title: Phosphorylated tau-Aβ42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer's disease in multiplex immunoassay panels of cerebrospinal fluid.
abstract: BACKGROUND
  Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome.
  
  
  METHODS
  A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aβ42 was used as a continuous trait in these analyses.
  
  
  RESULTS
  The ptau181-Aβ42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aβ42) compared with elderly control subjects with no pathology (low ptau181, high Aβ42). The FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD.
  
  
  CONCLUSIONS
  Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Oscar
authors.initials: O
authors.lastname: Harari
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah.
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.affiliation: Division of Biology & Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Ainscough
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut.
authors.forename: Kelly
authors.initials: K
authors.lastname: Bales
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut.
authors.forename: Eve H
authors.initials: EH
authors.lastname: Pickering
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri; Developmental Biology, Washington University School of Medicine, St. Louis, Missouri; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri; Department of Neurology, Washington University School of Medicine, St. Louis, Missouri; Department of Genetics, Washington University School of Medicine, St. Louis, Missouri; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri. Electronic address: goatea@psychiatry.wustl.edu.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D015331:Cohort Studies; D018450:Disease Progression; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins / Q000134:cerebrospinal fluid; D005260:Female; D006801:Humans; D007118:Immunoassay / Q000379:methods; D019746:Intramolecular Oxidoreductases / Q000134:cerebrospinal fluid; D053208:Kaplan-Meier Estimate; D008263:Macrophage Migration-Inhibitory Factors / Q000134:cerebrospinal fluid; D008297:Male; D015999:Multivariate Analysis; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000134:cerebrospinal fluid; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; C493408:FABP3 protein, human; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; C054369:MAPT protein, human; D008263:Macrophage Migration-Inhibitory Factors; D010446:Peptide Fragments; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
keywords: Alzheimer’s disease; biomarkers; brain proteome—Rules Based Medicine Discovery Multi-Analyte Profile 1.0; cerebrospinal fluid (CSF); heart-type fatty acid binding protein; ptau-Aβ(42) ratio