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NEUROLOGY 2009;73:761-767
© 2009 American Academy of Neurology

Effect of a CYP2D6 polymorphism on the efficacy of donepezil in patients with Alzheimer disease

Alberto Pilotto, MD, M. Franceschi, MD, G. D’Onofrio, PsyD, A. Bizzarro, MD, F. Mangialasche, MD, L. Cascavilla, MD, F. Paris, MD, M. G. Matera, BiolD, Andrea Pilotto, MD, A. Daniele, MD, P. Mecocci, MD, C. Masullo, MD, B. Dallapiccola, MD and D. Seripa, BiolD

From the Geriatric Unit and Gerontology-Geriatrics Research Laboratory (Alberto Pilotto, M.F., G.D., L.C., F.P., M.G.M., D.S.), Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza," San Giovanni Rotondo (FG); Department of Neurology (A.B., A.D., C.M.), Catholic University School of Medicine, Rome; Institute of Gerontology and Geriatrics (F.M., P.M.), Department of Clinical and Experimental Medicine, University of Perugia; University of Padova (Andrea Pilotto); IRCCS "Casa Sollievo della Sofferenza" (B.D.), San Giovanni Rotondo (FG); "Casa Sollievo della Sofferenza"–"Mendel Institute" (B.D.), Rome; and Department of Experimental Medicine and Pathology (B.D.), University "La Sapienza," Rome, Italy.

Address correspondence and reprint requests to Dr. Alberto Pilotto, Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini 1, 71013 San Giovanni Rotondo (FG), Italy alberto.pilotto{at}operapadrepio.it

Objective: To evaluate the influence of the single nucleotide polymorphism rs1080985 in the cytochrome P450 2D6 (CYP2D6) gene on the efficacy of donepezil in patients with mild to moderate Alzheimer disease (AD).

Methods: This was a multicenter, prospective cohort study of 127 white patients with AD according to the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association Work Group criteria. Patients were treated with donepezil 5–10 mg/daily for 6 months. Cognitive and functional statuses were evaluated at baseline and at 6-month follow-up. Response to therapy was defined according to the National Institute for Health and Clinical Excellence criteria. Compliance and drug-related adverse events were also evaluated. The analyses identifying the CYP2D6 and APOE polymorphisms were performed in blinded fashion.

Results: At 6-month follow-up, 69 of 115 patients (60%) were responders and 46 patients (40%) were nonresponders to donepezil treatment. A significantly higher frequency of patients with the G allele of rs1080985 was found in nonresponders than in responders (58.7% vs 34.8%, p = 0.013). Logistic regression analysis adjusted for age, sex, Mini-Mental State Examination score at baseline, and APOE demonstrated that patients with the G allele had a significantly higher risk of poor response to donepezil treatment (odds ratio 3.431, 95% confidence interval 1.490–7.901).

Conclusions: The single nucleotide polymorphism rs1080985 in the CYP2D6 gene may influence the clinical efficacy of donepezil in patients with mild to moderate Alzheimer disease (AD). The analysis of CYP2D6 genotypes may be useful in identifying subgroups of patients with AD who have different clinical responses to donepezil.

Abbreviations: AChE = acetylcholinesterase; AD = Alzheimer disease; ADAS-Cog = Alzheimer’s Disease Assessment Scale–Cognitive Section; ADL = activities of daily living; bp = base pair; CDR = Clinical Dementia Rating Scale; CI = confidence interval; CYP = cytochrome P450; DM = dextromethorphan; DX = dextrorphan; HW = Hardy–Weinberg; IADL = Instrumental Activities of Daily Living; ICD-9 = International Classification of Diseases, 9th Revision; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; NICE = National Institute for Health and Clinical Excellence; NINCDS-ADRDA = National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association Work Group; OR = odds ratio; SNP = single nucleotide polymorphism.

Supported by "Ministero della Salute," IRCCS Research Program, Ricerca Corrente 2006–2008, Linea n. 2 "Malattie di rilevanza sociale."

Disclosure: Author disclosures are provided at the end of the article.

Received March 4, 2009. Accepted in final form June 9, 2009.






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