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.
| Original language | English |
|---|---|
| Pages (from-to) | 707-722 |
| Number of pages | 16 |
| Journal | Alzheimers & Dementia |
| Volume | 14 |
| Issue number | 6 |
| Early online date | 6 Jan 2018 |
| DOIs | |
| Publication status | Published - Jun 2018 |
Funding
None of the funders had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. This work was performed within the framework of the BBMRI Metabolomics Consortium funded by BBMRI-NL, a research infrastructure financed by the Dutch government (NWO, grant nr 184.021.007 and 184033111). This work is funded by the European Union's Horizon 2020 research and innovation programme as part of the Common mechanisms and pathways in Stroke and Alzheimer's disease (CoSTREAM) project ( www.costream.eu , grant agreement No 667375); the Netherlands Organisation for Health Research and Development (ZonMW) as part of the Joint Programming for Neurological Disease (JPND) project PERADES (Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease using multiple powerful cohorts, focused Epigenetics and Stem cell metabolomics - grant number 733051021); the European Union Innovative Medicine Initiative (IMI) programme under grant agreement No 115975 as part of the Alzheimer Disease Apolipoprotein Pathology for Treatment Elucidation and Development (ADAPTED, https://www.imi-adapted.eu ) and the European Union’s Horizon 2020 research and innovation programme Marie Skłodowska-Curie Research and Innovation Staff Exchange (RISE) under the grant agreement No 645740 as part of the Personalized pREvention of Chronic DIseases (PRECeDI) project. The Erasmus Rucphen Family (ERF) has received funding from the Centre for Medical Systems Biology (CMSB) and Netherlands Consortium for Systems Biology (NCSB), both within the framework of the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO). The ERF study is also a part of EUROSPAN (European Special Populations Research Network; FP6 STRP grant number 018947 [LSHG-CT-2006-01947]); European Network of Genomic and Genetic Epidemiology (ENGAGE) from the European Community’s Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413; “Quality of Life and Management of the Living Resources” of fifth Framework Programme (no. QLG2-CT-2002-01254); FP7 project EUROHEADPAIN (nr 602633), the Internationale Stichting Alzheimer Onderzoek (ISAO); the Hersenstichting Nederland (HSN). Metabolomics measurements of ERF have been funded by Biobanking and Biomolecular Resources Research Infrastructure (BBMRI)–NL (184.021.007). A.D. is supported by a Veni grant (2015) from ZonMw. The ERF–follow up study is funded by CardioVasculair Onderzoek Nederland (CVON 2012-03). We are grateful to all study participants and their relatives, general practitioners, and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work, both S.J.v.d.L. and A. van der Spek for collection of the follow-up data, and P. Snijders, M.D., for his help in data collection of both baseline and follow-up data. The Rotterdam Study is supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; The Netherlands Organisation for Scientific Research (NWO); The Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The contribution of inhabitants, general practitioners, and pharmacists of the Ommoord district to the Rotterdam Study is gratefully acknowledged. Metabolomics measurements were funded by Biobanking and Biomolecular Resources Research Infrastructure (BBMRI)–NL (184.021.007). The Whitehall II study is supported by the Medical Research Council ( K013351 ), the British Heart Foundation, and the National Institute on Aging ( R01 AG013196 ). Netherlands Twin Register (NTR): Funding was obtained from the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL, 184.021.007); VU University's Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the European Community's Seventh Framework Program (FP7/2007-2013), ENGAGE (HEALTH-F4-2007-201413); and the European Science Council (ERC Advanced, 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA), and the National Institutes of Health (NIH, R01D0042157-01A , MH081802 , Grand Opportunity grants 1RC2 MH089951). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. FINRISK 1997 has been mainly funded by the budgetary funds of the National Institute for Health and Welfare. Important additional funding has been obtained from the Academy of Finland, Finnish Foundation for Cardiovascular Research and other domestic foundations. The NMR metabolomics determinations were funded by a grant from the Academy of Finland (#139635 to V.S.). DILGOM 2007 baseline survey was funded by the Academy of Finland (grant # 136895 and 263836). V.S. was supported by the Finnish Foundation for Cardiovascular Research. SHIP is part of the Community Medicine Research Net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603 , 01ZZ0103 , and 01ZZ0403 ), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research (grant 03IS2061A ). FHS: This work was supported by the dedication of the Framingham Heart Study participants. This work received support from the National Heart, Lung, and Blood Institute's Framingham Heart Study (contracts no. N01-HC-25195 and HHSN268201500001I) and grants from the National Institute of Neurological Disorders and Stroke ( NS17950 and UH2 NS100605 ), the National Institute on Aging ( AG008122 , R01 AG054076 , R01 AG049607 , R01 AG033193 , U01 AG049505 , and U01 AG052409 ) and the National Institute of Diabetes and Digestive and Kidney Diseases ( R01-DK081572 ). Estonian Biobank was funded by the European Union through the European Regional Development Fund in the framework of the Centre of Excellence for Genomics and Translational Medicine (GENTRANSMED, Project No. 2014-2020.4.01.15-0012), ePerMed–EU 2020 grant no. 692145 and Estonian Research Council grant IUT20-60 and PUT1665. AgeCoDe: We want to thank both all participating patients and their general practitioners for their good collaboration. We also thank all additional members of the AgeCoDe Study Group. This publication is part of the German Research Network on Dementia (KND) and the German Research Network on Degenerative Dementia (KNDD) and was funded by the German Federal Ministry of Education and Research (grants KND: 01GI0102 , 01GI0420 , 01GI0422 , 01GI0423 , 01GI0429 , 01GI0431 , 01GI0433 , and 01GI0434 ; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, and 01ET1006B). The German Federal Ministry of Education and Research had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Analyses were also funded by the German Federal Ministry of Education and Research (BMBF 01EA1410A) within the project “Diet-Body-Brain: from epidemiology to evidence-based communication”. VUmc Amsterdam Dementia Cohort: Research of the VUmc Alzheimer Center is part of the neurodegeneration research program of the Neuroscience Campus Amsterdam. The VUmc Alzheimer Center is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Metabolomics measurements were funded by Biobanking and Biomolecular Resources Research Infrastructure (BBMRI)–NL (184.021.007). F.A.d.L. is appointed at the NWO-FCB project NUDAD (project number 057-14-004). C.E.T. serves on the advisory board of Fujirebio and Roche received research consumables from Euroimmun, IBL, Fujirebio, Invitrogen, and Meso Scale Discovery and performed contract research for IBL, Shire, Boehringer, Roche, and Probiodrug and received grants from the European Commission, the Dutch Research Council (ZonMW), Association of Frontotemporal Dementia/Alzheimer's Drug Discovery Foundation, ISAO, and the Alzheimer's Drug Discovery Foundation.
| Funders | Funder number |
|---|---|
| Hersenstichting | |
| Centre for Medical Systems Biology | |
| Boehringer | |
| Universität Greifswald | |
| Erasmus Universiteit Rotterdam | |
| European Union Innovative Medicine Initiative | |
| German Federal Ministry of Education and Research | |
| Biobanking and Biomolecular Resources Research Infrastructure | |
| RISE | |
| Internationale Stichting Alzheimer Onderzoek | |
| VU University's Institute for Health and Care Research | |
| Shire | |
| Research Institute for Diseases in the Elderly | |
| Netherlands Genomics Initiative | |
| European Science Council | |
| European Special Populations Research Network | |
| German Research Network on Degenerative Dementia | |
| German Research Network on Dementia | |
| European Commission | |
| Erasmus MC University Medical Center | |
| Ministerie van Volksgezondheid, Welzijn en Sport | |
| Dutch Government | |
| Avera Institute | |
| Bundesministerium für Bildung und Frauen | |
| BBMRI-NL | |
| British Heart Foundation | |
| European Union’s Horizon 2020 research and innovation programme Marie Skłodowska-Curie Research and Innovation Staff Exchange | |
| Roche | |
| ZonMw | |
| European Refugee Fund | |
| Terveyden ja hyvinvoinnin laitos | |
| BiG Grid | |
| Alzheimer Disease Apolipoprotein Pathology for Treatment Elucidation and Development | |
| Netherlands Consortium for Systems Biology | |
| Association of Frontotemporal Dementia/Alzheimer's Drug Discovery Foundation | |
| Sydäntutkimussäätiö | |
| European Network of Genomic and Genetic Epidemiology | |
| KNDD | |
| European Research Council | |
| Innovative Medicines Initiative | |
| Ministerie van Onderwijs, Cultuur en Wetenschap | |
| Alzheimer's Drug Discovery Foundation | |
| KND | |
| Ministry of Cultural Affairs | |
| National Institute of Mental Health | U24 MH068457-06 |
| National Institutes of Health | 1RC2 MH089951, MH081802, R01D0042157-01A |
| National Institute of Diabetes and Digestive and Kidney Diseases | R01-DK081572 |
| Bundesministerium für Bildung und Forschung | 01ZZ0403, 01GI0714, 01GI0713, 01GI0716, 01GI0715, 01GI0429, 01GI0710, 01GI0434, 01GI0423, 01GI0712, 01GI0711, 01GI0431, 01GI0420, 01GI0422, 01GI0433, 01GI0102, 01ZZ0103, 01ZZ9603, 01EA1410A, 01ET1006B |
| Cardiovasculair Onderzoek Nederland | CVON 2012-03 |
| Seventh Framework Programme | FP7/2007-2013, 230374, 201413, 263836, 602633, HEALTH-F4-2007-201413 |
| Horizon 2020 Framework Programme | 667375, 692145, 645740, 115975 |
| Medical Research Council | MR/K013351/1, K013351 |
| Spinozapremie | 56-464-14192 |
| Quality of Life and Management of the Living Resources” of Fifth Framework Programme | QLG2-CT-2002-01254 |
| Federal State of Mecklenburg-West Pomerania | 03IS2061A |
| National Institute of Neurological Disorders and Stroke | UH2 NS100605, NS17950 |
| National Heart, Lung, and Blood Institute's Framingham Heart Study | N01-HC-25195, HHSN268201500001I |
| Academy of Finland | 136895, 139635 |
| Eesti Teadusagentuur | IUT20-60, PUT1665 |
| National Institute on Aging | R01 AG049607, R01 AG013196, AG008122, R56AG056477, R01 AG054076, U01 AG049505, R01 AG033193, U01 AG052409 |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 184033111, 904-61-090, 904-61-193,480-04-004, 400-05-717, 985-10-002, 057-14-004, 184.021.007 |
| EU Joint Programme – Neurodegenerative Disease Research | 733051021 |
| European Regional Development Fund | 2014-2020.4.01.15-0012 |
| ENGAGE | HEALTH-F4-2007-201413 |
| FP6 STRP | 018947, LSHG-CT-2006-01947 |
UN SDGs
This output contributes to the following UN Sustainable Development Goals (SDGs)
-
SDG 3 Good Health and Well-being
Keywords
- Alzheimer's disease
- Cognitive function
- Dementia
- General cognitive ability
- Lifestyle factors
- Metabolites
- Metabolomics
- NMR
Cohort Studies
- Netherlands Twin Register (NTR)
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