title: CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis.
abstract: BACKGROUND
  Alzheimer's disease biomarkers are important for early diagnosis in routine clinical practice and research. Three core CSF biomarkers for the diagnosis of Alzheimer's disease (Aβ42, T-tau, and P-tau) have been assessed in numerous studies, and several other Alzheimer's disease markers are emerging in the literature. However, there have been no comprehensive meta-analyses of their diagnostic performance. We systematically reviewed the literature for 15 biomarkers in both CSF and blood to assess which of these were most altered in Alzheimer's disease.
  
  
  METHODS
  In this systematic review and meta-analysis, we screened PubMed and Web of Science for articles published between July 1, 1984, and June 30, 2014, about CSF and blood biomarkers reflecting neurodegeneration (T-tau, NFL, NSE, VLP-1, and HFABP), APP metabolism (Aβ42, Aβ40, Aβ38, sAPPα, and sAPPβ), tangle pathology (P-tau), blood-brain-barrier function (albumin ratio), and glial activation (YKL-40, MCP-1, and GFAP). Data were taken from cross-sectional cohort studies as well as from baseline measurements in longitudinal studies with clinical follow-up. Articles were excluded if they did not contain a cohort with Alzheimer's disease and a control cohort, or a cohort with mild cognitive impairment due to Alzheimer's disease and a stable mild cognitive impairment cohort. Data were extracted by ten authors and checked by two for accuracy. For quality assessment, modified QUADAS criteria were used. Biomarker performance was rated by random-effects meta-analysis based on the ratio between biomarker concentration in patients with Alzheimer's disease and controls (fold change) or the ratio between biomarker concentration in those with mild cognitive impariment due to Alzheimer's disease and those with stable mild cognitive impairment who had a follow-up time of at least 2 years and no further cognitive decline.
  
  
  RESULTS
  Of 4521 records identified from PubMed and 624 from Web of Science, 231 articles comprising 15 699 patients with Alzheimer's disease and 13 018 controls were included in this analysis. The core biomarkers differentiated Alzheimer's disease from controls with good performance: CSF T-tau (average ratio 2·54, 95% CI 2·44-2·64, p<0·0001), P-tau (1·88, 1·79-1·97, p<0·0001), and Aβ42 (0·56, 0·55-0·58, p<0·0001). Differentiation between cohorts with mild cognitive impairment due to Alzheimer's disease and those with stable mild cognitive impairment was also strong (average ratio 0·67 for CSF Aβ42, 1·72 for P-tau, and 1·76 for T-tau). Furthermore, CSF NFL (2·35, 1·90-2·91, p<0·0001) and plasma T-tau (1·95, 1·12-3·38, p=0·02) had large effect sizes when differentiating between controls and patients with Alzheimer's disease, whereas those of CSF NSE, VLP-1, HFABP, and YKL-40 were moderate (average ratios 1·28-1·47). Other assessed biomarkers had only marginal effect sizes or did not differentiate between control and patient samples.
  
  
  CONCLUSIONS
  The core CSF biomarkers of neurodegeneration (T-tau, P-tau, and Aβ42), CSF NFL, and plasma T-tau were strongly associated with Alzheimer's disease and the core biomarkers were strongly associated with mild cognitive impairment due to Alzheimer's disease. Emerging CSF biomarkers NSE, VLP-1, HFABP, and YKL-40 were moderately associated with Alzheimer's disease, whereas plasma Aβ42 and Aβ40 were not. Due to their consistency, T-tau, P-tau, Aβ42, and NFL in CSF should be used in clinical practice and clinical research.
  
  
  BACKGROUND
  Swedish Research Council, Swedish State Support for Clinical Research, Alzheimer's Association, Knut and Alice Wallenberg Foundation, Torsten Söderberg Foundation, Alzheimer Foundation (Sweden), European Research Council, and Biomedical Research Forum.
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. Electronic address: bob.olsson@neuro.gu.se.
authors.forename: Bob
authors.initials: B
authors.lastname: Olsson
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: Ronald
authors.initials: R
authors.lastname: Lautner
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Andreasson
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Öhrfelt
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Biomedical Sciences, University of Antwerp, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Bjerke
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: Mikko
authors.initials: M
authors.lastname: Hölttä
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Rosén
authors.affiliation: Department of Radiation Physics, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Olsson
authors.affiliation: Alzforum, Cambridge, MA, USA.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Strobel
authors.affiliation: Alzforum, Cambridge, MA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wu
authors.affiliation: Alzforum, Cambridge, MA, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Dakin
authors.affiliation: Unit for Health Metrics, Department of Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Max
authors.initials: M
authors.lastname: Petzold
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
mesh_terms: D000544:Alzheimer Disease / Q000097:blood* / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D006801:Humans
chemical_list: D015415:Biomarkers