Centre for Neuroscience and Regenerative Medicine, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia.
St Vincent's Centre for Applied Medical Research (AMR), St Vincent's Hospital Sydney Limited, Darlinghurst, Sydney, Australia.
Acta Neuropathol. 2018 Nov;136(5):663-689. doi: 10.1007/s00401-018-1918-8. Epub 2018 Oct 22.
The dominant hypothesis of Alzheimer's disease (AD) aetiology, the neuropathological guidelines for diagnosing AD and the majority of high-profile therapeutic efforts, in both research and in clinical practice, have been built around one possible causal factor, amyloid-β (Aβ). However, the causal link between Aβ and AD remains unproven. Here, in the context of a detailed assessment of historical and contemporary studies, we raise critical questions regarding the role of Aβ in the definition, diagnosis and aetiology of AD. We illustrate that a holistic view of the available data does not support an unequivocal conclusion that Aβ has a central or unique role in AD. Instead, the data suggest alternative views of AD aetiology are potentially valid, at this time. We propose that an unbiased way forward for the field, beyond the current Aβ-centric approach, without excluding a role for Aβ, is required to come to an accurate understanding of AD dementia and, ultimately, an effective treatment.
阿尔茨海默病（AD）发病机制的主流假说、AD 的神经病理学诊断指南以及大多数备受瞩目的治疗方法，无论是在研究还是临床实践中，都围绕着一个可能的致病因素——β 淀粉样蛋白（Aβ）。然而，Aβ 与 AD 之间的因果关系尚未得到证实。在这里，我们在详细评估历史和当代研究的背景下，对 Aβ 在 AD 的定义、诊断和发病机制中的作用提出了关键性的问题。我们表明，对现有数据的全面分析并不支持 Aβ 在 AD 中具有核心或独特作用的明确结论。相反，这些数据表明，目前替代 AD 发病机制的观点可能是合理的。我们建议，为了更准确地了解 AD 痴呆，并最终找到有效的治疗方法，该领域需要采取一种不偏袒的方法，超越当前以 Aβ 为中心的方法，但不排除 Aβ 的作用。
