Department of Pharmacology & Toxicology Room 4207, University of Toronto, Medical Sciences Building 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada.
Alzheimers Res Ther. 2021 Feb 11;13(1):43. doi: 10.1186/s13195-021-00778-8.
The antihypertensive angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) have similar indications and mechanisms of action, but prior work suggests divergence in their effects on cognition.
Participants in the National Alzheimer's Coordinating Center database with a clinical diagnosis of dementia due to Alzheimer's disease (AD) using an ACE-I or an ARB at any visit were selected. The primary outcome was delayed recall memory on the Wechsler Memory Scale Revised - Logical Memory IIA. Other cognitive domains were explored, including attention and psychomotor processing speed (Trail Making Test [TMT]-A and Digit Symbol Substitution Test [DSST]), executive function (TMT-B), and language and semantic verbal fluency (Animal Naming, Vegetable Naming, and Boston Naming Tests). Random slopes mixed-effects models with inverse probability of treatment weighting were used, yielding rate ratios (RR) or regression coefficients (B), as appropriate to the distribution of the data. Apolipoprotein (APOE) ε4 status and blood-brain barrier (BBB) penetrance were investigated as effect modifiers.
Among 1689 participants with AD, ARB use (n = 578) was associated with 9.4% slower decline in delayed recall performance over a mean follow-up of 2.28 years compared with ACE-I use (n = 1111) [RR = 1.094, p = 0.0327]; specifically, users of BBB-crossing ARBs (RR = 1.25, p = 0.002), BBB-crossing ACE-Is (RR = 1.16, p = 0.010), and non-BBB-crossing ARBs (RR = 1.20, p = 0.005) had better delayed recall performance over time compared with non-BBB-crossing ACE-I users. An interaction with APOE ε4 status (drug × APOE × time RR = 1.196, p = 0.033) emerged; ARBs were associated with better delayed recall scores over time than ACE-Is in non-carriers (RR = 1.200, p = 0.003), but not in carriers (RR = 1.003, p = 0.957). ARB use was also associated with better performance over time on the TMT-A (B = 2.023 s, p = 0.0004) and the DSST (B = 0.573 symbols, p = 0.0485), and these differences were significant among APOE ε4 non-carriers (B = 4.066 s, p = 0.0004; and B = 0.982 symbols, p = 0.0230; respectively). Some differences were seen also in language and verbal fluency among APOE ε4 non-carriers.
Among APOE ε4 non-carriers with AD, ARB use was associated with greater preservation of memory and attention/psychomotor processing speed, particularly compared to ACE-Is that do not cross the blood-brain-barrier.
具有相似适应证和作用机制的降压血管紧张素受体阻滞剂（ARBs）和血管紧张素转换酶抑制剂（ACE-Is），但其对认知的影响存在差异。
从国家阿尔茨海默病协调中心数据库中选取在任何一次就诊时使用 ACE-I 或 ARB 且临床诊断为阿尔茨海默病（AD）相关痴呆的参与者。主要结局是韦氏记忆量表修订版逻辑记忆 IIA 的延迟回忆记忆。还探索了其他认知领域，包括注意力和精神运动处理速度（连线测试 A 和数字符号替换测试）、执行功能（连线测试 B）以及语言和语义流畅性（动物命名、蔬菜命名和波士顿命名测试）。使用具有逆概率治疗加权的随机斜率混合效应模型，得出率比（RR）或回归系数（B），具体取决于数据的分布。载脂蛋白（APOE）ε4 状态和血脑屏障（BBB）通透性被视为效应修饰剂。
在 1689 名 AD 参与者中，与使用 ACE-I（n=1111）相比，ARB 使用者（n=578）在平均 2.28 年的随访中延迟回忆表现的下降速度慢 9.4%[RR=1.094，p=0.0327]；具体而言，使用 BBB 穿透性 ARB（RR=1.25，p=0.002）、BBB 穿透性 ACE-I（RR=1.16，p=0.010）和非 BBB 穿透性 ARB（RR=1.20，p=0.005）的患者，其延迟回忆表现随时间推移而逐渐改善，而非 BBB 穿透性 ACE-I 使用者的表现则相反。出现了与 APOE ε4 状态的相互作用（药物×APOE×时间 RR=1.196，p=0.033）；与 ACE-I 相比，ARB 与非携带者的延迟回忆评分随时间的推移而提高（RR=1.200，p=0.003），但在携带者中则没有（RR=1.003，p=0.957）。ARB 的使用还与 TMT-A（B=2.023s，p=0.0004）和 DSST（B=0.573 个符号，p=0.0485）的表现改善有关，在 APOE ε4 非携带者中这些差异具有统计学意义（B=4.066s，p=0.0004；B=0.982 个符号，p=0.0230）。在 APOE ε4 非携带者中，还观察到语言和言语流畅性方面的一些差异。
在 APOE ε4 非携带者中，与 ACE-I 相比，ARB 的使用与记忆和注意力/精神运动处理速度的更好保留相关，特别是与不能穿透血脑屏障的 ACE-I 相比。
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