Blennow Kaj, Hampel Harald, Zetterberg Henrik
Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
Neuropsychopharmacology. 2014 Jan;39(1):189-201. doi: 10.1038/npp.2013.154. Epub 2013 Jun 25.
Drug candidates directed against amyloid-β (Aβ) are mainstream in Alzheimer's disease (AD) drug development. Active and passive Aβ immunotherapy is the principle that has come furthest, both in number and in stage of clinical trials. However, an increasing number of reports on major difficulties in identifying any clinical benefit in phase II-III clinical trials on this type of anti-Aβ drug candidates have caused concern among researchers, pharmaceutical companies, and other stakeholders. This has provided critics of the amyloid cascade hypothesis with fire for their arguments that Aβ deposition may merely be a bystander, and not the cause, of the disease or that the amyloid hypothesis may only be valid for the familial form of AD. On the other hand, most researchers argue that it is the trial design that will need refinement to allow for identifying a positive clinical effect of anti-Aβ drugs. A consensus in the field is that future trials need to be performed in an earlier stage of the disease and that biomarkers are essential to guide and facilitate drug development. In this context, it is reassuring that, in contrast to most brain disorders, research advances in the AD field have led to both imaging (magnetic resonance imaging (MRI) and PET) and cerebrospinal fluid (CSF) biomarkers for the central pathogenic processes of the disease. AD biomarkers will have a central role in future clinical trials to enable early diagnosis, and Aβ biomarkers (CSF Aβ42 and amyloid PET) may be essential to allow for testing a drug on patients with evidence of brain Aβ pathology. Pharmacodynamic Aβ and amyloid precursor protein biomarkers will be of use to verify target engagement of a drug candidate in humans, thereby bridging the gap between mechanistic data from transgenic AD models (that may not be relevant to the neuropathology of human AD) and large and expensive phase III trials. Last, downstream biomarker evidence (CSF tau proteins and MRI volumetry) that the drug ameliorates neurodegeneration will, together with beneficial clinical effects on cognition and functioning, be essential for labeling an anti-Aβ drug as disease modifying.
针对淀粉样β蛋白（Aβ）的候选药物是阿尔茨海默病（AD）药物研发的主流方向。主动和被动Aβ免疫疗法是在临床试验数量和阶段方面进展最为深入的原则。然而，越来越多关于在这类抗Aβ候选药物的II-III期临床试验中难以确定任何临床益处的报告，引起了研究人员、制药公司及其他利益相关者的关注。这为淀粉样蛋白级联假说的批评者提供了口实，他们认为Aβ沉积可能仅仅是该疾病的旁观者而非病因，或者淀粉样蛋白假说可能仅对家族性AD形式有效。另一方面，大多数研究人员认为，需要改进试验设计以确定抗Aβ药物的积极临床效果。该领域的共识是，未来的试验需要在疾病的早期阶段进行，并且生物标志物对于指导和促进药物研发至关重要。在这种背景下，令人欣慰的是，与大多数脑部疾病不同，AD领域的研究进展已经产生了针对该疾病核心致病过程的影像学（磁共振成像（MRI）和PET）及脑脊液（CSF）生物标志物。AD生物标志物在未来临床试验中将发挥核心作用以实现早期诊断，而Aβ生物标志物（CSF Aβ42和淀粉样蛋白PET）对于在有脑Aβ病理学证据的患者身上测试药物可能至关重要。药效学Aβ和淀粉样前体蛋白生物标志物将有助于验证候选药物在人体中的靶点结合情况，从而弥合转基因AD模型的机制数据（可能与人类AD的神经病理学无关）与大型且昂贵的III期试验之间的差距。最后，药物改善神经退行性变的下游生物标志物证据（CSF tau蛋白和MRI容积测量），连同对认知和功能的有益临床效果，对于将抗Aβ药物标记为疾病修饰药物至关重要。
