Microglia protein profiles in CSF across Alzheimer’s disease clinical stages

Microglia are implicated in the progression of Alzheimer's disease (AD) pathology from its earliest stages, suggesting that cerebrospinal fluid (CSF) microglia profiling across clinical AD stages can aid in treatment development and monitoring. We analyzed two CSF cohorts (n = 834) that span from unimpaired controls to preclinical and dementia AD stages, identifying 109 dysregulated microglia-related proteins. Enrichment analyses revealed innate immune processes and cellular recruitment in preclinical AD, whereas AD dementia revealed adaptive immunity and macrophage responses. Next, we aligned the in vivo microglia protein profiles with ex vivo-derived microglial transcriptomic signatures, such as disease-associated microglia phenotypes. Transcriptomic signatures were not specific to either clinical stage but spanned both. We classified an 18-protein panel highlighting distinct changes between the preclinical and dementia stages. Our findings underscore the potential of microglia-based biomarker research for AD staging, offering insights into microglia dynamics in clinical AD stages and how transcriptomic signatures translate to proteomic profiles.

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Publication Details

Journal
Nature Aging
Published
2026-03-11
DOI
https://doi.org/10.1038/s43587-026-01088-0
Primary Topic
Neuroinflammation and Neurodegeneration Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

Microglia protein profiles in CSF across Alzheimer’s disease clinical stages

Pieter van Bokhoven, Ayda Rostamzadeh, Lukas Preis, Sandra Roeske et al.
Nature Aging
Neuroinflammation and Neurodegeneration Mechanisms
article

Microglia protein profiles in CSF across Alzheimer’s disease clinical stages

Pieter van Bokhoven, Ayda Rostamzadeh, Lukas Preis, Sandra Roeske, Daria Gref, Ellen Vromen, Walter Boiten, Victoria Marshe, Pieter-Jelle Visser, Ruud H. Wijdeven, Sebastian Sodenkamp, Alice S Chen-Plotkin, Marta del Campo, Klaus Fliessbach, Afina W. Lemstra, Stefan Teipel, Michael Wagner, Doreen Goerss, Lisa Vermunt, Enise I. Incesoy, Anja Schneider, Yanaika S. Hok-A-Hin, Ingo Kilimann, Claudia Bartels, Frank Jessen, Christoph Laske, Daniel Janowitz, Katharina Buerger, Yolande Pijnenburg, Alfredo Ramirez, Robert Perneczky, Philip L. De Jager, Wenzel Glanz, Betty M. Tijms, Eike Jakob Spruth, Boris-Stephan Rauchmann, Marie Theres Kronmüller, Maria Gemenetzi, Elena-Raluca Blujdea, Julian Hellmann-Regen, Josef Priller, David J. Irwin, Oliver Peters, Emrah Düzel, Frederic Brosseron, Pamela V. Martino-Adami, Annika Spottke, Wiesje M. van der Flier, Michael Ewers, Jens Wiltfang, Charlotte E. Teunissen
article en

Abstract

Microglia are implicated in the progression of Alzheimer's disease (AD) pathology from its earliest stages, suggesting that cerebrospinal fluid (CSF) microglia profiling across clinical AD stages can aid in treatment development and monitoring. We analyzed two CSF cohorts (n = 834) that span from unimpaired controls to preclinical and dementia AD stages, identifying 109 dysregulated microglia-related proteins. Enrichment analyses revealed innate immune processes and cellular recruitment in preclinical AD, whereas AD dementia revealed adaptive immunity and macrophage responses. Next, we aligned the in vivo microglia protein profiles with ex vivo-derived microglial transcriptomic signatures, such as disease-associated microglia phenotypes. Transcriptomic signatures were not specific to either clinical stage but spanned both. We classified an 18-protein panel highlighting distinct changes between the preclinical and dementia stages. Our findings underscore the potential of microglia-based biomarker research for AD staging, offering insights into microglia dynamics in clinical AD stages and how transcriptomic signatures translate to proteomic profiles.

Nature AgingVol. 6(3)
University of Bonn (DE), University of Cologne (DE), University Hospital Bonn (DE), German Center for Neurodegenerative Diseases (DE), Karolinska Institutet (SE), LMU Klinikum (DE), Maastricht University (NL), Pasqual Maragall Foundation (ES), Amsterdam Neuroscience (NL), Institute for Neurodegenerative Disorders (US), Munich Cluster for Systems Neurology (DE), UK Dementia Research Institute (GB), Barcelonaβeta Brain Research Center (ES), Hospital Del Mar (ES), Alzheimer Nederland (NL), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), University Hospital Magdeburg (DE), Hertie Institute for Clinical Brain Research (DE), GGD Amsterdam (NL), Amsterdam University Medical Centers (NL), University Hospital Cologne (DE), University of Rostock (DE), Imperial College London (GB), University of Aveiro (PT), Technical University of Munich (DE), University of Göttingen (DE), Columbia University (US), Charité - Universitätsmedizin Berlin (DE), University of Pennsylvania (US), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), Vrije Universiteit Amsterdam (NL), University of Sheffield (GB), Otto-von-Guericke-Universität Magdeburg (DE), University of Edinburgh (GB)
Eli Lilly and Company, Sanofi, Biogen, Celgene, University of Pennsylvania, Universidade de Aveiro, Demensförbundet, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Bundesministerium für Bildung und Forschung, Eisai, Novo Nordisk, Deutsches Zentrum für Neurodegenerative Erkrankungen, Technische Universität München, Universität zu Köln, Rheinische Friedrich-Wilhelms-Universität Bonn, Alzheimer Nederland, Amsterdam Neuroscience, National Institutes of Health
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