Plasma pTau-217 in preclinical Alzheimer’s disease

Background and Objectives An accurate blood test for Alzheimer’s disease (AD) that is sensitive to preclinical proteinopathy and cognitive decline has clear implications for early detection and secondary prevention of AD. We assessed the performance of plasma pTau against brain PET markers of amyloid ([ 11 C]-PiB) and tau ([ 18 F]MK-6240), and its utility for predicting longitudinal cognition. Methods Samples were analyzed from a subset of participants with up to 8 years follow-up in the Wisconsin Registry for Alzheimer’s Prevention (WRAP; 2001-present; plasma 2011-present), a longitudinal cohort study of adults from midlife, enriched for parental history of AD. Participants were a convenience sample who volunteered for at least one PiB scan, had usable banked plasma, and were cognitively unimpaired at first plasma collection. Study personnel who interacted with participants or samples were blind to amyloid status. We used mixed effects models and receiver-operator characteristic curves to assess concordance between plasma pTau 217 and PET biomarkers of AD, and mixed effects models to understand the ability of plasma pTau 217 to predict longitudinal performance on WRAP’s preclinical Alzheimer’s cognitive composite (PACC-3). Results The primary analysis included 165 people (108 women; mean age=62.9 ± 6.06; 160 still enrolled; 2 deceased; 3 discontinued). Plasma pTau 217 was strongly related to PET-based estimates of concurrent brain amyloid (β̂ DVR = 0.83 (0.75, 0.90), p<.001). Concordance was high between plasma pTau 217 and both amyloid PET (AUC=0.91, specificity=0.80, sensitivity=0.85, PPV=0.58, NPV=0.94, LR − =5.48) and tau PET (AUC=0.95, specificity=1, sensitivity=0.85, PPV=1, NPV=0.98, LR − =6.47). Higher baseline pTau 217 levels were associated with worse cognitive trajectories (β̂ pTau=age = -0.07 (-0.09, -0.06), p<.001). Conclusions and Relevance In a convenience sample of unimpaired adults, plasma pTau 217 levels correlate well with concurrent brain AD pathophysiology and with prospective cognitive performance. These data indicate that this marker can detect AD before clinical signs and thus may disambiguate presymptomatic AD from normal cognitive aging. Classification of Evidence This study meets Class III evidential criteria for diagnostic accuracy of plasma pTau 217 .