Phosphorylated tau181 in plasma as a potential biomarker for Alzheimer's disease in adults with Down syndrome

Abstract

Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer's disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 [95% CI 0.73-0.87] and 0.92 [95% CI 0.89-0.95] for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS.

Conflict of interest statement

Dr. Lleó has served as a consultant or at advisory boards for Fujirebio-Europe, Roche, Biogen and Nutricia. In addition, Dr. Lleó has a patent WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease issued. Dr. Zetterberg has served as a consultant or at advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Dr. Alcolea has served as a consultant or at advisory boards for Krka Farmacéutica S.L., Fujirebio-Europe, Roche Diagnostics and Nutricia. In addition, Dr. Alcolea has a patent WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease issued. Dr. Blennow has served as a consultant or at advisory boards for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Dr. Fortea has served as a consultant or at advisory boards for AC Immune, Novartis, and Merck. In addition, Dr. Fortea has a patent WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease issued. The other authors declare no competing interests.

© 2021. The Author(s).

Figures

Fig. 1. Changes with age in plasma p-tau181 concentrations in Down syndrome and euploid controls.

a Age-related changes in p-tau181 levels in individuals with Down syndrome (asymptomatic, prodromal Alzheimer’s disease and Alzheimer’s disease dementia, all in red) and in euploid controls (blue). The central lines indicate the fitted linear model for each group and the shadowed ribbons show the 95% confidence level intervals. b Integrated model of the natural history of Alzheimer’ disease in Down syndrome. Comparison of the evolution of the standardized differences between participants with Down syndrome and controls fitted with a locally estimated scatterplot smoothing curve. Plasma p-tau levels are represented in a solid red line and are compared with CSF p-tau levels and both plasma and CSF NfL levels (modified from ref. ). Positive standardized differences represent higher biomarker values in participants with Down syndrome compared to euploid controls and negative values represent lower biomarker values. Standardized differences were computed by the difference between the DS and the controls divided by the standard deviation of both groups.

Fig. 2. Plasma p-tau181 and NfL concentrations in Down syndrome clinical groups and controls.

a, b Box and whisker plots of the median concentrations of plasma p-tau181 and plasma NfL. Plasma p-tau181 concentrations a for aDS (n = 240), pDS (n = 43), dDS (n = 83) and euploid controls (n = 44) and plasma NfL concentrations b for aDS (n = 193), pDS (n = 26), dDS (n = 56) and euploid controls (n = 14). The central black lines indicate the median values. The boxes above and below these lines show the upper and lower quartiles, respectively, and the whiskers illustrate upper and lower 1.5× IQR limits. c, d ROC curves for plasma p-tau181 (c) and NfL (d) comparing the asymptomatic group with the Alzheimer’s disease dementia (full curve) and with the prodromal Alzheimer’s disease group (dotted curve). ROC receiver operating characteristic, NfL neurofilament light protein, p-tau tau phosphorylated at threonine 181.

Fig. 3. Association of plasma p-tau181 levels with imaging biomarkers in Down syndrome.

a Association of p-tau181 levels with cortical thickness measured by MRI in Down syndrome subjects. Levels of plasma p-tau181 correlated with atrophy in Alzheimer’s disease typical regions. b Association of plasma p-tau181 levels with brain metabolism measured by 18FDG-PET in Down syndrome subjects. Levels of plasma p-tau181 correlated with lower brain metabolism, also driven by patients with symptomatic Alzheimer’s disease. aDS asymptomatic Down syndrome, sDS Down syndrome with symptomatic Alzheimer’s disease.

Fig. 4. Plasma p-tau181 levels to predict Amyloid-β PET positivity in Down syndrome.

a Plasma p-tau181 levels for Down syndrome subjects stratified by amyloid-β PET status (n PET negative = 0; n PET positive = 35). The central black lines indicate the median values. The boxes above and below these lines show the upper and lower quartiles, respectively, and the whiskers illustrate upper and lower 1.5× IQR limits. b ROC curves for plasma p-tau181 comparing the individuals with Down syndrome with positive and negative amyloid-β PET. ROC receiver operating characteristic, p-tau tau phosphorylated at threonine 181.