title: The effect of galantamine on brain atrophy rate in subjects with mild cognitive impairment is modified by apolipoprotein E genotype: post-hoc analysis of data from a randomized controlled trial.
abstract: BACKGROUND
  The aim of this investigation was to assess the effect of galantamine, an acetylcholinesterase inhibitor and allosteric modulator of nicotinic receptors, on brain atrophy in individuals with mild cognitive impairment (MCI), and to assess effect modification by apolipoprotein E (APOE) genotype.
  
  
  METHODS
  We used data from the Galantamine-International-11 (Gal-Int-11) trial, a 24-month, randomized, double blind, placebo-controlled, flexible-dose (16 to 24 mg daily) study in patients with MCI. Brain magnetic resonance imaging (MRI), including a 3-dimensional T1-weighted gradient echo volumetric sequence, was performed at screening and at 24 months. We recorded whole brain and hippocampal volumes, and calculated annual atrophy rates. Linear regression analysis was used to calculate adjusted mean differences in the rate of whole brain and hippocampal atrophy, between MCI patients treated with galantamine and with placebo. Additionally, we performed stratified analyses according to APOE genotype.
  
  
  RESULTS
  Data from 364 MCI patients with 24-month MRI data (galantamine, n = 176; placebo, n = 188) were included in the volumetric analysis. Subjects treated with galantamine demonstrated a lower rate of whole brain atrophy compared to those treated with placebo (adjusted mean difference 0.18% per year (95% confidence interval (CI) 0.04; 0.30)). Stratified analyses according to APOE genotype, showed that this effect was confined to patients who carried an APOE ϵ4 allele (adjusted mean difference 0.28% per year (95% CI 0.07; 0.50)). Rates of hippocampal atrophy did not differ significantly between study groups.
  
  
  CONCLUSIONS
  Patients with MCI who were treated with galantamine demonstrated a lower rate of whole brain atrophy, but not of hippocampal atrophy, over a 24-month treatment period, compared to those treated with placebo. This protective effect of galantamine on whole brain atrophy rate in MCI was only present in APOE ϵ4 carriers.
authors.affiliation: Alzheimer Centre, Department of Neurology, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, the Netherlands ; Alzheimer Research Center, Gebouw Cronenburg, Cronenburg 75, 1081 GM Amsterdam, the Netherlands.
authors.forename: Niels D
authors.initials: ND
authors.lastname: Prins
authors.affiliation: Alzheimer Centre, Department of Neurology, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, the Netherlands ; Alzheimer Research Center, Gebouw Cronenburg, Cronenburg 75, 1081 GM Amsterdam, the Netherlands.
authors.forename: Wiesje A
authors.initials: WA
authors.lastname: van der Flier
authors.affiliation: Department of Epidemiology & Biostatistics, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, the Netherlands.
authors.forename: Dirk L
authors.initials: DL
authors.lastname: Knol
authors.affiliation: Dementia Research Centre (N.C.F.), Department of Neurodegenerative Disease, Institute of Neurology, University College London, 8-11 Queen Square, London WC1N 3BG, UK.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.affiliation: Janssen Alzheimer Immunotherapy Research and Development, 700 Gateway Blvd, South San Francisco, CA 94080, USA.
authors.forename: H Robert
authors.initials: HR
authors.lastname: Brashear
authors.affiliation: Janssen Research and Development, LLC Johnson and Johnson Innovation, One Cambridge Center, 7th Floor, Cambridge, MA 02142, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Nye
authors.affiliation: Alzheimer Centre, Department of Neurology, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, the Netherlands ; Department of Radiology, Image Analysis Centre, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, the Netherlands.
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: Alzheimer Centre, Department of Neurology, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, the Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens