title: Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease.
abstract: BACKGROUND
  Given the slow and variable clinical course of Alzheimer disease, very large and extended clinical trials are needed to identify a beneficial clinical effect of disease-modifying treatments. Therefore, biomarkers are essential to prove that an anti-β-amyloid (Aβ) drug candidate affects both Aβ metabolism and plaque load as well as downstream pathogenic mechanisms.
  
  
  OBJECTIVE
  To evaluate the effect of the anti-Aβ monoclonal antibody bapineuzumab on cerebrospinal fluid (CSF) biomarkers reflecting Aβ homeostasis, neuronal degeneration, and tau-related pathology in patients with Alzheimer disease.
  
  
  METHODS
  Two phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trials of 12-month duration.
  
  
  METHODS
  Academic centers in the United States (Study 201) and England and Finland (Study 202).
  
  
  METHODS
  Forty-six patients with mild to moderate Alzheimer disease.
  
  
  METHODS
  Patients received either placebo (n = 19) or bapineuzumab (n = 27) in 3 or 4 ascending dose groups.
  
  
  METHODS
  Changes between end of study and baseline in the exploratory CSF biomarkers Aβ1-42, AβX-42, AβX-40; total tau (T-tau); and phosphorylated tau (P-tau).
  
  
  RESULTS
  Within the bapineuzumab group, a decrease at end of study compared with baseline was found both for CSF T-tau (-72.3 pg/mL) and P-tau (-9.9 pg/mL). When comparing the treatment and placebo groups, this difference was statistically significant for P-tau (P = .03), while a similar trend for a decrease was found for T-tau (P = .09). No clear-cut differences were observed for CSF Aβ.
  
  
  CONCLUSIONS
  To our knowledge, this study is the first to show that passive Aβ immunotherapy with bapineuzumab results in decreases in CSF T-tau and P-tau, which may indicate downstream effects on the degenerative process. Cerebrospinal fluid biomarkers may be useful to monitor the effects of novel disease-modifying anti-Aβ drugs in clinical trials. TRIAL REGISTRATIONS clinicaltrials.gov Identifier: NCT00112073, EudraCT Identifier: 2004-004120-12, and isrctn.org Identifier: ISRCTN17517446.
authors.affiliation: Clinical Neurochemistry Laboratory, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden. kaj.blennow@neuro.gu.se
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.forename: Juha O
authors.initials: JO
authors.lastname: Rinne
authors.forename: Stephen
authors.initials: S
authors.lastname: Salloway
authors.forename: Jenny
authors.initials: J
authors.lastname: Wei
authors.forename: Ronald
authors.initials: R
authors.lastname: Black
authors.forename: Michael
authors.initials: M
authors.lastname: Grundman
authors.forename: Enchi
authors.initials: E
authors.lastname: Liu
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000188:drug therapy* / Q000453:epidemiology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D015331:Cohort Studies; D004311:Double-Blind Method; D004739:England / Q000453:epidemiology; D005260:Female; D005387:Finland / Q000453:epidemiology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C545458:bapineuzumab