Scacchi Renato, Gambina Giuseppe, Broggio Elisabetta, Corbo Rosa Maria
CNR Institute of Molecular Biology and Pathology, c/o Department of Biology and Biotechnology, Sapienza University, Rome, Italy.
Int J Geriatr Psychiatry. 2014 Jun;29(6):610-5. doi: 10.1002/gps.4043. Epub 2013 Oct 22.
Many factors could be responsible for the different response to treatment with the cholinesterase inhibitors (ChEIs) donepezil and rivastigmine in Alzheimer's disease (AD) patients. Sex and the variants of the estrogen receptor α (ESR1) gene are reported to modulate AD susceptibility or the course of the disease. The aim of the present study was to verify whether patient's sex and ESR1 genotype could influence the response to ChEI treatment, as there is evidence that estrogens affect cholinergic system functioning.
Two ESR1 intronic polymorphisms (PvuII, rs2234693; XbaI, rs9340799) were examined in 184 AD patients: 157 were receiving treatment with donepezil or rivastigmine and 27 were receiving no treatment. Cognitive status was assessed using the mini mental state examination at four time points (1, 3, 9, and 15 months into therapy).
Among the patients under treatment with either ChEI, the women responded more markedly than the men. As compared with the untreated patients, the effects of treatment were statistically significant for both donepezil and rivastigmine. A significant effect of ESR1 genotypes was observed for the donepezil-treated patients, among which those carrying at least one copy of P and X alleles showed a significantly lower cognitive decline than the noncarriers.
The present data seem to confirm a sex-related influence on treatment, as the women seemed to be more sensitive to therapy and to have experienced less cognitive decline. ESR1 may be another gene contributing to interindividual variability in response to treatment with ChEIs.
阿尔茨海默病（AD）患者对胆碱酯酶抑制剂（ChEIs）多奈哌齐和卡巴拉汀治疗反应不同的原因可能有多种。据报道，性别和雌激素受体α（ESR1）基因的变异可调节AD易感性或疾病进程。本研究的目的是验证患者性别和ESR1基因型是否会影响ChEI治疗反应，因为有证据表明雌激素会影响胆碱能系统功能。
对184例AD患者检测了两个ESR1内含子多态性（PvuII，rs2234693；XbaI，rs9340799）：157例接受多奈哌齐或卡巴拉汀治疗，27例未接受治疗。在治疗的四个时间点（治疗1、3、9和15个月）使用简易精神状态检查表评估认知状态。
在接受任何一种ChEI治疗的患者中，女性的反应比男性更明显。与未治疗的患者相比，多奈哌齐和卡巴拉汀治疗的效果均具有统计学意义。在接受多奈哌齐治疗的患者中观察到ESR1基因型有显著影响，其中携带至少一份P和X等位基因拷贝的患者认知下降明显低于非携带者。
目前的数据似乎证实了治疗存在性别相关影响，因为女性似乎对治疗更敏感，认知下降更少。ESR1可能是另一个导致ChEIs治疗个体反应差异的基因。
