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 ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>pTa</mml:mi></mml:mrow> <mml:msub><mml:mrow><mml:mi>u</mml:mi></mml:mrow> <mml:mn>217</mml:mn></mml:msub> </mml:math> ) against brain PET markers of amyloid [ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mo>[</mml:mo> <mml:mrow><mml:msup><mml:mi></mml:mi> <mml:mn>11</mml:mn></mml:msup> <mml:mrow><mml:mi>C</mml:mi></mml:mrow> </mml:mrow> <mml:mo>]</mml:mo></mml:math> -labelled Pittsburgh compound B (PiB)] and tau ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mo>[</mml:mo> <mml:mrow><mml:msup><mml:mi></mml:mi> <mml:mn>18</mml:mn></mml:msup> <mml:mrow><mml:mi>F</mml:mi></mml:mrow> </mml:mrow> <mml:mo>]</mml:mo></mml:math> MK-6240) and its utility for predicting longitudinal cognition. Samples were analysed 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 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>pTa</mml:mi></mml:mrow> <mml:msub><mml:mrow><mml:mi>u</mml:mi></mml:mrow> <mml:mn>217</mml:mn></mml:msub> </mml:math> and PET biomarkers of Alzheimer's disease and mixed effects models to understand the ability of plasma <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>pTa</mml:mi></mml:mrow> <mml:msub><mml:mrow><mml:mi>u</mml:mi></mml:mrow> <mml:mn>217</mml:mn></mml:msub> </mml:math> 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 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mo>±</mml:mo></mml:math> 6.06; 160 still enrolled; 2 deceased; 3 discontinued). Plasma <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>pTa</mml:mi></mml:mrow> <mml:msub><mml:mrow><mml:mi>u</mml:mi></mml:mrow> <mml:mn>217</mml:mn></mml:msub> </mml:math> was strongly related to PET-based estimates of concurrent brain amyloid ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub> <mml:mrow><mml:mover><mml:mi>β</mml:mi> <mml:mo>^</mml:mo></mml:mover> </mml:mrow> <mml:mrow></mml:mrow></mml:msub> </mml:math> = 0.83 (0.75, 0.90), <i>P</i> < 0.001). Concordance was high between plasma <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>pTa</mml:mi></mml:mrow> <mml:msub><mml:mrow><mml:mi>u</mml:mi></mml:mrow> <mml:mn>217</mml:mn></mml:msub> </mml:math> 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 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>pTa</mml:mi></mml:mrow> <mml:msub><mml:mrow><mml:mi>u</mml:mi></mml:mrow> <mml:mn>217</mml:mn></mml:msub> </mml:math> levels were associated with worse cognitive trajectories ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub> <mml:mrow><mml:mover><mml:mi>β</mml:mi> <mml:mo>^</mml:mo></mml:mover> </mml:mrow> <mml:mrow><mml:mspace></mml:mspace> <mml:mi>p</mml:mi> <mml:mi>T</mml:mi> <mml:mi>a</mml:mi> <mml:mi>u</mml:mi> <mml:mo>×</mml:mo> <mml:mi>a</mml:mi> <mml:mi>g</mml:mi> <mml:mi>e</mml:mi></mml:mrow> </mml:msub> </mml:math> = -0.07 (-0.09, -0.06), <i>P</i> < 0.001). In a convenience sample of unimpaired adults, plasma <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>pTa</mml:mi></mml:mrow> <mml:msub><mml:mrow><mml:mi>u</mml:mi></mml:mrow> <mml:mn>217</mml:mn></mml:msub> </mml:math> 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 ageing.