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 (US) |
|---|---|
| Pages (from-to) | 707-722 |
| Number of pages | 16 |
| Journal | Alzheimer's and Dementia |
| Volume | 14 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2018 |
Keywords
- Alzheimer's disease
- Cognitive function
- Dementia
- General cognitive ability
- Lifestyle factors
- Metabolites
- Metabolomics
- NMR
ASJC Scopus subject areas
- Epidemiology
- Health Policy
- Developmental Neuroscience
- Clinical Neurology
- Geriatrics and Gerontology
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
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Circulating metabolites and general cognitive ability and dementia : Evidence from 11 cohort studies. / van der Lee, Sven J.; Teunissen, Charlotte E.; Pool, René; Shipley, Martin J.; Teumer, Alexander; Chouraki, Vincent; Melo van Lent, Debora; Tynkkynen, Juho; Fischer, Krista; Hernesniemi, Jussi; Haller, Toomas; Singh-Manoux, Archana; Verhoeven, Aswin; Willemsen, Gonneke; de Leeuw, Francisca A.; Wagner, Holger; van Dongen, Jenny; Hertel, Johannes; Budde, Kathrin; Willems van Dijk, Ko; Weinhold, Leonie; Ikram, M. Arfan; Pietzner, Maik; Perola, Markus; Wagner, Michael; Friedrich, Nele; Slagboom, P. Eline; Scheltens, Philip; Yang, Qiong; Gertzen, Robert E.; Egert, Sarah; Li, Shuo; Hankemeier, Thomas; van Beijsterveldt, Catharina E.M.; Vasan, Ramachandran S.; Maier, Wolfgang; Peeters, Carel F.W.; Jörgen Grabe, Hans; Ramirez, Alfredo; Seshadri, Sudha; Metspalu, Andres; Kivimäki, Mika; Salomaa, Veikko; Demirkan, Ayşe; Boomsma, Dorret I.; van der Flier, Wiesje M.; Amin, Najaf; van Duijn, Cornelia M.
In: Alzheimer's and Dementia, Vol. 14, No. 6, 06.2018, p. 707-722.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Circulating metabolites and general cognitive ability and dementia
T2 - Evidence from 11 cohort studies
AU - van der Lee, Sven J.
AU - Teunissen, Charlotte E.
AU - Pool, René
AU - Shipley, Martin J.
AU - Teumer, Alexander
AU - Chouraki, Vincent
AU - Melo van Lent, Debora
AU - Tynkkynen, Juho
AU - Fischer, Krista
AU - Hernesniemi, Jussi
AU - Haller, Toomas
AU - Singh-Manoux, Archana
AU - Verhoeven, Aswin
AU - Willemsen, Gonneke
AU - de Leeuw, Francisca A.
AU - Wagner, Holger
AU - van Dongen, Jenny
AU - Hertel, Johannes
AU - Budde, Kathrin
AU - Willems van Dijk, Ko
AU - Weinhold, Leonie
AU - Ikram, M. Arfan
AU - Pietzner, Maik
AU - Perola, Markus
AU - Wagner, Michael
AU - Friedrich, Nele
AU - Slagboom, P. Eline
AU - Scheltens, Philip
AU - Yang, Qiong
AU - Gertzen, Robert E.
AU - Egert, Sarah
AU - Li, Shuo
AU - Hankemeier, Thomas
AU - van Beijsterveldt, Catharina E.M.
AU - Vasan, Ramachandran S.
AU - Maier, Wolfgang
AU - Peeters, Carel F.W.
AU - Jörgen Grabe, Hans
AU - Ramirez, Alfredo
AU - Seshadri, Sudha
AU - Metspalu, Andres
AU - Kivimäki, Mika
AU - Salomaa, Veikko
AU - Demirkan, Ayşe
AU - Boomsma, Dorret I.
AU - van der Flier, Wiesje M.
AU - Amin, Najaf
AU - van Duijn, Cornelia M.
N1 - Funding Information: 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. Funding Information: 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.). Funding Information: 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. Funding Information: 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 ). Funding Information: 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. Funding Information: 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?. Funding Information: 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 ). Funding Information: The Whitehall II study is supported by the Medical Research Council ( K013351 ), the British Heart Foundation, and the National Institute on Aging ( R01 AG013196 ). Funding Information: 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. Funding Information: 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. Funding Information: 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”. Funding Information: 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. Funding Information: 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). Publisher Copyright: © 2018 The Authors
PY - 2018/6
Y1 - 2018/6
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Cognitive function
KW - Dementia
KW - General cognitive ability
KW - Lifestyle factors
KW - Metabolites
KW - Metabolomics
KW - NMR
UR - http://www.scopus.com/inward/record.url?scp=85041352859&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041352859&partnerID=8YFLogxK
U2 - 10.1016/j.jalz.2017.11.012
DO - 10.1016/j.jalz.2017.11.012
M3 - Article
C2 - 29316447
AN - SCOPUS:85041352859
VL - 14
SP - 707
EP - 722
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
SN - 1552-5260
IS - 6
ER -