【摘要】 阿尔茨海默病(AD)的主要病理表现包括:β淀粉样蛋白(Aβ)沉积形成的老年斑、神经元纤维缠结同时合并突触功能障碍及其他神经退行性病变。Aducanumab是一种选择性针对聚集态Aβ的人单克隆抗体。在AD转基因小鼠的基础实验中,aducanumab通过血脑屏障进入脑内,与脑实质内的Aβ结合,降低脑内可溶性及不可溶性Aβ,且呈剂量效应关系。临床试验中,在AD临床前驱期和轻度阶段,每月静脉滴注1次aducanumab,持续1年,能有效减少脑内Aβ,作用也呈剂量依赖性和时间依赖性,受试者的认知功能衰退速度也有所减缓,表现为简明精神状态量表(MMSE)及临床痴呆量表总分(CDR-SB)评分下降速度减缓。Aducanumab的安全性和耐受性的主要问题是Aβ相关的影像学异常(ARIA)。目前aducanumab治疗AD的Ⅲ期临床试验正在进行,如能证实其具有延缓AD认知功能衰退,将是Aβ学说的强有力支持。更多还原

【Abstract】 Amyloid-β(Aβ) plaques, together with neurofibrillary tangles, are hallmarks of Alzheimer’s disease(AD). Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. The preclinical data and main results of a phase Ib clinical trial of a monoclonal antibody that selectively targets aggregated Aβ, aducanumab was introduced. In a transgenic mouse model of AD, aducanumab were shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduced brain Aβ in a dose- and time-dependent manner. The slowing of clinical decline was also shown by the Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings were amyloid-related imaging abnormalities. These results justified further development of aducanumab for the treatment of AD. If the slowing of clinical decline can be confirmed in ongoing phase 3 clinical trials, it will provide compelling support for the amyloid hypothesis.更多还原