Plasma phosphorylated tau 217 in preclinical Alzheimer’s disease

Abstract

An accurate blood test for Alzheimer’s disease that is sensitive to preclinical proteinopathy and cognitive decline has clear implications for early detection and secondary prevention. We assessed the performance of plasma phosphorylated tau 217 (pTau217) against brain PET markers of amyloid ([11C]-labeled Pittsburgh compound B (PiB)) and tau ([18F]MK-6240), and its utility for predicting longitudinal cognition. 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 Alzheimer’s disease. 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 pTau217 and PET biomarkers of Alzheimer’s disease, and mixed effects models to understand the ability of plasma pTau217 to predict longitudinal performance on WRAP’s preclinical Alzheimer’s cognitive composite (PACC-3). The primary analysis included 165 people (108 women; mean age = 62.9 ± 6.06; 160 still enrolled; 2 deceased; 3 discontinued). Plasma pTau217 was strongly related to PET-based estimates of concurrent brain amyloid (β^ = 0.83 (0.75, 0.90), p < .001). Concordance was high between plasma pTau217 and both amyloid PET (area under the curve = 0.91, specificity = 0.80, sensitivity = 0.85, positive predictive value = 0.58, negative predictive value = 0.94) and tau PET (area under the curve = 0.95, specificity = 1, sensitivity = 0.85, positive predictive value = 1, negative predictive value = 0.98). Higher baseline pTau217 levels were associated with worse cognitive trajectories (β^pTau×age = -0.07 (-0.09, -0.06), p < .001). In a convenience sample of unimpaired adults, plasma pTau217 levels correlate well with concurrent brain Alzheimer’s disease pathophysiology and with prospective cognitive performance. These data indicate that this marker can detect disease before clinical signs and thus may disambiguate presymptomatic Alzheimer’s disease from normal cognitive aging.

A novel ultrasensitive assay for plasma p-tau217: performance in individuals with subjective cognitive decline and early Alzheimer’s disease

“…Whilst previous studies have shown good biomarker accuracies for plasma p-tau217 17,20 , performances among CU participants in population-based cohorts have been scanty and in the few available papers the results have been less consistent 6,12,34 . This can be mainly attributable to the weak analytical performance (e.g., lack of quantifiable signals, poor precision) of first-generation p-tau217 assays in individuals with very low concentrations including CU participants and those in early symptomatic stages 2,3 .…”

Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

“…Notably, p-tau217 exhibits larger-fold changes compared with p-tau181 and p-tau231, often achieving high discrimination, with areas under the curve (AUC) exceeding 90% . Additionally, p-tau217 demonstrates a unique longitudinal trajectory, showing increases associated with worsening brain atrophy and declining cognitive performance in individuals with elevated Aβ pathology …”

“…19,23 Additionally, p-tau217 demonstrates a unique longitudinal trajectory, showing increases associated with worsening brain atrophy and declining cognitive performance in individuals with elevated Aβ pathology. 24,25 With the imminent implementation of anti-Aβ therapies in dementia management, validated blood biomarkers are urgently needed to guide timely treatment decisions. While plasma p-tau217 has shown promise as a diagnostic tool for AD, its widespread evaluation has been hindered by limited availability of commercial assays.…”

Comparison of plasma biomarkers and amyloid PET for predicting memory decline in cognitively unimpaired individuals

“…The most important recent advance in diagnostics for Alzheimer's disease (AD) has been the development of ultrasensitive plasma biomarker assays. Prior publications have assessed the ability of plasma [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] or amyloid positron emission tomography (PET) [18][19][20][21][22] to predict continuous cognitive decline or categorical clinical progression.…”