title: BCHE and CYP2D6 genetic variation in Alzheimer's disease patients treated with cholinesterase inhibitors.
abstract: OBJECTIVE
  Cholinesterase inhibitors are commonly prescribed to patients with Alzheimer's disease (AD) to enhance cholinergic neurotransmission. Differential response to these treatments has been observed, and claims have been made that individual genetic variants may influence the pharmacokinetic and pharmacodynamic properties of these drugs. Here we assess the effects of genetic variation at two loci involved in the activity of cholinesterase inhibitors on longitudinal clinical change in AD patients being treated with donepezil, galantamine, and rivastigmine.
  
  
  METHODS
  This was an open study in which 171 Italian AD patients treated with donepezil (n = 92), galantamine (n = 33), or rivastigmine (n = 46) were enrolled. Response to treatment was quantified by grading the patient's cognitive state (Mini-Mental State Examination) and the patient's ability to perform normal daily activities (Activities of Daily Living, Instrumental Activities of Daily Living) at baseline and after 6 and 12 months of treatment. Genetic variation was comprehensively characterized and analyzed at two loci: CYP2D6, which is involved in donepezil and galantamine metabolism, and BCHE, which codes for an enzyme (butyrylcholinesterase) which is both target and metabolizer of rivastigmine. APOE (coding for apolipoprotein E), which is associated with the risk of AD and inefficacy of specific AD treatments, was genotyped to control for patient stratification. The influence of the CYP2D6 and BCHE genotype on clinical changes after 12 months was evaluated by several tests of association.
  
  
  RESULTS
  After 1 year of treatment, 29, 12, and 12 of the patients receiving donepezil, galantamine, and rivastigmine, respectively, showed a cognitive decrement, while eight patients interrupted the therapy before 12 months of treatment. No significant differences between the three treatments were observed in terms of response and tolerability. Non-responders show a higher proportion of BCHE and CYP2D6 mutated alleles, but genetic variation at the two loci was not a reliable predictor of clinical changes in AD patients treated with cholinesterase inhibitors.
  
  
  CONCLUSIONS
  Individualized therapy based on CYP2D6 and BCHE genotypes is unlikely to be beneficial for treating Alzheimer's disease patients in routine clinical practice.
authors.affiliation: Department of Biology and Evolution, University of Ferrara, via Borsari 46, 44100 Ferrara, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Chianella
authors.forename: Daniela
authors.initials: D
authors.lastname: Gragnaniello
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Maisano Delser
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Visentini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Sette
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Tola
authors.forename: Guido
authors.initials: G
authors.lastname: Barbujani
authors.forename: Silvia
authors.initials: S
authors.lastname: Fuselli
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000235:genetics; D002091:Butyrylcholinesterase / Q000235:genetics*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D000077265:Donepezil; D005260:Female; D005702:Galantamine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D048448:Phenylcarbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068836:Rivastigmine; D016896:Treatment Outcome
chemical_list: D001057:Apolipoproteins E; D002800:Cholinesterase Inhibitors; D007189:Indans; D048448:Phenylcarbamates; D010880:Piperidines; D005702:Galantamine; D000077265:Donepezil; D019389:Cytochrome P-450 CYP2D6; D002091:Butyrylcholinesterase; D000068836:Rivastigmine