Circulating metabolites and general cognitive ability and dementia: Evidence from 11 cohort studies

Sven J van der Lee; Charlotte E Teunissen; René Pool; Martin J Shipley; Alexander Teumer; Vincent Chouraki; Debora Melo van Lent; Juho Tynkkynen; Krista Fischer; Jussi Hernesniemi; Toomas Haller; Archana Singh-Manoux; Aswin Verhoeven; Gonneke Willemsen; Francisca A de Leeuw; Holger Wagner; Jenny van Dongen; Johannes Hertel; Kathrin Budde; Ko Willems van Dijk; Leonie Weinhold; M Arfan Ikram; Maik Pietzner; Markus Perola; Michael Wagner; Nele Friedrich; P Eline Slagboom; Philip Scheltens; Qiong Yang; Robert E Gertzen; Sarah Egert; Shuo Li; Thomas Hankemeier; Catharina E M van Beijsterveldt; Ramachandran S Vasan; Wolfgang Maier; Carel F W Peeters; Hans Jörgen Grabe; Alfredo Ramirez; Sudha Seshadri; Andres Metspalu; Mika Kivimäki; Veikko Salomaa; Ayşe Demirkan; Dorret I Boomsma; Wiesje M van der Flier; Najaf Amin; Cornelia M van Duijn

doi:10.1016/j.jalz.2017.11.012

Circulating metabolites and general cognitive ability and dementia: Evidence from 11 cohort studies

Alzheimers Dement. 2018 Jun;14(6):707-722. doi: 10.1016/j.jalz.2017.11.012. Epub 2018 Jan 6.

Authors

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

Affiliations

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.

PMID: 29316447
DOI: 10.1016/j.jalz.2017.11.012

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.

Keywords: Alzheimer's disease; Cognitive function; Dementia; General cognitive ability; Lifestyle factors; Metabolites; Metabolomics; NMR.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Alzheimer Disease / metabolism
Biomarkers / metabolism*
Cognitive Dysfunction / metabolism*
Cohort Studies
Dementia / metabolism*
Female
Humans
Life Style
Male
Middle Aged
Reproducibility of Results
Risk Factors

Substances

Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding