CSF turnover reshapes biomarker interpretation in neurodegeneration studies
Cerebrospinal fluid (CSF) biomarkers are central to Alzheimer's disease (AD) diagnosis and research. However, CSF composition is shaped not only by neurodegeneration, but also by underlying physiological and pathological processes that remain poorly characterized. By integrating multi-omics data from the deeply characterized memory-clinic ACE CSF cohort (N=1,372), the Global Neurodegeneration Proteomics Consortium (N=1,863), and publicly available quantitative trait <i>loci</i> data, we reveal that 73.2-85.9% of the molecular variance in CSF omics data is driven by two main factors: one reflecting CSF turnover rate, and another representing blood-brain barrier (BBB) integrity. CSF turnover mainly determines brain-derived molecules, while BBB damage leads to increased blood-derived protein abundance. CSF turnover/clearance severely impacted core AD biomarker levels, affecting the classification of subjects in the A/T framework. Adjusting biomarker levels for OPCML, a novel reference marker, improved biomarker-based prediction of AD progression and removed confounded associations, revealing a proteomic signature of sporadic AD pathology that closely resembles that of autosomal dominant AD. Finally, using the ACE CSF cohort as discovery (N=1,221) and Knight ADRC as replication (N=1,073), we report a curated AD signature comprising 446 unique proteins. Our findings identify CSF dynamics as a major source of molecular variation, reshaping the interpretation of CSF biomarkers.
Authors
- Jonas Dehairs (ORCID: https://orcid.org/0000-0002-6789-2264)
- Johannes V. Swinnen (ORCID: https://orcid.org/0000-0002-7720-5077)
- Álvaro Muñoz-Morales
- Chengran Yang (ORCID: https://orcid.org/0000-0003-4577-5590)
- Ciyang Wang (ORCID: https://orcid.org/0000-0001-5253-0490)
- C. Olive (ORCID: https://orcid.org/0000-0001-6682-4502)
- Boada Rovira M
- Bart Smets (ORCID: https://orcid.org/0000-0001-8480-0782)
- Pilar Sánz
- Victoria M. Fernandez
- Jigyasha Timsina (ORCID: https://orcid.org/0000-0003-4794-9187)
- Marta Marquié
- María Luisa Sarrate Capdevila
- Paula Bayón-Buján
- Berta Calm
- Mercè Boada
- Raquel Puerta
- Sergi Valero
- Xavier Montalban
- Montse Alegret
- Lluis Tarraga
- Maria Eugenia Saez
- Pablo Garcia-Gonzalez
- Carlos Cruchaga
- Amanda Cano
- Adelina Orellana
- Suzanne E Schindler
- Alejandro Valenzuela
- Agustin Ruiz
- Itziar de Rojas
- Alfredo Cabrera-Socorro
- Asif Khan
- John C Morris
- Menghan Liu
- David M Holtzman
- Muhammad Kashif Ali
Institutions
- Universitat de Vic - Universitat Central de Catalunya (ES)
- Universitat Autònoma de Barcelona (ES)
- The University of Texas at San Antonio Health Science Center (US)
- University of Luxembourg (LU)
- Washington University in St. Louis (US)
- Instituto de Salud Carlos III (ES)
- Universitat Internacional de Catalunya (ES)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Alzheimer’s Disease Neuroimaging Initiative (US)
- Centro Andaluz de Biología del Desarrollo (ES)
- VIB-KU Leuven Center for Microbiology (BE)
- Johnson & Johnson (Germany) (DE)
- Hope Center for Neurological Disorders (US)
- Vall d'Hebron Hospital Universitari (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- medRxiv
- Published
- 2026-02-03
- DOI
- https://doi.org/10.64898/2026.02.02.26345363
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Agentschap Innoveren en Ondernemen
- European Federation of Pharmaceutical Industries and Associations
- Fonds Wetenschappelijk Onderzoek
- KU Leuven
- Ministerio de Ciencia e Innovación
- Universitat de Barcelona
- Vlaamse regering
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
- Instituto de Salud Carlos III
- European Regional Development Fund