title: Identifying amyloid pathology-related cerebrospinal fluid biomarkers for Alzheimer's disease in a multicohort study.
abstract: BACKGROUND
  The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1-42) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important.
  
  
  METHODS
  Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP-RBM). Due to underlying heterogeneity and unbalanced sample size, we combined subjects (344 AD and 325 CN) from three cohorts: Alzheimer's Disease Neuroimaging Initiative, Penn Center for Neurodegenerative Disease Research of the University of Pennsylvania, and Knight Alzheimer's Disease Research Center at Washington University in St. Louis. We focused on samples whose cognitive and amyloid status was consistent. We performed linear regression (accounted for age, gender, number of APOE e4 alleles, and cohort variable) to identify amyloid-related proteins for symptomatic AD subjects in this largest ever CSF-based MAP-RBM study. ANOVA and Tukey's test were used to evaluate if these proteins were related to cognitive impairment changes as measured by mini-mental state examination (MMSE).
  
  
  RESULTS
  Seven proteins were significantly associated with Aβ1-42levels in the combined cohort (false discovery rate adjustedP< .05), of which lipoprotein a (Lp(a)), prolactin (PRL), resistin, and vascular endothelial growth factor (VEGF) have consistent direction of associations across every individual cohort. VEGF was strongly associated with MMSE scores, followed by pancreatic polypeptide and immunoglobulin A (IgA), suggesting they may be related to staging of AD.
  
  
  CONCLUSIONS
  Lp(a), PRL, IgA, and tissue factor/thromboplastin have never been reported for AD diagnosis in previous individual CSF-based MAP-RBM studies. Although some of our reported analytes are related to AD pathophysiology, others' roles in symptomatic AD samples worth further explorations.
authors.affiliation: Department of Pathology & Laboratory Medicine, Institute on Aging, Institute for Biomedical Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Yuk Yee
authors.initials: YY
authors.lastname: Leung
authors.affiliation: Department of Pathology & Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, Philadelphia, PA, USA.
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.affiliation: Department of Pathology & Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Nefedov
authors.affiliation: Department of Electrical and Computer Engineering, Rowan University, Glassboro, NJ, USA.
authors.forename: Robi
authors.initials: R
authors.lastname: Polikar
authors.affiliation: Department of Quantitative Science, Janssen Research & Development, LLC, Titusville, NJ, USA.
authors.forename: Nandini
authors.initials: N
authors.lastname: Raghavan
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Sharon X
authors.initials: SX
authors.lastname: Xie
authors.affiliation: Department of Neuroscience, Janssen Research & Development, LLC, Titusville, NJ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Farnum
authors.affiliation: Department of Neuroscience, Janssen Research & Development, LLC, Titusville, NJ, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Schultz
authors.affiliation: Department of Pathology & Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, Philadelphia, PA, USA.
authors.forename: Young
authors.initials: Y
authors.lastname: Baek
authors.affiliation: Department of Pathology & Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, Philadelphia, PA, USA.
authors.forename: Vivianna V
authors.initials: VV
authors.lastname: Deerlin
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Hu
authors.affiliation: Department of Neurology, Knight Alzheimer's Disease Research Center, Hope Center for Neurodegenerative Disorders, Washington University, St Louis, MO, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: Department of Neurology, Knight Alzheimer's Disease Research Center, Hope Center for Neurodegenerative Disorders, Washington University, St Louis, MO, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.affiliation: Department of Pathology and Immunology, Division of Neuropathology, Knight Alzheimer Disease Research Center, Hope Center for Neurological Disorders, Washington University, St Louis, MO, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Perrin
authors.affiliation: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.affiliation: Clinical Biomarkers, Bristol-Meyer Squibb, Hopewell, NJ, USA.
authors.forename: Holly D
authors.initials: HD
authors.lastname: Soares
authors.affiliation: Behavioral Health Service, Philadelphia VA Medical Center, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Mitchel A
authors.initials: MA
authors.lastname: Kling
authors.affiliation: Department of Neuroscience, Janssen Research & Development, LLC, Titusville, NJ, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mailman
authors.affiliation: Department of Neurology, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
authors.affiliation: Department of Neuroscience, Janssen Research & Development, LLC, Titusville, NJ, USA.
authors.forename: Vaibhav A
authors.initials: VA
authors.lastname: Narayan
authors.affiliation: Department of Pathology & Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, Philadelphia, PA, USA.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Pathology & Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, Philadelphia, PA, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.affiliation: Department of Neuroscience, Janssen Research & Development, LLC, Titusville, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.affiliation: Department of Neurology, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Gayle M
authors.initials: GM
authors.lastname: Wittenberg
authors.affiliation: Department of Pathology & Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, Philadelphia, PA, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Department of Pathology & Laboratory Medicine, Institute on Aging, Institute for Biomedical Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Li-San
authors.initials: LS
authors.lastname: Wang
keywords: Alzheimer’s disease; Amyloid beta; Biomarkers; Cerebrospinal fluid; Cognitive impairment; Dementia