Effect of the CYP2D6 and APOE Polymorphisms on the Efficacy of Donepezil in Patients with Alzheimer's Disease: A Systematic Review and Meta-Analysis.
Differential responses to donepezil treatment in patients with Alzheimer's disease (AD) have been observed in clinical practice. It remains controversial whether, and to what extent, individual variation in the genes responsible for drug metabolism (CYP2D6) or those associated with AD pathogenesis (APOE) modulate the response to donepezil treatment.



The aim of this study was to better understand the potential link between donepezil treatment response and CYP2D6 or APOE polymorphisms.



We performed a meta-analysis based on data collected from 1266 donepezil-treated AD patients, and evaluated the association of CYP2D6 or APOE polymorphisms with treatment effectiveness.



No significant difference was observed in the responder rate of donepezil treatment between the normal function CYP2D6 alleles group and the decreased/non-functional group [odds ratio (OR) 1.34, 95 % confidence interval (CI) 0.5-3.58; p = 0.56]. However, compared with the increased function CYP2D6 alleles group, the normal function group had a better response to donepezil treatment (OR 1.52, 95 % CI 1.14-2.03; p = 0.005). For the specific CYP2D6 single nucleotide polymorphism rs1080985, patients who carried the G allele had a significantly higher risk of poor response to donepezil treatment. After adjusting the data based on APOE genotype, it was observed that only individuals bearing both the APOE-ε4 allele and the rs1080985-G allele showed a significant increase in the frequency of treatment non-response (OR 1.73, 95 % CI 1.07-2.09; p = 0.03). No independent effect of APOE polymorphism on donepezil clinical responses was found (OR 1.08, 95 % CI 0.85-1.38; p = 0.53). Lastly, in a subgroup analysis based on ethnicity, all results remained consistent.



The CYP2D6 genotype may be potentially effective for predicting the response to donepezil treatment in AD patients.
Department of Neurology, Xiangya Hospital, Central South University, 87# Xiangya Rd, Changsha, 410008, China.
Tingting
T
Xiao
Department of Neurology, Xiangya Hospital, Central South University, 87# Xiangya Rd, Changsha, 410008, China.
Bin
B
Jiao
Department of Neurology, Xiangya Hospital, Central South University, 87# Xiangya Rd, Changsha, 410008, China.
Weiwei
W
Zhang
Department of Neurology, Xiangya Hospital, Central South University, 87# Xiangya Rd, Changsha, 410008, China.|State Key Laboratory of Medical Genetics, Changsha, China.|Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China.
Beisha
B
Tang
Department of Neurology, Xiangya Hospital, Central South University, 87# Xiangya Rd, Changsha, 410008, China. shenlu2505@126.com.|State Key Laboratory of Medical Genetics, Changsha, China. shenlu2505@126.com.|Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China. shenlu2505@126.com.
Lu
L
Shen
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D000077265:Donepezil; D006801:Humans; D007189:Indans / Q000627:therapeutic use*; D018697:Nootropic Agents / Q000627:therapeutic use*; D010597:Pharmacogenetics; D010880:Piperidines / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D001057:Apolipoproteins E; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil; D019389:Cytochrome P-450 CYP2D6