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Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer's disease
Open accessAbstract
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.
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“Importantly, 20% of the upregulated proteins were part of the Hif1a downstream network predicted here and included the HIF1A target proteins ALDOA, SPP1, PLD3, PGK1, FABP3, LDHA and STMN1”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [78]
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“Recent analyses showed a reproducible protein signature in 3 independent patient cohorts (total 197 patients) specifically in AD CSF relative to depression and mild cognitive impairment (MCI)78.”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [78]
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“Proteins with associations in this region featured known AD biomarkers, including four members of the 14-3-3 protein family and neurofilament light and heavy chains37,38.”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [37]
Experimental — accuracy not yet measuredIn the citing paper
“In two separate smaller analyses of AD CSF, many of the same AD-associated synaptic and metabolic biomarkers were identified, further supporting the reproducibility these systems-based CSF marker panels [78, 172].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [172]
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Metadata
- Authors
- Bader, J. M., Geyer, P. E., Müller, J. B., Strauss, M. T., Koch, M., Leypoldt, F., Koertvelyessy, P., Bittner, D., Schipke, C. G., Incesoy, E. I., Peters, O., Deigendesch, N., Simons, M., Jensen, M. K., Zetterberg, H., & Mann, M.
- Affiliations
- Max Planck Institute of Biochemistry (DE)
- University of Copenhagen (DK)
- Harvard University (US)
- Christian-Albrechts-Universität zu Kiel (DE)
- Otto-von-Guericke-Universität Magdeburg (DE)
- Humboldt-Universität zu Berlin (DE)
- German Center for Neurodegenerative Diseases (DE)
- University Hospital of Basel (CH)
- Sahlgrenska University Hospital (SE)
- Corresponding author
- Mann, Matthias
- ORCID
- Venue
- Molecular Systems Biology
- Published
- 2020-06-01
- Volume
- 16
- Issue
- 6
- Pages
- e9356-e9356
- ISSN
- 1744-4292 (ISSN-L)
- PMC
- PMC7266499
- OpenAlex
- W3030835098
- Cited by
- 286
- References
- 78
- Citations by year
- 2026: 30 · 2025: 54 · 2024: 55 · 2023: 68 · 2022: 44 · 2021: 27 · 2020: 8
- FWCI
- 22.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Systems Biology (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- Multimedialen Archiv und Publikationsserver der Christian-Albrechts-Universität zu Kiel (Christian-Albrechts-Universität zu Kiel) (submittedVersion, cc-by)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- DZNE Pub (submittedVersion, cc-by)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Novo Nordisk Fonden (NNF15CC0001, NNF15OC0016692)
- EC|Horizon 2020 Framework Programme (825694)
- Deutsche Forschungsgemeinschaft (412136960)
- H2020 European Research Council (ERC‐2012‐SyG_318987)
- Funding from the Harvard T.H. Chan School of Public Health Dean's Challenge Program sponsored by the McLennan Family Fund
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, cerebrospinal fluid proteome, biomarkers, tau protein, SOD1, DJ-1, neurodegeneration, mass spectrometry-based proteomics, machine learning, clinical utility
- MeSH terms
- Machine Learning, Alzheimer Disease, Glycolysis, Humans, Nerve Degeneration, Neurons, Reproducibility of Results, Cohort Studies, Biomarkers, tau Proteins, Proteome, Proteomics
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