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Multicenter Study
. 2022 Aug 1;79(8):797-807.
doi: 10.1001/jamaneurol.2022.1740.

Detection of Brain Tau Pathology in Down Syndrome Using Plasma Biomarkers

Shorena Janelidze  1 , Bradley T Christian  2 , Julie Price  3 , Charles Laymon  4 , Nicole Schupf  5 , William E Klunk  4 , Ira Lott  6 , Wayne Silverman  6 , H Diana Rosas  3   7 , Shahid Zaman  8 , Mark Mapstone  9 , Florence Lai  7 , Beau M Ances  10 , Benjamin L Handen  4 , Oskar Hansson  1   11
Affiliations
Multicenter Study

Detection of Brain Tau Pathology in Down Syndrome Using Plasma Biomarkers

Shorena Janelidze et al. JAMA Neurol. .

Abstract

Importance: Novel plasma biomarkers, especially phosphorylated tau (p-tau), can detect brain tau aggregates in Alzheimer disease.

Objective: To determine which plasma biomarker combinations can accurately detect tau pathological brain changes in Down syndrome (DS).

Design, setting, and participants: The cross-sectional, multicenter Alzheimer's Biomarker Consortium-Down Syndrome study included adults with DS and a control group of siblings without DS. All participants with plasma, positron emission tomography (PET), and cognitive measures available by the time of data freeze 1.0 were included. Participants were enrolled between 2016 and 2019, and data were analyzed from August 2021 to April 2022.

Exposures: Plasma p-tau217, glial fibrillary acidic protein (GFAP), amyloid β42/40 (Aβ42/Aβ40), neurofilament light (NfL), and total tau (t-tau); tau positron emission tomography (tau-PET) and Aβ-PET.

Main outcomes and measures: The primary outcome was tau-PET status. Secondary outcomes included Aβ-PET status and cognitive performance.

Results: Among 300 participants with DS and a control group of 37 non-DS siblings, mean (SD) age was 45.0 (10.1) years, and 167 (49.6%) were men. Among participants with DS who all underwent plasma p-tau217 and GFAP analyses, 258 had other plasma biomarker data available and 119, 213, and 288 participants had tau-PET, Aβ-PET, and cognitive assessments, respectively. Plasma p-tau217 and t-tau were significantly increased in Aβ-PET-positive tau-PET-positive (A+T+) DS and A+T- DS compared with A-T- DS while GFAP was only increased in A+T+ DS. Plasma p-tau217 levels were also significantly higher in A+T+ DS than A+T- DS. In participants with DS, plasma p-tau217 and GFAP (but not other plasma biomarkers) were consistently associated with abnormal tau-PET and Aβ-PET status in models covaried for age (odds ratio range, 1.59 [95% CI, 1.05-2.40] to 2.32 [95% CI, 1.36-3.96]; P < .03). A combination of p-tau217 and age performed best when detecting tau-PET abnormality in temporal and neocortical regions (area under the curve [AUC] range, 0.96-0.99). The most parsimonious model for Aβ-PET status included p-tau217, t-tau, and age (AUC range, 0.93-0.95). In multivariable models, higher p-tau217 levels but not other biomarkers were associated with worse performance on DS Mental Status Examination (β, -0.24, 95% CI, -0.36 to -0.12; P < .001) and Cued Recall Test (β, -0.40; 95% CI, -0.53 to -0.26; P < .001).

Conclusions and relevance: Plasma p-tau217 is a very accurate blood-based biomarker of both tau and Aβ pathological brain changes in DS that could help guide screening and enrichment strategies for inclusion of individuals with DS in future AD clinical trials, especially when it is combined with age as a covariate.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Christian reported grants from the National Institutes of Health (NIH) and nonfinancial support from Avid Radiopharmaceuticals during the conduct of the study. Dr Price reported grants from Massachusetts General Hospital (U01 AG051412) during the conduct of the study. Dr Laymon reported grants from the NIH during the conduct of the study and grants from the NIH outside the submitted work. Dr Schupf reported grants from the NIH National Institute on Aging (NIA) during the conduct of the study. Dr Klunk reported a license from GE Healthcare for the University of Pittsburgh for Pittsburgh compound B (PiB) PET technology during the conduct of the study, grants from NIA outside the submitted work, and a patent for PiB PET technology licensed to GE Healthcare. Dr Silverman reported grants from the NIH during the conduct of the study and grants and other activities from the NIH outside the submitted work. Dr Mapstone reported grants from the NIH during the conduct of the study; personal fees from Brain Neurotherapy Bio, LLC, outside the submitted work; and a patent issued for biomarkers for dementia. Dr Handen reported grants from the NIA and Eunice Kennedy Shriver National Institute of Child Health and Human Development during the conduct of the study and grants from Autism Speaks and Roche Pharma outside the submitted work. Dr Hansson reported having acquired research support (for the institution) from ADx, Avid Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche and having received consultancy, speaker, and other fees from Amylyx, Alzpath, BioArtic, Biogen, Cerveau, Fujirebio, Genentech, Lundbeck, Novartis, NovoNordisk, Roche, and Siemens outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Plasma Biomarkers by Positron Emission Tomography (PET) Status for Participants With Down Syndrome (DS) and a Control Group of Siblings Without DS
Plasma concentrations of the biomarkers were compared between Aβ-PET negative (A–) non-DS siblings, A– DS and A+ DS, and between A– participants with DS who were tau-PET negative in the temporal meta region of interest (A– T–), A+ T– DS, and A+ T+ DS. P values are from univariate general linear models adjusted for age and sex with Bonferroni correction for multiple comparisons. Boxes show IQR, horizontal lines are medians, and whiskers and outliers were plotted using the Tukey method. Aβ indicates amyloid β; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; p-tau, phosphorylated tau; t-tau, total tau. aP < .05. bP < .001.
Figure 2.
Figure 2.. Associations Between Plasma Biomarkers and Tau Positron Emission Tomography (PET) and Amyloid β (Aβ) PET Measures in Participants With Down Syndrome (DS)
Associations of plasma biomarkers with tau-PET SUVR in the temporal meta-region of interest (ROI) and Aβ-PET centiloid. Data are shown as β (standardized coefficient) and P value from linear regression models adjusted for age and sex. Two total tau (t-tau) values not shown in panels D and I were included in the statistical analysis. Aβ indicates amyloid β; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; p-tau, phosphorylated tau; SUVR, standardized uptake value ratio.
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