最近一项尸检研究表明，使用血管紧张素受体拮抗剂（ARB）类的降压药与脑内阿尔茨海默病样病理出现少相关。研究者发现采用CERAD制定的神经病理学标准，生前服用ARB类降压药的AD患者与服用其它降压药的患者相比（37% vs. 54%，P=0.005），病理表现较轻。在校正年龄、性别、APOE分型和血压等变量后，生前服用ARB类降压药的AD患者与服用其它降压的患者尸检AD病理变化的OR为0.47（95%CI,0,27-0.81）。该研究在线发表于最新一期的《神经病学文献》（Archives of Neurology）。

之前曾有观察性研究表明ARB类药物治疗高血压具有保护认知的功能，动物研究显示这类药物可以减少脑内与AD相关的病理性标志物Aβ集聚。ARB类药物如何作用于Aβ的机制尚不清楚。

于是，研究者们对全国阿尔茨海默病中心登记的890位患者进行研究，该中心汇集了全国29个阿尔茨海默病中心的数据库的数据，研究包括神经病理学及临床资料方面的分析。患者临床资料包括病史、药物治疗史，神经精神病学史等，其中包含MMSE和临床痴呆量表等多种测验结果。对尸检神经病理方面的评估主要采用CREAD评分。另外，对患者进行Braak评分以评估不同部位神经变性的程度。纳入研究的患者中，80%接受过抗高血压药物治疗，15%患者使用ARB类药物，64%服用其它类型降压药。

研究发现，与接受非ARB类降压药物治疗患者及不服药的患者相比，使用ARB类降压药的患者其死亡年龄更大（P<0.001），逻辑记忆测验及MMSE得分更高，痴呆评定量表得分更低，这表明他们的认知功能更好。

研究者称，根据阿尔茨海默病神经病理学的诊断标准的不同，使用ARB类药物可使患者被诊断为“病理尸解确诊的阿尔茨海默病”的可能性下降32-35%。依据NIH的Khachaturian标准，服ARB类降压药的AD 患者与服其它降压药患者相比，OR值为0.43（95%CI0.21-0.91），而根据Braakf分期的评分其OR值是0.52（95%CI0.31-0.85）。

对服用ARB类药物与ACEI类药物的AD患者直接比较发现，前者淀粉样蛋白沉积及神经炎性斑块的比例较少，这表明ARB的保护作用具有特异性。对血管相关病理评估显示，使用ARB类药物卒中的可能性稍高（P=0.03），其也与梗塞、大动脉出血相关，但经过其他因素校正后，其相关性不太显著。研究人员说，使用ARB类药物的患者其之所以血管病理的情况较糟糕可能与这些患者本身血管情况就较使用其他类降压药物的患者重，而不是由于使用ARB类药物所致。

研究者指出，ARB类药物干扰Aβ沉积的机制仍未完全阐明，但是ARB类药物治疗可能是通过促进膜相关胰岛素降解酶介导的机制来降低脑内的Aβ蛋白总量。

这项研究结果可能对今后ARB类药物治疗对是否能确实改善阿尔茨海默病患者临床症状的研究提供依据，为阿尔茨海默病治疗的研究开辟了新的途径。

英文原文：

Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series.

Hajjar I, Brown L, Mack WJ, Chui H.

BACKGROUND Angiotensin II may be involved in amyloid metabolism in the brain. Angiotensin receptor blockers （ARBs） may also prevent cognitive decline. OBJECTIVE To evaluate the impact of treatment with ARBs on the neuropathology of Alzheimer disease （AD） in the National Alzheimer Coordinating Center database, which includes aggregated data and brain autopsies from 29 AD centers throughout the United States. DESIGN Multiple logistic regression was used to compare the pathologic findings in hypertensive subjects taking ARBs with those taking other antihypertensive treatments as well as with hypertensive subjects who did not receive antihypertensive medications. SETTING Neuropathologic data included neuritic plaque and neurofibrillary tangle measures and vascular injury markers. PATIENTS Data were collected from participants who were self-referred or provider-referred and included those with and without cognitive disorders. Our sample included only hypertensive participants and excluded cognitively and neuropathologically normal participants （N = 890; mean age at death, 81 years [range, 39-107 years]; 43% women; 94% white）。 RESULTS Participants with or without AD who were treated with ARBs showed less amyloid deposition markers compared with those treated with other antihypertensive medications （lower Consortium to Establish a Registry of Alzheimer Disease score: odds ratio, 0.47, 95% CI, 0.27-0.81; Alzheimer Disease and Related Disorders Association score: odds ratio, 0.43, 95% CI, 0.21-0.91; Braak and Braak stage: odds ratio, 0.52, 95% CI, 0.31-0.85; neuritic plaques: odds ratio, 0.59, 95% CI, 0.37-0.96）。 They also had less AD-related pathology compared with untreated hypertensive subjects. Participants who received ARBs were more likely to have had a stroke; hence, they had more frequent pathologic evidence of large vessel infarct and hemorrhage. CONCLUSION Treatment with ARBs is associated with less AD-related pathology on autopsy evaluations. The effect of ARBs on cognitive decline in those with dementia or AD needs further investigation.