Purpose This study aims to evaluate the influence of genetic polymorphisms of CYP2D6, CYP3A5, ABCB1 , and APOE genes and nongenetic factors on steady-state plasma concentrations (Cpss) of donepezil and therapeutic outcomes in Thai patients with Alzheimer’s disease (AD) and vascular dementia (VAD). Patients and methods Eighty-five dementia patients who received donepezil for at least six months were recruited. CYP2D6, CYP3A5, ABCB1 , and APOE polymorphisms were genotyped. Cpss of donepezil was measured. Association of genetic and non-genetic factors with Cpss and clinical outcomes of donepezil (cognitive function as measured by the Thai Mental State Examination score; TMSE) were determined by using univariate and multivariate analysis. Results Both univariate and multiple linear regression analysis indicated that only CYP2D6*10 allele was associated with higher Cpss ( p -value =0.029 and B =0.478, p -value =0.032, respectively) that might influence the clinical outcomes of donepezil. ie, TMSE ( p -value =0.010 and B =4.527, p -value =0.001) and ΔTMSE ( p -value =0.023 and B =4.107, p -value =0.002), especially in patients with AD. Interestingly, concomitant use of memantine was found to be associated with increased Cpss of donepezil ( p -value =0.007 and B =0.511, p -value =0.014). Whereas, co-medication with antidepressant drugs attenuated clinical responses in patients with AD (TMSE: B =−2.719, p -value =0.013 and ΔTMSE: B =−2.348, p -value =0.028). Age was a significant predictor of donepezil response in VAD patients. No significant association of CYP3A5*3, ABCB1 3435C>T or ABCB1 1236C>T, and APOE ε4 genotypes with Cpss or clinical outcomes of donepezil was found in this study. Conclusion Our results suggests that CYP2D6*10 strongly influences Cpss and there is a trend toward better outcomes of donepezil in patients with AD. Nongenetic factors including concomitant drugs treatment might alter Cpss of donepezil or clinical outcomes.

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