Influence of polymorphisms and nongenetic factors on donepezil treatment in patients with Alzheimer's disease and vascular dementia.

Purpose: This study aims to evaluate the influence of genetic polymorphisms of , and 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. , and 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 allele was associated with higher Cpss (-value =0.029 and B =0.478, -value =0.032, respectively) that might influence the clinical outcomes of donepezil. ie, TMSE (-value =0.010 and B =4.527, -value =0.001) and ΔTMSE (-value =0.023 and B =4.107, -value =0.002), especially in patients with AD. Interestingly, concomitant use of memantine was found to be associated with increased Cpss of donepezil (-value =0.007 and B =0.511, -value =0.014). Whereas, co-medication with antidepressant drugs attenuated clinical responses in patients with AD (TMSE: B =-2.719, -value =0.013 and ΔTMSE: B =-2.348, -value =0.028). Age was a significant predictor of donepezil response in VAD patients. No significant association of 3435C>T or 1236C>T, and genotypes with Cpss or clinical outcomes of donepezil was found in this study.

Conclusion: Our results suggests that 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.