Delrieu J, Ousset P J, Voisin T, Vellas B
Alzheimer's Disease Clinical Research Centre, Gérontopôle, Toulouse University Hospital, 170, avenue de Casselardit, 31059 Toulouse cedex 9, France.
Alzheimer's Disease Clinical Research Centre, Gérontopôle, Toulouse University Hospital, 170, avenue de Casselardit, 31059 Toulouse cedex 9, France; Inserm 1027, Faculté de médecine, 37, allées Jules-Guesde, 31000 Toulouse, France.
Rev Neurol (Paris). 2014 Dec;170(12):739-48. doi: 10.1016/j.neurol.2014.10.003. Epub 2014 Nov 6.
Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation.
对阿尔茨海默病发病机制认识的最新进展促使了众多可能改变疾病进程的化合物的研发。淀粉样β肽是干预阿尔茨海默病的一个重要分子靶点。这项工作的主要目的是综述与阿尔茨海默病相关的免疫治疗研究。针对阿尔茨海默病的几种淀粉样β肽免疫治疗方法正在研究中，包括主动免疫和用针对淀粉样β肽的单克隆抗体进行被动给药。尽管免疫治疗方法使阿尔茨海默病患者的淀粉样斑块得以清除，但目前这种清除并未显示出显著的认知效果。目前，几种淀粉样β肽免疫治疗方法正在研究中，而且也针对tau病理。临床试验中基于淀粉样蛋白的免疫治疗研究结果表明，干预在淀粉样蛋白积累的早期阶段似乎更有效，尤其是solanezumab对轻度阿尔茨海默病可能有影响，这突出了尽早诊断阿尔茨海默病并在此阶段开展临床试验的重要性。在solanezumab和bapineuzumab的III期试验中，PET成像显示约四分之一的患者在基线时缺乏纤维状淀粉样病理，这表明他们一开始就没有患阿尔茨海默病。因此，一项针对轻度阿尔茨海默病且有淀粉样蛋白负荷证据的患者的solanezumab新的III期临床试验，即“探索3号”已经启动。因此，目前在临床试验中，淀粉样蛋白干预是在阿尔茨海默病的早期阶段、前驱性阿尔茨海默病、或无症状受试者或有患阿尔茨海默病风险的受试者、或有常染色体显性突变的无症状受试者中进行的。
