Foley Kate E, Wilcock Donna M
Stark Neurosciences Research Institute, Indiana University, Indianapolis, IN, United States.
Department of Neurology, School of Medicine, Indiana University, Indianapolis, IN, United States.
Front Aging Neurosci. 2024 May 2;16:1412006. doi: 10.3389/fnagi.2024.1412006. eCollection 2024.
The targeting of amyloid-beta (Aβ) plaques therapeutically as one of the primary causes of Alzheimer's disease (AD) dementia has been an ongoing effort spanning decades. While some antibodies are extremely promising and have been moved out of clinical trials and into the clinic, most of these treatments show similar adverse effects in the form of cerebrovascular damage known as amyloid-related imaging abnormalities (ARIA). The two categories of ARIA are of major concern for patients, families, and prescribing physicians, with ARIA-E presenting as cerebral edema, and ARIA-H as cerebral hemorrhages (micro- and macro-). From preclinical and clinical trials, it has been observed that the greatest genetic risk factor for AD, APOE, is also a major risk factor for anti-Aβ immunotherapy-induced ARIA. APOE carriers represent a large population of AD patients, and, therefore, limits the broad adoption of these therapies across the AD population. In this review we detail three hypothesized mechanisms by which APOE influences ARIA risk: (1) reduced cerebrovascular integrity, (2) increased neuroinflammation and immune dysregulation, and (3) elevated levels of CAA. The effects of APOE on ARIA risk is clear, however, the underlying mechanisms require more research.
将β-淀粉样蛋白（Aβ）斑块作为阿尔茨海默病（AD）痴呆的主要病因之一进行治疗性靶向，这一努力已经持续了数十年。虽然一些抗体极具前景，已从临床试验进入临床应用，但这些治疗大多表现出类似的不良反应，形式为被称为淀粉样蛋白相关成像异常（ARIA）的脑血管损伤。ARIA的两类情况是患者、家属和开处方的医生主要关注的问题，ARIA-E表现为脑水肿，ARIA-H表现为脑出血（微出血和大出血）。从临床前和临床试验中观察到，AD最大的遗传风险因素APOE也是抗Aβ免疫治疗诱导ARIA的主要风险因素。APOE携带者占AD患者的很大一部分，因此限制了这些疗法在AD人群中的广泛应用。在本综述中，我们详细阐述了APOE影响ARIA风险的三种假设机制：（1）脑血管完整性降低，（2）神经炎症增加和免疫失调，（3）脑淀粉样血管病（CAA）水平升高。APOE对ARIA风险的影响是明确的，然而，其潜在机制需要更多研究。
