Effect of a CYP2D6 polymorphism on the efficacy of donepezil in patients with Alzheimer disease.
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.
Pilotto
Alberto
A
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@operapadrepio.it
Franceschi
M
M
D'Onofrio
G
G
Bizzarro
A
A
Mangialasche
F
F
Cascavilla
L
L
Paris
F
F
Matera
M G
MG
Pilotto
Andrea
A
Daniele
A
A
Mecocci
P
P
Masullo
C
C
Dallapiccola
B
B
Seripa
D
D
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D000077265:Donepezil; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007189:Indans / Q000627:therapeutic use*; D008297:Male; D010880:Piperidines / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies
D001057:Apolipoproteins E; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D019389:Cytochrome P-450 CYP2D6