Plasma pTau181 and pTau217 predict asymptomatic amyloid accumulation equally well as amyloid-PET

Abstract The dynamic phase of preclinical Alzheimer’s disease, as characterised by accumulating cortical amyloid-β (Aβ), is a window of opportunity for Aβ lowering therapies to have greater efficacy. Biomarkers that accurately predict Aβ accumulation may be of critical importance for participant inclusion in secondary prevention trials and thus enhance development of early Alzheimer’s disease therapies. We compared the ability of baseline plasma phosphorylated tau at threonine181 (pTau181), pTau217 and Aβ-PET load to predict future Aβ accumulation in asymptomatic elderly. In this longitudinal cohort study, baseline plasma pTau181 and pTau217 were quantified using single molecule array (Simoa) assays in cognitively unimpaired elderly selected from the community-recruited Flemish Prevent Alzheimer’s disease Cohort KU Leuven (F-PACK) based on the availability of baseline plasma samples and longitudinal Aβ-PET data (average time interval = 5 years, range 2 - 10 years). The predictive abilities of pTau181, pTau217 and PET-based Aβ measures for PET-based Aβ accumulation were investigated using receiver operating characteristic analyses, correlations and stepwise regression analyses. We included 75 F-PACK subjects (mean age = 70 years, 48% female), of which 16 were classified as Aβ accumulators (median [IQR] Centiloid rate of change = 3.42 [1.60] Centiloids/year). Plasma pTau181 (area under the curve (AUC) [95% CI] = 0.72 [0.59–0.86]) distinguished Aβ accumulators from non-accumulators with similar accuracy as pTau217 (AUC [95% CI] = 0.75 [0.62–0.88] and Aβ-PET (AUC [95% CI] = 0.72 [0.56–0.87]). Plasma pTau181 and pTau217 strongly correlated with each other (r = 0.93, PFDR < 0.001) and, together with Aβ-PET, similarly correlated with Aβ rate of change (rpTau181 = 0.33, rpTau217 = 0.36, rAβ-PET = 0.35, all PFDR ≤ 0.01). Addition of either plasma pTau181, plasma pTau217, or Aβ-PET to a linear demographic model including age, sex and APOE-ε4 carriership similarly improved the prediction of Aβ accumulation (ΔAkaike Information Criterion ≤ 4.1). In a multimodal biomarker model including all three biomarkers, each biomarker lost their individual predictive ability. These findings indicate that plasma pTau181, plasma pTau217 and Aβ-PET convey overlapping information and therefore predict the dynamic phase of asymptomatic amyloid-β accumulation with comparable performances. In clinical trial recruitment, confirmatory PET scans following blood-based prescreening might thus not provide additional value for detecting participants in these early disease stages who are destined to accumulate cortical Aβ. Given the moderate performances, future studies should investigate whether integrating plasma pTau species with other factors can improve performance and thus enhance clinical and research utility.