Alzheimer’s Disease (AD), the most prevalent neurodegenerative disease of aging, affects one in eight older Americans. Nearly all drug treatments tested for AD today have failed to show any efficacy. There is a great need for therapies to prevent and/or slow the progression of AD. The major challenge in AD drug development is lack of clarity about the mechanisms underlying AD pathogenesis and pathophysiology. Several studies support the notion that AD is a multifactorial disease. While there is abundant evidence that amyloid plays a role in AD pathogenesis, other mechanisms have been implicated in AD such as tangle formation and spread, dysregulated protein degradation pathways, neuroinflammation, and loss of support by neurotrophic factors. Therefore, current paradigms of AD drug design have been shifted from single target approach (primarily amyloid-centric) to developing drugs targeted at multiple disease aspects, and from treating AD at later stages of disease progression to focusing on preventive strategies at early stages of disease development. Here, we summarize current strategies and new trends of AD drug development, including pre-clinical and clinical trials that target different aspects of disease (mechanism-based versus non-mechanism based, e.g. symptomatic treatments, lifestyle modifications and risk factor management).

中文翻译：

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开发阿尔茨海默病新治疗策略的进展

阿尔茨海默病 (AD) 是最常见的衰老神经退行性疾病，影响八分之一的美国人。如今，几乎所有针对 AD 进行测试的药物治疗均未显示出任何疗效。非常需要预防和/或减缓 AD 进展的疗法。AD 药物开发的主要挑战是对 AD 发病机制和病理生理学的机制缺乏明确性。多项研究支持 AD 是一种多因素疾病的观点。虽然有大量证据表明淀粉样蛋白在 AD 发病机制中发挥作用，但 AD 中还涉及其他机制，例如缠结的形成和扩散、蛋白质降解途径失调、神经炎症和神经营养因子支持的丧失。因此，目前AD药物设计的范式已经从单一靶点方法（主要以淀粉样蛋白为中心）转向开发针对多个疾病方面的药物，从在疾病进展的后期治疗AD转向关注疾病早期的预防策略发展。在此，我们总结了AD药物开发的当前策略和新趋势，包括针对疾病不同方面（基于机制与基于非机制，例如对症治疗、生活方式改变和危险因素管理）的临床前和临床试验。