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Microglia protein profiles in CSF across Alzheimer's disease clinical stages.

Nature aging

Authors: Elena-Raluca Blujdea, Pieter van Bokhoven, Pamela V Martino-Adami, Victoria S Marshe, Ellen M Vromen, Yanaika S Hok-A-Hin, Walter A Boiten, David J Irwin, Alice S Chen-Plotkin, Afina W Lemstra, Yolande Pijnenburg, Wiesje M van der Flier, Oliver Peters, Julian Hellmann-Regen, Josef Priller, Anja Schneider, Jens Wiltfang, Frank Jessen, Emrah Düzel, Katharina Buerger, Robert Perneczky, Stefan Teipel, Christoph Laske, Frederic Brosseron, Marta Del Campo, Ruud Wijdeven, Pieter-Jelle Visser, Betty M Tijms, Philip L De Jager, Alfredo Ramirez, Charlotte E Teunissen, Lisa Vermunt

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.

© 2026. The Author(s).

PMID: 41814022

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