Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer's disease

Jakob M. Bader, Philipp E. Geyer, Johannes B. Müller, Maximilian T. Strauss, Manja Koch, Frank Leypoldt, Peter Koertvelyessy, Daniel Bittner, Carola G. Schipke, Enise I. Incesoy, Oliver Peters, Nikolaus Deigendesch, Mikael Simons, Majken K. Jensen, Henrik Zetterberg, Matthias Mann

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

Abstract

Neurodegenerative diseases are a growing burden, and there is an urgent need for better biomarkers for diagnosis, prognosis, and treatment efficacy. Structural and functional brain alterations are reflected in the protein composition of cerebrospinal fluid (CSF). Alzheimer's disease (AD) patients have higher CSF levels of tau, but we lack knowledge of systems-wide changes of CSF protein levels that accompany AD. Here, we present a highly reproducible mass spectrometry (MS)-based proteomics workflow for the in-depth analysis of CSF from minimal sample amounts. From three independent studies (197 individuals), we characterize differences in proteins by AD status (> 1,000 proteins, CV < 20%). Proteins with previous links to neurodegeneration such as tau, SOD1, and PARK7 differed most strongly by AD status, providing strong positive controls for our approach. CSF proteome changes in Alzheimer's disease prove to be widespread and often correlated with tau concentrations. Our unbiased screen also reveals a consistent glycolytic signature across our cohorts and a recent study. Machine learning suggests clinical utility of this proteomic signature.

Original languageEnglish
Article numbere9356
JournalMolecular Systems Biology
Volume16
Issue number6
DOIs
StatePublished - 1 Jun 2020
Externally publishedYes

Keywords

  • Alzheimer's disease
  • cerebrospinal fluid
  • mass spectrometry
  • neurodegeneration
  • proteomics

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