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Alzheimers Dement. 2018 Jun;14(6):723-733. doi: 10.1016/j.jalz.2018.01.003. Epub 2018 Mar 6.

Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts.

Author information

1
Department of Cardiology, Tays Heart Hospital, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
2
Department of Neurology, Boston University School of Medicine, Boston, MA, USA; The Framingham Heart Study, Framingham, MA, USA; Lille University, Inserm, Lille University Hospital, Institut Pasteur de Lille, U1167 - RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases, Labex Distalz, Lille, France.
3
Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands.
4
The Framingham Heart Study, Framingham, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
5
Department of Neurology, Boston University School of Medicine, Boston, MA, USA; The Framingham Heart Study, Framingham, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
6
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
7
Department of Epidemiology and Public Health, University College London, London, UK.
8
Department of Epidemiology and Public Health, University College London, London, UK; INSERM, U1018, Centre for Research in Epidemiology and Population Health, France.
9
Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
10
Vanderbilt Heart and Vascular Institute, Vanderbilt University School of Medicine, Nashville, TN, USA.
11
Nightingale Health Ltd, Helsinki, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
12
Estonian Genome Center, University of Tartu, Tartu, Estonia.
13
Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.
14
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
15
Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland; Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
16
Department of Health, National Institute for Health and Welfare, Helsinki, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Estonian Genome Center, University of Tartu, Tartu, Estonia.
17
Nightingale Health Ltd, Helsinki, Finland.
18
Nightingale Health Ltd, Helsinki, Finland; Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
19
Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland; Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, Victoria, Australia.
20
The Framingham Heart Study, Framingham, MA, USA; Department of Medicine, Sections of Preventive Medicine and Cardiology, Boston University School of Medicine, Boston, MA, USA.
21
Department of Epidemiology and Public Health, University College London, London, UK; Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
22
Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands; Leiden Academic Center for Drug Reseach (LACDR), Leiden University, Leiden, The Netherlands.
23
Department of Neurology, Boston University School of Medicine, Boston, MA, USA; The Framingham Heart Study, Framingham, MA, USA; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA. Electronic address: suseshad@bu.edu.
24
Department of Health, National Institute for Health and Welfare, Helsinki, Finland. Electronic address: veikko.salomaa@thl.fi.

Abstract

INTRODUCTION:

Metabolite, lipid, and lipoprotein lipid profiling can provide novel insights into mechanisms underlying incident dementia and Alzheimer's disease.

METHODS:

We studied eight prospective cohorts with 22,623 participants profiled by nuclear magnetic resonance or mass spectrometry metabolomics. Four cohorts were used for discovery with replication undertaken in the other four to avoid false positives. For metabolites that survived replication, combined association results are presented.

RESULTS:

Over 246,698 person-years, 995 and 745 cases of incident dementia and Alzheimer's disease were detected, respectively. Three branched-chain amino acids (isoleucine, leucine, and valine), creatinine and two very low density lipoprotein (VLDL)-specific lipoprotein lipid subclasses were associated with lower dementia risk. One high density lipoprotein (HDL; the concentration of cholesterol esters relative to total lipids in large HDL) and one VLDL (total cholesterol to total lipids ratio in very large VLDL) lipoprotein lipid subclass was associated with increased dementia risk. Branched-chain amino acids were also associated with decreased Alzheimer's disease risk and the concentration of cholesterol esters relative to total lipids in large HDL with increased Alzheimer's disease risk.

DISCUSSION:

Further studies can clarify whether these molecules play a causal role in dementia pathogenesis or are merely markers of early pathology.

KEYWORDS:

Alzheimer's disease; Amino acids; Biomarkers; Dementia; Metabolomics

PMID:
29519576
PMCID:
PMC6082422
DOI:
10.1016/j.jalz.2018.01.003
[Indexed for MEDLINE]
Free PMC Article

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