title: CSF complement 3 and factor H are staging biomarkers in Alzheimer's disease.
abstract: BACKGROUND
  CSF levels of established Alzheimer's disease (AD) biomarkers remain stable despite disease progression, and non-amyloid non-tau biomarkers have the potential of informing disease stage and progression. We previously identified complement 3 (C3) to be decreased in AD dementia, but this change was not found by others in earlier AD stages. We hypothesized that levels of C3 and associated factor H (FH) can potentially distinguish between mild cognitive impairment (MCI) and dementia stages of AD, but we also found their levels to be influenced by age and disease status.
  
  
  RESULTS
  We developed a biochemical/bioinformatics pipeline to optimize the handling of complex interactions between variables in validating biochemical markers of disease. We used data from the Alzheimer's Disease Neuro-imaging Initiative (ADNI, n = 230) to build parallel machine learning models, and objectively tested the models in a test cohort (n = 73) of MCI and mild AD patients independently recruited from Emory University. Whereas models incorporating age, gender, APOE ε4 status, and CSF amyloid and tau levels failed to reliably distinguish between MCI and mild AD in ADNI, introduction of CSF C3 and FH levels reproducibly improved the distinction between the two AD stages in ADNI (p < 0.05) and the Emory cohort (p = 0.014). Within each AD stage, the final model also distinguished between fast vs. slower decliners (p < 0.001 for MCI, p = 0.007 for mild AD), with lower C3 and FH levels associated with more advanced disease and faster progression.
  
  
  CONCLUSIONS
  We propose that CSF C3 and FH alterations may reflect stage-associated biomarker changes in AD, and can complement clinician diagnosis in diagnosing and staging AD using the publically available ADNI database as reference.
authors.affiliation: Department of Neurology, Emory University School of Medicine, 615 Michael Street, 505 F, Atlanta, GA, 30322, USA. william.hu@emory.edu.|Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, USA. william.hu@emory.edu.|Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA. william.hu@emory.edu.|School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA, USA. william.hu@emory.edu.
authors.forename: William T
authors.initials: WT
authors.lastname: Hu
authors.affiliation: Department of Neurology, Emory University School of Medicine, 615 Michael Street, 505 F, Atlanta, GA, 30322, USA.|Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Watts
authors.affiliation: Department of Neurology, Emory University School of Medicine, 615 Michael Street, 505 F, Atlanta, GA, 30322, USA.|School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Prashant
authors.initials: P
authors.lastname: Tailor
authors.affiliation: Department of Neurology, Emory University School of Medicine, 615 Michael Street, 505 F, Atlanta, GA, 30322, USA.|Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Trung P
authors.initials: TP
authors.lastname: Nguyen
authors.affiliation: Department of Neurology, Emory University School of Medicine, 615 Michael Street, 505 F, Atlanta, GA, 30322, USA.|Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Howell
authors.affiliation: Department of Neurology, Emory University School of Medicine, 615 Michael Street, 505 F, Atlanta, GA, 30322, USA.|Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Raven C
authors.initials: RC
authors.lastname: Lee
authors.affiliation: Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, USA.|Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Seyfried
authors.affiliation: Department of Neurology, Emory University School of Medicine, 615 Michael Street, 505 F, Atlanta, GA, 30322, USA.|Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, USA.|Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Marla
authors.initials: M
authors.lastname: Gearing
authors.affiliation: Department of Neurology, Emory University School of Medicine, 615 Michael Street, 505 F, Atlanta, GA, 30322, USA.|Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, USA.|Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Chadwick M
authors.initials: CM
authors.lastname: Hales
authors.affiliation: Department of Neurology, Emory University School of Medicine, 615 Michael Street, 505 F, Atlanta, GA, 30322, USA.|Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, USA.|Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
authors.affiliation: Department of Neurology, Emory University School of Medicine, 615 Michael Street, 505 F, Atlanta, GA, 30322, USA.|Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, USA.|Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Lah
authors.affiliation: School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Eva K
authors.initials: EK
authors.lastname: Lee
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid; D015331:Cohort Studies; D003176:Complement C3 / Q000134:cerebrospinal fluid*; D017242:Complement Factor H / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D000069550:Machine Learning; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D003176:Complement C3; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D017242:Complement Factor H