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根据-ϵ4等位基因及阿尔茨海默病中的插入/缺失多态性研究血管紧张素调节剂的药物遗传学。

Pharmacogenetics of angiotensin modulators according to -ϵ4 alleles and the insertion/deletion polymorphism in Alzheimer's disease.

作者信息

Oliveira Fabricio Ferreira de, Almeida Sandro Soares de, Chen Elizabeth Suchi, Smith Marilia Cardoso, Bertolucci Paulo Henrique Ferreira

机构信息

Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.

Department of Biophysics, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.

出版信息

Acta Neuropsychiatr. 2023 Dec;35(6):346-361. doi: 10.1017/neu.2023.38. Epub 2023 Aug 22.

Abstract

OBJECTIVE

In Alzheimer's disease (AD), angiotensin II receptor blockers (ARBs) could reduce cerebrovascular dysfunction, while angiotensin-converting enzyme inhibitors (ACEis) might increase brain amyloid-β by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-β-degrading enzyme. However, ACEis could benefit patients with AD by reducing the amyloidogenic processing of the amyloid precursor protein, by central cholinergic and anti-inflammatory mechanisms, and by peripheral modulation of glucose homeostasis. We aimed to investigate whether the insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering apolipoprotein E ()-ϵ4 carrier status and blood pressure response to angiotensin modulators.

METHODS

Consecutive outpatients with late-onset AD were screened with cognitive tests and anthropometric measurements, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic associations were estimated for 1 year, taking -ϵ4 carrier status and genotypes of the insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs.

RESULTS

For 193 patients (67.4% women, 53.4% -ϵ4 carriers), the insertion/deletion polymorphism was in Hardy-Weinberg equilibrium ( = 0.281), while arterial hypertension was prevalent in 80.3% ( = 124 used an ACEi, = 21 used an ARB). ARBs benefitted mostly -ϵ4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted -ϵ4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations.

CONCLUSION

Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies.

摘要

目的

在阿尔茨海默病(AD)中,血管紧张素II受体阻滞剂(ARB)可减轻脑血管功能障碍,而血管紧张素转换酶抑制剂(ACEI)可能通过抑制血管紧张素转换酶1(一种淀粉样β蛋白降解酶)的作用来增加脑淀粉样β蛋白。然而,ACEI可通过减少淀粉样前体蛋白的淀粉样生成过程、通过中枢胆碱能和抗炎机制以及通过外周调节葡萄糖稳态而使AD患者受益。我们旨在研究插入/缺失多态性是否与AD患者的临床变化相关,同时考虑载脂蛋白E(ApoE)-ε4携带者状态以及对血管紧张素调节剂的血压反应。

方法

对连续的晚发性AD门诊患者进行认知测试和人体测量筛查,同时向其照顾者询问功能和照顾者负担评分。考虑ApoE-ε4携带者状态、插入/缺失多态性的基因型以及ACEI或ARB治疗情况,对前瞻性药物遗传学关联进行了1年的评估。

结果

对于193例患者(67.4%为女性,53.4%为ApoE-ε4携带者),插入/缺失多态性处于Hardy-Weinberg平衡(P = 0.281),而动脉高血压在患者中普遍存在(80.3%;共124例使用ACEI,21例使用ARB)。在照顾者负担变化、认知和功能下降方面,ARB对ApoE-ε4携带者大多有益。除了可能的中枢机制外,由于血压控制改善,ACEI对ApoE-ε4非携带者的认知和功能下降有益。插入/缺失多态性导致对血管紧张素调节剂在神经学结局和血压变化方面的反应存在差异。

结论

血管紧张素调节剂可能是AD的疾病修饰剂,而在临床研究中建议对样本进行基因分层。

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