. 3. Mediation analyses with brain PET uptakes as pathological outcomes.

The relationships of plasma p-tau181 with brain amyloid PET uptake (A), tau PET uptake (B), and FDG PET uptake (C) were mediated by CSF biomarkers. IE indirect effect, DE direct effect.

Fig. 4. Relationships of baseline plasma p-tau181 level with the risk of pathological progression.

Unadjusted Kaplan–Meier plots show the risk of conversion from amyloid PET negative to amyloid PET positive (A), and from FDG PET negative to FDG PET positive (B) between baseline plasma p-tau181 status. PTAU−, individuals with baseline plasma p-tau181 concentration less than 18.85 pg/ml; PTAU+, individuals with baseline plasma p-tau181 concentration more than 18.85 pg/ml.