A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease

Abstract

Development of tau-based therapies for Alzheimer’s disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer’s disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Keywords

protein, tau, therapies, Alzheimer’s disease, amyloid-β, neurodegeneration

Document Type

Journal Article

Date of Publication

1-1-2020

Publication Title

Nature Medicine

Publisher

Nature Research

School

Centre for Exercise and Sports Science Research

RAS ID

31413

Funders

National Institute on Aging

Deutsches Zentrum Neurodegenerative Erkrankungen

Japan Agency for Medical Research and Development

Fondation Plan Alzheimer

Korea Health Industry Development Institute

Medical Research Council

National Institute of Neurological Disorders and Stroke

Comments

Barthélemy, N. R., Li, Y., Joseph-Mathurin, N., Gordon, B. A., Hassenstab, J., Benzinger, T. L., ... & Morris, J. C. (2020). A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nature Medicine, 26(3), 398-407. https://doi.org/10.1038/s41591-020-0781-z

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Link to publisher version (DOI)

10.1038/s41591-020-0781-z