Center for the Study of Human Cognition, Department of Psychology, University of Oslo, Pb. 1094 Blindern, 0317 Oslo, Norway.
Mol Neurobiol. 2012 Feb;45(1):153-72. doi: 10.1007/s12035-011-8228-7. Epub 2011 Dec 27.
Huge progress has been made in unraveling the mysteries of Alzheimer's disease (AD), but we still do not understand the basic mechanisms that set off the cascade of pathological events. In May 2011, the National Institute on Aging-Alzheimer's Association published new diagnostic guidelines, expected to have huge impact on AD research and clinical practice. However, the new guidelines are already criticized for being biased in favor of a specific theory of the pathophysiological origins of AD-the amyloid cascade hypothesis. Shortly before publication of the guidelines, a hypothetical model of the dynamic biomarkers of the Alzheimer's pathological cascade was published, taking as starting point that biomarkers reflecting brain levels of amyloid become deviant long before brain atrophy, cognitive dysfunction, or clinical symptoms are manifest. This model has already attracted substantial interest and arguably represents a dominating view within human research on AD. Here we critically review the evidence for the view of amyloid as an initiating event in the pathological cascade and discuss how central assumptions of this hypothesis affect how results from contemporary human AD research are understood. Interpretations of new results are greatly impacted by researchers' view on the role of amyloid, and identical observations are sometimes taken to support radically opposing views on the amyloid hypothesis. We argue that the canonical view of the role of amyloid as the main causal factor in AD may not be correct and that evidence from recent neuroimaging studies indicates that amyloid is neither necessary nor sufficient, for the manifestation of AD-like brain atrophy.
在揭示阿尔茨海默病（AD）的奥秘方面已经取得了巨大进展，但我们仍然不了解引发病理事件级联反应的基本机制。2011 年 5 月，美国国家老龄化研究所-阿尔茨海默病协会发布了新的诊断指南，预计将对 AD 研究和临床实践产生巨大影响。然而，新的指南已经因其偏向于 AD 病理生理学起源的特定理论——淀粉样蛋白级联假说而受到批评。在指南发布前不久，发表了一个关于阿尔茨海默病病理级联的动态生物标志物的假设模型，该模型以这样一个假设为起点，即反映大脑淀粉样蛋白水平的生物标志物在大脑萎缩、认知功能障碍或临床症状出现之前很久就出现异常。该模型已经引起了广泛的关注，可以说在 AD 的人类研究中代表了一种主导观点。在这里，我们批判性地回顾了淀粉样蛋白作为病理级联起始事件的观点的证据，并讨论了该假说的核心假设如何影响对当代人类 AD 研究结果的理解。研究人员对淀粉样蛋白作用的看法极大地影响了对新结果的解释，有时相同的观察结果被用来支持对淀粉样蛋白假说的截然相反的观点。我们认为，淀粉样蛋白作为 AD 主要因果因素的典型观点可能不正确，最近的神经影像学研究证据表明，淀粉样蛋白既不是 AD 样脑萎缩表现的必要条件，也不是充分条件。
