Year: 2026
Type: preprint
Abstract: 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 loci 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.
Source: medRxiv
Authors: Pablo García-González, Raquel Puerta, Jonas Dehairs, Chengran Yang, Ciyang Wang, Jigyasha Timsina, Itziar de Rojas, Claudia Olivé, Alejandro Valenzuela, Paula Bayón-Buján, Marta Rovira, Laura Montrreal, Maria Capdevila, Álvaro Muñoz-Morales, Berta Calm, Sergi Valero, Montse Alegret, Marta Marquié, John C. Morris, Suzanne E. Schindler, David M. Holtzman, Pilar Sanz, Lluís Tárraga, Asif Khan, Maria E. Sáez, Bart Smets, Adelina Orellana, Xavier Montalbán, Mercè Boada, Amanda Cano, Menghan Liu, Muhammad Ali, Carlos Cruchaga, Johannes V. Swinnen, Victoria Fernández, Alfredo Cabrera-Socorro, Agustín Ruiz
Institutions: Instituto de Salud Carlos III, Universitat Internacional de Catalunya, Biomedical Research Networking Center on Neurodegenerative Diseases, Universitat de Barcelona, KU Leuven, Washington University in St. Louis, University of Luxembourg, Luxembourg Centre for Systems Biomedicine, Hope Center for Neurological Disorders, Johnson & Johnson (Germany), Universitat de Vic - Universitat Central de Catalunya, Universitat Autònoma de Barcelona, Vall d'Hebron Hospital Universitari, The University of Texas at San Antonio Health Science Center
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
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
Awards: G1059605238, Estudio de quasispecies por metagenómica en neuropatías asociadas a virus por secuenciación masiva de nueva generación., G3038188779, G3690828678, Utilidad de la combinación de la puntuación FACEmemory® automatizada, las puntuaciones de riesgo poligénico y los biomarcadores plasmáticos para la identificación precoz de individuos con alto riesgo de enfermedad de Alzheimer, G5611199677, G5799658593, G6828942038, Utilidad de los exosomas neuronales como biomarcadores plasmáticos en la caracterización clínico-biológica del deterioro cognitivo leve de inicio precoz, Utilidad de la Angiografía por Tomografía de Coherencia Óptica (OCT-A) como biomarcador de la patología vascular cerebral en la Enfermedad de Alzheimer preclínica y prodrómica, G7680307114, G7815222579, G8015867108, G8195368653, G8348400257, G8599964989, G904308495
OpenAlex ID: W7127274681