---
title: "CSF complement proteins, especially C1q, link to early tau pathology and synaptic damage in precli"
id: "biorxiv-11-csf-complement-proteins-are-associated-with-early-tau-pathology-and-synaptic"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-11-csf-complement-proteins-are-associated-with-early-tau-pathology-and-synaptic"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.08.24.742564v1?rss=1"
published_at: "2026-08-27T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# CSF complement proteins, especially C1q, link to early tau pathology and synaptic damage in precli
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-11-csf-complement-proteins-are-associated-with-early-tau-pathology-and-synaptic
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.08.24.742564v1?rss=1)
- **Published At:** 2026-08-27T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- In a cognitively unimpaired, at‑risk cohort (PREVENT-AD), cerebrospinal fluid (**CSF**) complement proteins were measured and compared with established Alzheimer disease (AD) biomarkers, synaptic protein markers, cognition, MRI volumetry, and amyloid/tau PET to assess early roles of complement activation. - Measured analytes included **C1q**, **C3**, **C3b**, and **Factor H**; key associations were tested for reproducibility in 708 participants from ADNI across cognitively normal, mild cognitive impairment (MCI), and dementia stages. - In PREVENT-AD, **C1q** correlated positively with CSF phosphorylated tau (P-tau181), total tau (T-tau), and multiple synaptic markers (ADAM23, GAP43, SNAP25, SYT1), and was the only complement analyte linked to lower global cognition. - **Factor H** also showed strong positive associations with P-tau181, T-tau, and synaptic markers (ADAM22, ADAM23, GAP43, SYT1). - **C3** displayed minimal associations with tau and synaptic markers, while **C3b** had weaker positive relationships with P-tau181, T-tau, and ADAM proteins. - Complement measures did not show robust associations with amyloid or tau PET in PREVENT-AD, suggesting fluid complement changes may precede PET-detectable pathology or reflect different processes. - In the ADNI replication sample, **C1q** produced the most consistent positive associations with tau, neurofilament light, and synaptic markers across diagnostic groups; **C3** tended toward negative associations; **C3b** and **Factor H** relationships varied by disease stage and were more evident with neurodegeneration and synaptic injury in symptomatic individuals. - Overall, results implicate **complement dysregulation**, notably involving **C1q**, as an early correlate of tau-linked synaptic pathology and support a potential role for complement activation in the AD molecular cascade. - Details on experimental design parameters, statistical models, numerical effect sizes, and limitations were not reported in the source abstract and would require consulting the full manuscript or supplementary material for complete methodology and quantification.
## Clinical Analysis & Structured Key Points
CSF complement proteins are associated with early tau pathology and synaptic damage in an asymptomatic population at risk of Alzheimer's disease | bioRxiv Skip to main content New Results CSF complement proteins are associated with early tau pathology and synaptic damage in an asymptomatic population at risk of Alzheimer's disease Julia Loncke , Melissa Savard , Cynthia Picard , Henrik Zetterberg , Daniel Auld , Mohamed Badawy , Simon Ducharme , View ORCID Profile Sylvia Villeneuve , John C. S. Breitner , Judes Poirier , The Alzheimer's Disease Neuroimaging Initiative , The PREVENT-AD Research Group doi: https://doi.org/10.64898/2026.08.24.742564 Julia Loncke 1 McGill University, Montreal, Quebec, Canada; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Melissa Savard 2 Centre for Studies on the Prevention of Alzheimer's Disease (StoP-AD), Douglas Mental Health University Institute, Montreal, Quebec, Canada; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Cynthia Picard 2 Centre for Studies on the Prevention of Alzheimer's Disease (StoP-AD), Douglas Mental Health University Institute, Montreal, Quebec, Canada; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Henrik Zetterberg 3 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniel Auld 4 Victor Phillip Dahdaleh Institute of Genomic Medicine, McGill University, Montreal, Quebec, Canada; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mohamed Badawy 5 Departments of Anesthesiology and Critical Care Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Simon Ducharme 6 Departments of Psychiatry and Neurology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sylvia Villeneuve 6 Departments of Psychiatry and Neurology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sylvia Villeneuve John C. S. Breitner 6 Departments of Psychiatry and Neurology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Judes Poirier 6 Departments of Psychiatry and Neurology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: judes.poirier{at}mcgill.ca Abstract Info/History Metrics Supplementary material Preview PDF Abstract Complement-mediated neuroinflammation has been implicated in Alzheimer's disease (AD), but its role during the pre-symptomatic phase of the disease remains unclear. In the PREVENT-AD cohort of cognitively unimpaired individuals at increased familial risk of AD, we investigated whether CSF complement proteins relate to early AD pathology and synaptic dysfunction, then assessed our results' reproducibility across the clinical AD spectrum. Baseline CSF C1q, C3, C3b, and Factor H were measured in relation to CSF AD biomarkers, synaptic proteins, cognition, MRI volumetry, and amyloid and tau PET. Key findings were then examined in 708 participants from ADNI spanning cognitively normal, mild cognitive impairment (MCI), and dementia stages of AD. In PREVENT-AD, C1q was positively associated with CSF P-tau181, T-tau, and multiple synaptic markers including ADAM23, GAP43, SNAP25, and SYT1. Factor H showed similarly strong positive associations with P-tau181, T-tau, ADAM22, ADAM23, GAP43, and SYT1. By contrast, C3 showed minimal associations, while C3b displayed weaker positive relationships with P-tau181, T-tau, ADAM22, and ADAM23. Complement proteins were not robustly associated with amyloid or tau PET, and only C1q related to lower global cognitive performance. In ADNI, C1q emerged as the most consistent analyte, showing positive associations with tau, neurofilament light, and synaptic markers across all diagnostic groups. C3 exhibited predominantly negative associations, whereas C3b and Factor H showed stage-dependent relationships, particularly with evident neurodegeneration and synaptic injury in symptomatic individuals. These findings identify complement dysregulation, especially involving C1q, as an early correlate of tau-linked synaptic pathology, and support a role for complement activation in the AD molecular cascade. Competing Interest Statement JP serves as a scientific advisor to the Alzheimer Society of France. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merck Sharp & Dohme, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, LabCorp, Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD, is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, and is a shareholder of CERimmune Therapeutics (outside submitted work). DM serves on the scientific advisory boards of SynapsDx, Mindimmune Therapeutics, and InMed Pharmaceuticals, and receives research support from Danaher Diagnostics and Bright Minds Biosciences. All other authors have nothing to disclose. Funder Information Declared Fonds de Recherche du Québec - Santé, https://ror.org/02eqrsj93 , 356162 Canadian Institutes of Health Research, https://ror.org/01gavpb45 , 153287 , 178210 , 178385 , 438655 , 175127 Swedish Research Council , 2019-02397 , 2022-01018 , 2023-00356 Horizon Europe , 101053962 , 860197 Swedish State Support for Clinical Research , ALFGBG-71320 Alzheimer's Drug Discovery Foundation , 201809-2016862 Alzheimer's Association, https://ror.org/0375f4d26 , ADSF-21-831376-C , ADSF-21-831381-C , ADSF-21-831377-C , ADSF-24-1284328-C The Bluefield Project Cure Alzheimer’s Fund, https://ror.org/05ewr7t48 Olav Thon (Norway) Familjen Erling-Perssons Stiftelse Familjen Rönströms Stiftelse Stiftelsen för Gamla Tjänarinnor Hjärnfonden , FO2022-0270 European Union, https://ror.org/019w4f821 , JPND2021-00694 National Institute for Health and Care Research Natural Sciences and Engineering Research Council, https://ror.org/01h531d29 J. L. Levesque Foundation Brain Canada Foundation, https://ror.org/01bcmwk98 UK Dementia Research Institute, https://ror.org/02wedp412 , UKDRI-1003 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Back to top Previous Next Posted August 27, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Breitner , Judes Poirier , The Alzheimer's Disease Neuroimaging Initiative , The PREVENT-AD Research Group bioRxiv 2026.08.24.742564; doi: https://doi.org/10.64898/2026.08.24.742564 Share This Article: Copy Citation Tools CSF complement proteins are associated with early tau pathology and synaptic damage in an asymptomatic population at risk of Alzheimer's disease Julia Loncke , Melissa Savard , Cynthia Picard , Henrik Zetterberg , Daniel Auld , Mohamed Badawy , Simon Ducharme , Sylvia Villeneuve , John C. S. Breitner , Judes Poirier , The Alzheimer's Disease Neuroimaging Initiative , The PREVENT-AD Research Group bioRxiv 2026.08.24.742564; doi: https://doi.org/10.64898/2026.08.24.742564 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (7935) Biochemistry (18548) Bioengineering (14708) Bioinformatics (43939) Biophysics (22351) Cancer Biology (19476) Cell Biology (26650) Clinical Trials (138) Developmental Biology (13850) Ecology (20788) Epidemiology (2067) Evolutionary Biology (25207) Genetics (16048) Genomics (23313) Immunology (18506) Microbiology (42051) Molecular Biology (17870) Neuroscience (92454) Paleontology (691) Pathology (2954) Pharmacology and Toxicology (5046) Physiology (8025) Plant Biology (15820) Scientific Communication and Education (2090) Synthetic Biology (4519) Systems Biology (10147) Zoology (2367)
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