BCHE and CYP2D6 genetic variation in Alzheimer’s disease patients treated with cholinesterase inhibitors
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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.
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.
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.
Individualized therapy based on CYP2D6 and BCHE genotypes is unlikely to be beneficial for treating Alzheimer’s disease patients in routine clinical practice.
Keywordspharmacogenetics Alzheimer CYP2D6 BCHE cholinesterase inhibitors
We gratefully thank Johanna Sistonen for helping with the CYP2D6 genotyping, Sara Raimondi and Giorgio Bertorelle for useful suggestions on data analysis, and Krisztina Vasarhelyi for language revision.
- 2.Dementia in Europe: Yearbook 2006 (2006). Alzheimer Europe. Available at: http://www.alzheimer-europe.org
- 4.Rabins PV, Blacker D, Rovner BW, Rummans T, Schneider LS, Tariot PN, Blass DM, McIntyre JS, Charles SC, Anzia DJ, Cook IA, Finnerty MT, Johnson BR, Nininger JE, Schneidman B, Summergrad P, Woods SM, Berger J, Cross CD, Brandt HA, Margolis PM, Shemo JP, Blinder BJ, Duncan DL, Barnovitz MA, Carino AJ, Freyberg ZZ, Gray SH, Tonnu T, Kunkle R, Albert AB, Craig TJ, Regier DA, Fochtmann LJ (2007) American Psychiatric Association practice guideline for the treatment of patients with Alzheimer’s disease and other dementias. Second edition. Am J Psychiatry 164:5–56PubMedGoogle Scholar
- 10.Pilotto A, Franceschi M, D’Onofrio G, Bizzarro A, Mangialasche F, Cascavilla L, Paris F, Matera MG, Pilotto A, Daniele A, Mecocci P, Masullo C, Dallapiccola B, Seripa D (2009) Effect of a CYP2D6 polymorphism on the efficacy of donepezil in patients with Alzheimer disease. Neurology 73:761–767PubMedCrossRefGoogle Scholar
- 11.Seripa D, Bizzarro A, Pilotto A, D’Onofrio G, Vecchione G, Gallo AP, Cascavilla L, Paris F, Grandone E, Mecocci P, Santini SA, Masullo C (2011) Role of cytochrome P4502D6 functional polymorphisms in the efficacy of donepezil in patients with Alzheimer’s disease. Pharmacogenet Genomics 21(4):225–320Google Scholar
- 15.Flockhart D (2007) Drug interactions: cytochrome P450 drug interaction table. Available at: http://medicine.iupui.edu/clinpharm/ddis/table.asp. Indiana University School of Medicine, version 5.0 released on 12 Jan 2009
- 18.Schipper HM (2011) Apolipoprotein E: implications for AD neurobiology, epidemiology and risk assessment. Neurobiol Aging 32(5):778–790Google Scholar
- 22.Excoffier L, Laval G, Schneider S (2005) Arlequin ver. 3.0: An integrated software package for population genetics data analysis. Evol Bioinform Online 1:47–50Google Scholar
- 27.StatSoft (2005) STATISTICA ver. 7.1. Available at: StatSoft.Italia_srl
- 29.Patterson CE, Todd SA, Passmore AP (2010) Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer’s disease. Pharmacogenomics J. doi: 10.1038/tpj.2010.61
- 33.O’Brien KK, Saxby BK, Ballard CG, Grace J, Harrington F, Ford GA, O’Brien JT, Swan AG, Fairbairn AF, Wesnes K, del Ser T, Edwardson JA, Morris CM, McKeith IG (2003) Regulation of attention and response to therapy in dementia by butyrylcholinesterase. Pharmacogenetics 13:231–239PubMedCrossRefGoogle Scholar
- 41.Poirier J, Delisle MC, Quirion R, Aubert I, Farlow M, Lahiri D, Hui S, Bertrand P, Nalbantoglu J, Gilfix BM, Gauthier S (1995) Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc Natl Acad Sci USA 92:12260–12264PubMedCrossRefGoogle Scholar