Denver Paul, McClean Paula L
Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles Medical Center and Department of Neurology, University of California, Los Angeles, CA, USA; Centre for Molecular Biosciences, University of Ulster, Coleraine, Northern Ireland, UK.
Northern Ireland Centre for Stratified Medicine, Clinical, Translational and Research Innovation Centre (C-TRIC), University of Ulster, Derry/Londonderry, Northern Ireland, UK.
Neural Regen Res. 2018 Oct;13(10):1719-1730. doi: 10.4103/1673-5374.238608.
As populations age, prevalence of Alzheimer's disease (AD) is rising. Over 100 years of research has provided valuable insights into the pathophysiology of the disease, for which age is the principal risk factor. However, in recent years, a multitude of clinical trial failures has led to pharmaceutical corporations becoming more and more unwilling to support drug development in AD. It is possible that dependence on the amyloid cascade hypothesis as a guide for preclinical research and drug discovery is part of the problem. Accumulating evidence suggests that amyloid plaques and tau tangles are evident in non-demented individuals and that reducing or clearing these lesions does not always result in clinical improvement. Normal aging is associated with pathologies and cognitive decline that are similar to those observed in AD, making differentiation of AD-related cognitive decline and neuropathology challenging. In this mini-review, we discuss the difficulties with discerning normal, age-related cognitive decline with that related to AD. We also discuss some neuropathological features of AD and aging, including amyloid and tau pathology, synapse loss, inflammation and insulin signaling in the brain, with a view to highlighting cognitive or neuropathological markers that distinguish AD from normal aging. It is hoped that this review will help to bolster future preclinical research and support the development of clinical tools and therapeutics for AD.
随着人口老龄化，阿尔茨海默病（AD）的患病率正在上升。超过100年的研究为该疾病的病理生理学提供了宝贵的见解，年龄是其主要风险因素。然而，近年来，众多临床试验的失败导致制药公司越来越不愿意支持AD药物的研发。对淀粉样蛋白级联假说作为临床前研究和药物发现指南的依赖可能是问题的一部分。越来越多的证据表明，淀粉样斑块和tau缠结在非痴呆个体中也很明显，减少或清除这些病变并不总是能带来临床改善。正常衰老与AD中观察到的病理和认知衰退相似，这使得区分与AD相关的认知衰退和神经病理学具有挑战性。在这篇小型综述中，我们讨论了区分正常的、与年龄相关的认知衰退和与AD相关的认知衰退的困难。我们还讨论了AD和衰老的一些神经病理学特征，包括淀粉样蛋白和tau病理学、突触丧失、炎症和大脑中的胰岛素信号，以期突出区分AD与正常衰老的认知或神经病理学标志物。希望这篇综述将有助于加强未来的临床前研究，并支持AD临床工具和治疗方法的开发。
