title: Blood metabolite markers of preclinical Alzheimer's disease in two longitudinally followed cohorts of older individuals.
abstract: Recently, quantitative metabolomics identified a panel of 10 plasma lipids that were highly predictive of conversion to Alzheimer's disease (AD) in cognitively normal older individuals (n = 28, area under the curve [AUC] = 0.92, sensitivity/specificity of 90%/90%).
  
  
  
  Quantitative targeted metabolomics in serum using an identical method as in the index study.
  
  
  
  We failed to replicate these findings in a substantially larger study from two independent cohorts-the Baltimore Longitudinal Study of Aging ([BLSA], n = 93, AUC = 0.642, sensitivity/specificity of 51.6%/65.7%) and the Age, Gene/Environment Susceptibility-Reykjavik Study ([AGES-RS], n = 100, AUC = 0.395, sensitivity/specificity of 47.0%/36.0%). In analyses applying machine learning methods to all 187 metabolite concentrations assayed, we find a modest signal in the BLSA with distinct metabolites associated with the preclinical and symptomatic stages of AD, whereas the same methods gave poor classification accuracies in the AGES-RS samples.
  
  
  
  We believe that ours is the largest blood biomarker study of preclinical AD to date. These findings underscore the importance of large-scale independent validation of index findings from biomarker studies with relatively small sample sizes.
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Ramon
authors.initials: R
authors.lastname: Casanova
authors.affiliation: HiThru Analytics LLC, Laurel, MD, USA.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Varma
authors.affiliation: Clinical and Translational Neuroscience Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; School of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Simpson
authors.affiliation: Institute of Pharmaceutical Science, King's College, London, UK.
authors.forename: Min
authors.initials: M
authors.lastname: Kim
authors.affiliation: Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: An
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Santiago
authors.initials: S
authors.lastname: Saldana
authors.affiliation: School of Electrical Engineering and Computer Science, University of Newcastle, Callaghan, Australia.
authors.forename: Carlos
authors.initials: C
authors.lastname: Riveros
authors.affiliation: School of Electrical Engineering and Computer Science, University of Newcastle, Callaghan, Australia.
authors.forename: Pablo
authors.initials: P
authors.lastname: Moscato
authors.affiliation: Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Griswold
authors.affiliation: BIOCRATES Life Sciences AG, Innsbruck, Austria.
authors.forename: Denise
authors.initials: D
authors.lastname: Sonntag
authors.affiliation: BIOCRATES Life Sciences AG, Innsbruck, Austria.
authors.forename: Judith
authors.initials: J
authors.lastname: Wahrheit
authors.affiliation: BIOCRATES Life Sciences AG, Innsbruck, Austria.
authors.forename: Kristaps
authors.initials: K
authors.lastname: Klavins
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Palmi V
authors.initials: PV
authors.lastname: Jonsson
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.
authors.forename: Gudny
authors.initials: G
authors.lastname: Eiriksdottir
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Icelandic Heart Association, Kopavogur, Iceland.
authors.forename: Thor
authors.initials: T
authors.lastname: Aspelund
authors.affiliation: Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, MD, USA.
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Icelandic Heart Association, Kopavogur, Iceland.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Institute of Pharmaceutical Science, King's College, London, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Legido Quigley
authors.affiliation: Clinical and Translational Neuroscience Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. Electronic address: thambisettym@mail.nih.gov.
authors.forename: Madhav
authors.initials: M
authors.lastname: Thambisetty
mesh_terms: D000368:Aged; D000375:Aging; D000544:Alzheimer Disease / Q000097:blood*; D015142:Baltimore; D015415:Biomarkers / Q000097:blood*; D006801:Humans; D008137:Longitudinal Studies; D055432:Metabolomics / Q000379:methods*; D062706:Prodromal Symptoms
chemical_list: D015415:Biomarkers
keywords: Biomarker; Machine learning; Metabolomics; Phospholipids; Preclinical Alzheimer's disease