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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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u2010p180 kit. Performance was validated in blinded replicates, and values were medication adjusted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Multivariable\u2010adjusted analyses showed that sphingomyelins and ether\u2010containing phosphatidylcholines were altered in preclinical biomarker\u2010defined AD stages, whereas acylcarnitines and several amines, including the branched\u2010chain amino acid valine and \u03b1\u2010aminoadipic 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 A\u03b2<jats:sub>1\u201342<\/jats:sub>, tau, imaging, and cognitive changes provided initial biochemical insights for disease\u2010related processes. Coexpression networks interconnected key metabolic effectors of disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Metabolomics identified key disease\u2010related metabolic changes and disease\u2010progression\u2010related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery.<\/jats:p><\/jats:sec>","DOI":"10.1016\/j.jalz.2017.01.020","type":"journal-article","created":{"date-parts":[[2017,3,22]],"date-time":"2017-03-22T01:48:55Z","timestamp":1490147335000},"page":"965-984","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":475,"title":["Metabolic network failures in Alzheimer's disease: A biochemical road\u00a0map"],"prefix":"10.1002","volume":"13","author":[{"given":"Jon B.","family":"Toledo","sequence":"first","affiliation":[{"name":"Department of Pathology &amp; Laboratory Medicine University of Pennsylvania  Philadelphia PA USA"},{"name":"Department of Neurology Houston Methodist Hospital  Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Arnold","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum M\u00fcnchen German Research Center for Environmental Health  Neuherberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabi","family":"Kastenm\u00fcller","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum M\u00fcnchen German Research Center for Environmental Health  Neuherberg Germany"},{"name":"German Center for Diabetes Research (DZD)  Neuherberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Science Icahn School of Medicine at Mount Sinai  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca A.","family":"Baillie","sequence":"additional","affiliation":[{"name":"Rosa &amp; Co LLC  San Carlos CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianlin","family":"Han","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute  Orlando FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhav","family":"Thambisetty","sequence":"additional","affiliation":[{"name":"Clinical and Translational Neuroscience Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging National Institutes of Health  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica D.","family":"Tenenbaum","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics Duke University  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Suhre","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum M\u00fcnchen German Research Center for Environmental Health  Neuherberg Germany"},{"name":"Department of Physiology and Biophysics Weill Cornell Medical College  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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