Metabolic network failures in Alzheimer's disease: A biochemical road map.
BACKGROUND
The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance.


METHODS
Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted.


RESULTS
Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ1-42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease.


CONCLUSIONS
Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery.
Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Neurology, Houston Methodist Hospital, Houston, TX, USA. Electronic address: jbtoledoatucha@houstonmethodist.org.
Jon B
JB
Toledo
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Matthias
M
Arnold
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
Gabi
G
Kastenmüller
Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Rui
R
Chang
Rosa & Co LLC, San Carlos, CA, USA.
Rebecca A
RA
Baillie
Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, USA.
Xianlin
X
Han
Clinical and Translational Neuroscience Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Madhav
M
Thambisetty
Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
Jessica D
JD
Tenenbaum
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Department of Physiology and Biophysics, Weill Cornell Medical College, Qatar, Doha, Qatar.
Karsten
K
Suhre
Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
J Will
JW
Thompson
Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
Lisa St
LS
John-Williams
Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC, USA.
Siamak
S
MahmoudianDehkordi
Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC, USA.
Daniel M
DM
Rotroff
Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC, USA.
John R
JR
Jack
Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC, USA.
Alison
A
Motsinger-Reif
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; The Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Shannon L
SL
Risacher
Duke Molecular Physiology Institute, Duke University, Durham, NC, USA; Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
Colette
C
Blach
Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA.
Joseph E
JE
Lucas
Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA.
Tyler
T
Massaro
Department of Psychiatry, Duke University, Durham, NC, USA; Duke Institute for Brain Sciences, Duke University, Durham, NC, USA.
Gregory
G
Louie
Department of Psychiatry, Duke University, Durham, NC, USA; Duke Institute for Brain Sciences, Duke University, Durham, NC, USA.
Hongjie
H
Zhu
BIOCRATES Life Sciences AG, Innsbruck, Austria.
Guido
G
Dallmann
BIOCRATES Life Sciences AG, Innsbruck, Austria.
Kristaps
K
Klavins
BIOCRATES Life Sciences AG, Innsbruck, Austria.
Therese
T
Koal
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; The Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Sungeun
S
Kim
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; The Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Kwangsik
K
Nho
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; The Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Li
L
Shen
Clinical and Translational Neuroscience Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Ramon
R
Casanova
Clinical and Translational Neuroscience Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Sudhir
S
Varma
IPS, Faculty of Life Sciences and Medicine, King's College London, London.
Cristina
C
Legido-Quigley
Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
M Arthur
MA
Moseley
Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Kuixi
K
Zhu
Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Marc Y R
MYR
Henrion
Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands.
Sven J
SJ
van der Lee
Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands.
Amy C
AC
Harms
Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands.
Ayse
A
Demirkan
Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands; Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands.
Thomas
T
Hankemeier
Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands; Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands.
Cornelia M
CM
van Duijn
Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
John Q
JQ
Trojanowski
Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Leslie M
LM
Shaw
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; The Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Andrew J
AJ
Saykin
Department of Radiology, Center for Imaging of Neurodegenerative Diseases, San Francisco VA Medical Center/University of California San Francisco, San Francisco, CA, USA.
Michael W
MW
Weiner
Department of Psychiatry, Duke University, Durham, NC, USA; Duke Institute for Brain Sciences, Duke University, Durham, NC, USA.
P Murali
PM
Doraiswamy
Department of Psychiatry, Duke University, Durham, NC, USA; Duke Institute for Brain Sciences, Duke University, Durham, NC, USA; Department of Medicine, Duke University Medical Center, Durham, NC, USA. Electronic address: kaddu001@mc.duke.edu.
Rima
R
Kaddurah-Daouk
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood; D000544:Alzheimer Disease / Q000097:blood* / Q000134:cerebrospinal fluid / Q000150:complications* / Q000000981:diagnostic imaging; D000596:Amino Acids / Q000097:blood; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000097:blood / Q000000981:diagnostic imaging / Q000209:etiology; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005215:Fasting; D005260:Female; D006801:Humans; D008297:Male; D008659:Metabolic Diseases / Q000097:blood / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging / Q000209:etiology*; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D055432:Metabolomics / Q000379:methods; D010446:Peptide Fragments / Q000378:metabolism; D010713:Phosphatidylcholines / Q000097:blood / Q000378:metabolism; D013109:Sphingomyelins / Q000097:blood; D013844:Thiazoles / Q000378:metabolism; D016875:tau Proteins / Q000134:cerebrospinal fluid
C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000596:Amino Acids; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D010446:Peptide Fragments; D010713:Phosphatidylcholines; D013109:Sphingomyelins; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
Acylcarnitines; Alzheimer's disease; Biochemical networks; Biomarkers; Branched-chain amino acids; Dementia; Metabolism; Metabolomics; Metabonomics; Pharmacometabolomics; Pharmacometabonomics; Phospholipids; Precision medicine; Serum; Sphingomyelins; Systems biology