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

  • the DELCODE Consortium

Research output: Contribution to JournalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)520-533
Number of pages14
JournalNature Aging
Volume6
Issue number3
Early online date11 Mar 2026
DOIs
Publication statusPublished - Mar 2026

Funding

A.C.P. is supported by the NIH, SPARK-NS, the Parker Family Chair and the Lipman Fund. She has received consulting fees for serving on the scientific advisory board of Novartis Neuroscience. She receives royalties as an inventor of a patent held by the Children’s Hospital of Philadelphia on therapies to treat frontotemporal dementia. As of 11 January 2025, W.M.v.d.F. is executive director at Alzheimer Nederland in Amersfoort, The Netherlands. Before 1 November 2025, research programs of W.M.v.d.F. were funded by ZonMW, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland (Topsector Life Sciences & Health), Stichting Dioraphte, the Noaber Foundation, Pieter Houbolt Fonds, Gieskes-Strijbis Fonds, Stichting Equilibrio, Edwin Bouw Fonds, Pasman Stichting, Philips, Biogen, Novartis NL, Life-MI, AVID, Roche BV, Eli Lilly NL, Fujifilm, Eisai and Combinostics. W.M.v.d.F. is a recipient of ABOARD, which is a public−private partnership receiving funding from ZonMW (no. 73305095007) and Health~Holland (Topsector Life Sciences & Health) (PPP allowance; no. LSHM20106). Before 11 January 2025, W.M.v.d.F. was an invited speaker at Biogen, Danone, Eisai, WebMD Neurology (Medscape), Novo Nordisk, Springer Healthcare and the European Brain Council. W.M.v.d.F. has been a consultant to Oxford Health Policy Forum CIC, Roche, Biogen, Eisai, Eli Lilly, Owkin France and Nationale Nederlanden Ventures. W.M.v.d.F. has participated in advisory boards of Biogen, Roche and Eli Lilly. All funding is paid to her institution. In 2024−2025, W.M.v.d.F. was a member of the steering committee of the phase 3 EVOKE/EVOKE+ studies (Novo Nordisk). In 2025, W.M.v.d.F. was a member of the steering committee of the phase 3 trontinemab study (Roche). All funding has been paid to Amsterdam UMC. In 2020−2021, W.M.v.d.F. was an associate editor of Alzheimerʼs Research & Therapy. In 2021−2025, W.M.v.d.F. was an associate editor of Brain. W.M.v.d.F. is chair of the Scientific Leadership Group of InRAD. W.M.v.d.F. is a member of the Supervisory Board (Raad van Toezicht) of the Trimbos Instituut. S.T. served on advisory boards of Eli Lilly, Eisai and GE Healthcare. He was member of the Data and Safety Monitoring Board of the ENVISION study (Biogen). K.B. has received payment or honoraria for lectures from Eisai and was supported for attending meetings by Eli Lilly Deutschland and Novo Nordisk. J.W. has received consulting fees from Immunogenetics, Noselab and Roboscreen; has received payment or honoraria for lectures from Beeijing Yibai Science and Technology, Gloryren, Janssen-Cilag, Pfizer, Med Update GmbH, Roche Pharma and Eli Lilly; is on the advisory board of Biogen, Abbott, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme and Roche; and has a fiduciary role with the Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP), the German Society for CSF Diagnostics and Clinical Neurochemistry (DGLN), the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN), Deutsche Hirnliga and the CSF Society. M.C. has been an invited speaker at Eisai and Novo Nordisk and has been an invited writer for Springer Healthcare. She is an associate editor at Alzheimerʼs Research & Therapy and a scientific advisor of the Michael J. Fox Foundation. C.E.T. has research contracts with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, C2N Diagnostics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Merck, Muna, Nitrase Therapeutics, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Sysmex, Toyama, Vaccinex and Vivoryon. She is editor-in-chief of Alzheimerʼs Research & Therapy; serves on the editorial boards of Molecular Neurodegeneration, Alzheimer’s & Dementia, Neurology: Neuroimmunology & Neuroinflammation and Medidact Neurologie/Springer; and is a committee member to define guidelines for cognitive disturbances and one for acute neurology in The Netherlands. She has consultancy/speaker contracts with Aribio, Biogen, Beckman Coulter, Cognition Therapeutics, Danaher, Eisai, Eli Lilly, Janssen, Merck, Neurogen Biomarking, Nordic Biosciences, Novo Nordisk, Novartis, Olink, Quanterix, Roche, Sanofi and Veravas. D.J.I. receives research funding from the NIH, the Michael J. Fox Foundation and the Lewy Body Dementia Association and research funding paid to the institution for clinical trials by Alector, Cervo Med, Denali, Passage Bio and Prevail. The remaining authors declare no competing interests. Research of Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. The PRIDE study was supported by Alzheimer Nederland (WE.03-2018-05, M.C. and C.E.T.) and the Selfridges Group Foundation (NR170065, M.C. and C.E.T.). University of Pennsylvania samples were supported by the following grants: P30 AG072979, PO1 AG084497, R37/RO1 NS115139 and U19 AG062418. Part of this study was supported by National Institutes of Health (NIH) grant U01 AG061356 and Chan-Zuckerberg Initiative CS-02018-191971. This study was supported by the EU Joint Program on Neurodegenerative Disease Research funded by the German Federal Ministry of Education and Research (BMBF grant numbers: ADpriOMICs project 01ED2404A and PreADAPT project 01ED2007A to A.R.) and the BMBF-funded consortium DESCARTES (grant numbers: 01EK2102B to A.R. and 01EK2102A to A.S.). The DELCODE study was funded by the German Center for Neurodegenerative Diseases (Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)) (reference number: BN012).

FundersFunder number
Edwin Bouw Fonds
Stichting Steun Alzheimercentrum Amsterdam
Hersenstichting CardioVascular Onderzoek Nederland
Michael J. Fox Foundation
Stichting Dioraphte
EU-IHI
Pieter Houbolt Fonds
Roche
Stichting Equilibrio
Noaber Foundation
EU Joint Programme – Neurodegenerative Disease Research
Gieskes-Strijbis Fonds
SPARK-NS
NIH
Lewy Body Dementia Association
NWO
EU-JPND
Health~Holland
ZonMw
Deutsches Zentrum für Neurodegenerative ErkrankungenBN012
Selfridges Group FoundationU19 AG062418, R37/RO1 NS115139, PO1 AG084497, NR170065, P30 AG072979
Alzheimer NederlandWE.03-2018-05
Bundesministerium für Forschung, Technologie und Raumfahrt01ED2007A, 01ED2404A
National Institutes of HealthU01 AG061356, CS-02018-191971
Eli Lilly NLLSHM20106
BMBF-funded consortium DESCARTES01EK2102B, 01EK2102A

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