Sven J van der Lee1, Charlotte E Teunissen2, René Pool3, Martin J Shipley4, Alexander Teumer5, Vincent Chouraki6, Debora Melo van Lent7, Juho Tynkkynen8, Krista Fischer9, Jussi Hernesniemi10, Toomas Haller9, Archana Singh-Manoux11, Aswin Verhoeven12, Gonneke Willemsen3, Francisca A de Leeuw13, Holger Wagner14, Jenny van Dongen3, Johannes Hertel15, Kathrin Budde16, Ko Willems van Dijk17, Leonie Weinhold18, M Arfan Ikram19, Maik Pietzner16, Markus Perola20, Michael Wagner21, Nele Friedrich16, P Eline Slagboom22, Philip Scheltens23, Qiong Yang24, Robert E Gertzen25, Sarah Egert26, Shuo Li24, Thomas Hankemeier27, Catharina E M van Beijsterveldt3, Ramachandran S Vasan28, Wolfgang Maier21, Carel F W Peeters29, Hans Jörgen Grabe30, Alfredo Ramirez31, Sudha Seshadri32, Andres Metspalu9, Mika Kivimäki4, Veikko Salomaa33, Ayşe Demirkan34, Dorret I Boomsma3, Wiesje M van der Flier35, Najaf Amin1, Cornelia M van Duijn36. 1. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. 2. Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands. 3. Department of Biological Psychology, Vrije Universiteit Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands. 4. Research Department of Epidemiology and Public Health, University College London, London, UK. 5. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. 6. Lille University, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases, Labex Distalz, Lille, France. 7. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. 8. University of Tampere, Tampere, Finland. 9. The Institute of Genomics, University of Tartu, Tartu, Estonia. 10. University of Tampere, Tampere, Finland; Heart Center, Tampere University Hospital, Tampere, Finland. 11. Research Department of Epidemiology and Public Health, University College London, London, UK; Inserm U1018, Centre for Research in Epidemiology and Population Health, Villejuif, France. 12. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands. 13. Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands; Alzheimer Center & Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands. 14. Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany. 15. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany. 16. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany. 17. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands. 18. Department of Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Bonn, Germany. 19. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. 20. National Institute of Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. 21. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany. 22. Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 23. Alzheimer Center & Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands. 24. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. 25. Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. 26. Department of Nutrition and Food Sciences, Nutritional Physiology, University of Bonn, Bonn, Germany. 27. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Faculty of Science, Universiteit Leiden, Leiden, The Netherlands; Translational Epidemiology, Faculty Science, Leiden University, Leiden, The Netherlands. 28. Department of Medicine, Boston University School of Medicine, Boston, MA, USA; The Framingham Heart Study, Framingham, MA, USA. 29. Department of Epidemiology & Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands. 30. Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Germany. 31. Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany. 32. Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Glenn Biggs Institute of Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA. 33. National Institute of Health and Welfare, Helsinki, Finland. 34. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 35. Alzheimer Center & Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands; Department of Epidemiology & Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands. 36. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Translational Epidemiology, Faculty Science, Leiden University, Leiden, The Netherlands. Electronic address: c.vanduijn@erasmusmc.nl.
Abstract
INTRODUCTION: Identifying circulating metabolites that are associated with cognition and dementia may improve our understanding of the pathogenesis of dementia and provide crucial readouts for preventive and therapeutic interventions. METHODS: We studied 299 metabolites in relation to cognition (general cognitive ability) in two discovery cohorts (N total = 5658). Metabolites significantly associated with cognition after adjusting for multiple testing were replicated in four independent cohorts (N total = 6652), and the associations with dementia and Alzheimer's disease (N = 25,872) and lifestyle factors (N = 5168) were examined. RESULTS: We discovered and replicated 15 metabolites associated with cognition including subfractions of high-density lipoprotein, docosahexaenoic acid, ornithine, glutamine, and glycoprotein acetyls. These associations were independent of classical risk factors including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, and apolipoprotein E (APOE) genotypes. Six of the cognition-associated metabolites were related to the risk of dementia and lifestyle factors. DISCUSSION: Circulating metabolites were consistently associated with cognition, dementia, and lifestyle factors, opening new avenues for prevention of cognitive decline and dementia.
INTRODUCTION: Identifying circulating metabolites that are associated with cognition and dementia may improve our understanding of the pathogenesis of dementia and provide crucial readouts for preventive and therapeutic interventions. METHODS: We studied 299 metabolites in relation to cognition (general cognitive ability) in two discovery cohorts (N total = 5658). Metabolites significantly associated with cognition after adjusting for multiple testing were replicated in four independent cohorts (N total = 6652), and the associations with dementia and Alzheimer's disease (N = 25,872) and lifestyle factors (N = 5168) were examined. RESULTS: We discovered and replicated 15 metabolites associated with cognition including subfractions of high-density lipoprotein, docosahexaenoic acid, ornithine, glutamine, and glycoprotein acetyls. These associations were independent of classical risk factors including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, and apolipoprotein E (APOE) genotypes. Six of the cognition-associated metabolites were related to the risk of dementia and lifestyle factors. DISCUSSION: Circulating metabolites were consistently associated with cognition, dementia, and lifestyle factors, opening new avenues for prevention of cognitive decline and dementia.
Authors: Burcu F Darst; Alisha Chou; Peggy Wan; Loreall Pooler; Xin Sheng; Emily A Vertosick; David V Conti; Lynne R Wilkens; Loïc Le Marchand; Andrew J Vickers; Hans G Lilja; Christopher A Haiman Journal: Cancer Epidemiol Biomarkers Prev Date: 2020-05-08 Impact factor: 4.254
Authors: Manja Koch; Steven T DeKosky; Matthew Goodman; Jiehuan Sun; Jeremy D Furtado; Annette L Fitzpatrick; Rachel H Mackey; Tianxi Cai; Oscar L Lopez; Lewis H Kuller; Kenneth J Mukamal; Majken K Jensen Journal: J Lipid Res Date: 2019-12-31 Impact factor: 5.922
Authors: Jun Liu; Lies Lahousse; Michel G Nivard; Mariska Bot; Lianmin Chen; Jan Bert van Klinken; Carisha S Thesing; Marian Beekman; Erik Ben van den Akker; Roderick C Slieker; Eveline Waterham; Carla J H van der Kallen; Irene de Boer; Ruifang Li-Gao; Dina Vojinovic; Najaf Amin; Djawad Radjabzadeh; Robert Kraaij; Louise J M Alferink; Sarwa Darwish Murad; André G Uitterlinden; Gonneke Willemsen; Rene Pool; Yuri Milaneschi; Diana van Heemst; H Eka D Suchiman; Femke Rutters; Petra J M Elders; Joline W J Beulens; Amber A W A van der Heijden; Marleen M J van Greevenbroek; Ilja C W Arts; Gerrit L J Onderwater; Arn M J M van den Maagdenberg; Dennis O Mook-Kanamori; Thomas Hankemeier; Gisela M Terwindt; Coen D A Stehouwer; Johanna M Geleijnse; Leen M 't Hart; P Eline Slagboom; Ko Willems van Dijk; Alexandra Zhernakova; Jingyuan Fu; Brenda W J H Penninx; Dorret I Boomsma; Ayşe Demirkan; Bruno H C Stricker; Cornelia M van Duijn Journal: Nat Med Date: 2020-01-13 Impact factor: 53.440