title: Variability of CSF Alzheimer's disease biomarkers: implications for clinical practice.
abstract: BACKGROUND
  Cerebrospinal fluid (CSF) biomarkers are increasingly being used for diagnosis of Alzheimer's disease (AD).
  
  
  OBJECTIVE
  We investigated the influence of CSF intralaboratory and interlaboratory variability on diagnostic CSF-based AD classification of subjects and identified causes of this variation.
  
  
  METHODS
  We measured CSF amyloid-β (Aβ) 1-42, total tau (t-tau), and phosphorylated tau (p-tau) by INNOTEST enzyme-linked-immunosorbent assays (ELISA) in a memory clinic population (n = 126). Samples were measured twice in a single or two laboratories that served as reference labs for CSF analyses in the Netherlands. Predefined cut-offs were used to classify CSF biomarkers as normal or abnormal/AD pattern.
  
  
  RESULTS
  CSF intralaboratory variability was higher for Aβ1-42 than for t-tau and p-tau. Reanalysis led to a change in biomarker classification (normal vs. abnormal) of 26% of the subjects based on Aβ1-42, 10% based on t-tau, and 29% based on p-tau. The changes in absolute biomarker concentrations were paralleled by a similar change in levels of internal control samples between different assay lots. CSF interlaboratory variability was higher for p-tau than for Aβ1-42 and t-tau, and reanalysis led to a change in biomarker classification of 12% of the subjects based on Aβ1-42, 1% based on t-tau, and 22% based on p-tau.
  
  
  CONCLUSIONS
  Intralaboratory and interlaboratory CSF variability frequently led to change in diagnostic CSF-based AD classification for Aβ1-42 and p-tau. Lot-to-lot variation was a major cause of intralaboratory variability. This will have implications for the use of these biomarkers in clinical practice.
authors: Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, the Netherlands.
authors: Stephanie J B
authors: SJ
authors: Vos
authors: Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, the Netherlands; Alzheimer center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors: Pieter Jelle
authors: PJ
authors: Visser
authors: Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, the Netherlands.
authors: Frans
authors: F
authors: Verhey
authors: Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, the Netherlands.
authors: Pauline
authors: P
authors: Aalten
authors: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.
authors: Dirk
authors: D
authors: Knol
authors: Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, the Netherlands.
authors: Inez
authors: I
authors: Ramakers
authors: Alzheimer center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors: Philip
authors: P
authors: Scheltens
authors: Department of Geriatric Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen and Radboud Alzheimer Centre, Nijmegen, The Netherlands.
authors: Marcel G M Olde
authors: MG
authors: Rikkert
authors: Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen and Radboud Alzheimer Centre, Nijmegen, The Netherlands; Department of Neurology and Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Marcel M
authors: MM
authors: Verbeek
authors: Department of Clinical Chemistry, Neurological Laboratory, VU University Medical Center, Amsterdam, The Netherlands.
authors: Charlotte E
authors: CE
authors: Teunissen
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D006801:Humans; D015203:Reproducibility of Results; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D016875:tau Proteins