Clinical Trials Unit, Kaiser Permanente, San Francisco, CA, USA.
Int J Geriatr Psychiatry. 2018 Jan;33(1):e14-e21. doi: 10.1002/gps.4730. Epub 2017 May 16.
The aim of this study is to examine the hypotheses stating the importance of amyloid or of its oligomers in the pathogenesis of Alzheimer's disease (AD).
Published studies were examined.
The importance of amyloid in the pathogenesis of AD is well established, yet accepting it as the main cause for AD is problematic, because amyloid-centric treatments have provided no clinical benefit and about one-third of cognitively normal, older persons have cerebral amyloid plaques. Also problematic is the alternative hypothesis that, instead of amyloid plaques, it is oligomers of amyloid precursor protein that cause AD.Evidence is presented suggesting amyloid/oligomers as necessary but insufficient causes of the dementia and that, for dementia to develop, requires the addition of cofactors known to be associated with AD. Those cofactors include several subcellular processes: mitochondrial impairments; the Wnt signaling system; the unfolded protein response; the ubiquitin proteasome system; the Notch signaling system; and tau, calcium, and oxidative damage.
A modified amyloid/oligomer hypothesis for the pathogenesis of AD is that activation of one or more of the aforementioned cofactors creates a burden of functional impairments that, in conjunction with amyloid/oligomers, now crosses a threshold of dysfunction that results in clinical dementia. Of considerable importance, several treatments that might reverse the activation of some of the subcellular processes are available, for example, lithium, pioglitazone, erythropoietin, and prazosin; they should be given in combination in a clinical trial to test their safety and efficacy. © 2017 John Wiley & Sons, Ltd.
本研究旨在检验关于淀粉样蛋白或其寡聚物在阿尔茨海默病（AD）发病机制中重要性的假说。
对已发表的研究进行了检查。
淀粉样蛋白在 AD 发病机制中的重要性已得到充分证实，但将其作为 AD 的主要病因存在问题，因为以淀粉样蛋白为中心的治疗方法没有带来临床益处，大约三分之一认知正常的老年人有脑淀粉样斑块。另一种假说也存在问题，即不是淀粉样斑块，而是淀粉样前体蛋白的寡聚物导致 AD。有证据表明，淀粉样蛋白/寡聚物是痴呆的必要但不充分的原因，并且为了发展为痴呆，需要添加已知与 AD 相关的辅助因子。这些辅助因子包括几个亚细胞过程：线粒体损伤；Wnt 信号系统；未折叠蛋白反应；泛素蛋白酶体系统；Notch 信号系统；以及 tau、钙和氧化损伤。
AD 发病机制的改良淀粉样蛋白/寡聚物假说认为，一个或多个上述辅助因子的激活会导致功能障碍的负担增加，与淀粉样蛋白/寡聚物一起，现在跨越了导致临床痴呆的功能障碍阈值。非常重要的是，有几种可能逆转一些亚细胞过程激活的治疗方法可用，例如锂、吡格列酮、促红细胞生成素和普萘洛尔；应在临床试验中联合使用它们，以测试其安全性和疗效。 © 2017 年 John Wiley & Sons, Ltd.
