Abstract Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function ( p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer’s disease (AD) risk ( p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility ( p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets. Subject terms: Prognostic markers, Alzheimer's disease
SHOW FULL ABSTRACT Adrienne Tin, Alison E Fohner, Qiong Yang, Jennifer A Brody, Gail Davies, Jie Yao, Dan Liu, Ilana Caro, Joni V Lindbohm, Michael R Duggan, Osorio Meirelles, Sarah E Harris, Valborg Gudmundsdottir, Adele M Taylor, Albert Henry, Alexa S Beiser, Ali Shojaie, Annabell Coors, Annette L Fitzpatrick, Claudia Langenberg, Claudia L Satizabal, Colleen M Sitlani, Eleanor Wheeler, Elliot M Tucker-Drob, Jan Bressler, Josef Coresh, Joshua C Bis, Julián Candia, Lori L Jennings, Maik Pietzner, Mark Lathrop, Oscar L Lopez, Paul Redmond, Robert E Gerszten, Stephen S Rich, Susan R Heckbert, Thomas R Austin, Timothy M Hughes, Toshiko Tanaka, Valur Emilsson, Ramachandran S Vasan, Xiuqing Guo, Yineng Zhu, Christophe Tzourio, Jerome I Rotter, Keenan A Walker, Luigi Ferrucci, Mika Kivimäki, Monique M B Breteler, Simon R Cox, Stephanie Debette, Thomas H Mosley, Vilmundur G Gudnason, Lenore J Launer, Bruce M Psaty, Sudha Seshadri, Myriam Fornage
1Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson, MS USA 2Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA 3Department of Epidemiology, University of Washington, Seattle, WA USA 4Institute for Public Health Genetics, University of Washington, Seattle, WA USA 5Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA USA 6Department of Biostatistics, Boston University, Boston, MA USA 7Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ UK 8The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA 9Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany 10University of Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux, Bordeaux, France 11Broad Institute of the Massachusetts Institute of Technology and Harvard University, The Klarman Cell Observatory, Cambridge, MA USA 12Clinicum, Department of Public Health, University of Helsinki, Helsinki, Finland 13Department of Epidemiology and Public Health, University College London, London, UK 14Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD USA 15National Institute on Aging, National Institutes of Health, Laboratory of Epidemiology and Population Science, Bethesda, MD USA 16Faculty of Medicine, University of Iceland, Reykjavik, Iceland 17Icelandic Heart Association, Kopavogur, Iceland 18Institute of Cardiovascular Science, University of London, London, UK 19Framingham Heart Study, Framingham, MA USA 20Department of Biostatistics, University of Washington, Seattle, WA USA 21Departments of Family Medicine, University of Washington, Seattle, WA USA 22Precision Healthcare Institute, Queen Mary University of London, London, UK 23MRC Epidemiology Unit, University of Cambridge, Cambridge, UK 24Computational Medicine, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany 25Department of Population Health Sciences and Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX USA 26Department of Neurology, Boston University School of Medicine, Boston, MA USA 27Department of Psychology, University of Texas, Austin, TX USA 28Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX USA 29Johns Hopkins University, Baltimore, MD USA 30Translational Gerontology Branch, National Institute on Aging, Baltimore, MD USA 31Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA USA 32McGill Genome Centre, Montreal, QC Canada 33Departments of Neurology and Psychiatry, University of Pittsburgh, Pittsburgh, PA USA 34Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA USA 35Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA USA 36Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC USA 37Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC USA 38University of Texas School of Public Health in San Antonio, San Antonio, TX USA 39University of Texas Health Sciences Center, San Antonio, TX USA 40UCL Brain Sciences, University College London, London, UK 41Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland 42Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Bonn, Germany 43Department of Neurology, Institute for Neurodegenerative Diseases, CHU de Bordeaux, Bordeaux, France 44Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Baltimore, MD USA 45Department of Health Systems and Population Health, University of Washington, Seattle, WA USA 46Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX USA 