Lichtenstein Mathieu P, Carriba Paulina, Masgrau Roser, Pujol Aurora, Galea Elena
Institut de Neurociències, Universitat Autònoma de Barcelona Barcelona, Spain.
Front Aging Neurosci. 2010 Oct 25;2:142. doi: 10.3389/fnagi.2010.00142. eCollection 2010.
The use of non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease (AD) is controversial because conclusions from numerous epidemiological studies reporting delayed onset of AD in NSAID users have not been corroborated in clinical trials. The purpose of this personal view is to revise the case for NSAIDs in AD therapeutics in light of: (i) the last report from the only primary prevention trial in AD, ADAPT, which, although incomplete, points to significant protection in long-term naproxen users, and (ii) the recently proposed dynamic model of AD evolution. The model contends that there is a clinical silent phase in AD that can last up to 20 years, the duration depending on life style habits, genetic factors, or cognitive reserve. The failure of many purported disease-modifying drugs in AD clinical trials is forcing the view that treatments will only be efficacious if administered pre-clinically. Here we will argue that NSAIDs failed in clinical trials because they are disease-modifying drugs, and they should be administered in early stages of the disease. A complete prevention trial in cognitively normal individuals is thus called for. Further, the shift of anti-inflammatory treatment to early stages uncovers a knowledge void about the targets of NSAIDs in asymptomatic individuals. AD researchers have mostly relied on post-mortem analysis of Aβ plaque-laden brains from demented patients or animal models, thus drawing conclusions about AD pathogenesis based on late symptoms. We will discuss evidence in support that defective, not excessive, inflammation underlies AD pathogenesis, that NSAIDs are multifunctional drugs acting on inflammatory and non-inflammatory targets, and that astrocytes and microglia may play differing roles in disease progression, with an emphasis of ApoEε4 as a key, undervalued target of NSAIDs. According to a meta-analysis of epidemiological data, NSAIDs afford an average protection of 58%. If this figure is true, and translated into patient numbers, NSAID treatment may revive as a worth pursuing strategy to significantly reduce the socio-economical burden imposed by AD.
在阿尔茨海默病（AD）治疗中使用非甾体抗炎药（NSAIDs）存在争议，因为众多流行病学研究报告称NSAIDs使用者的AD发病延迟，但这些结论在临床试验中并未得到证实。本文个人观点的目的是根据以下两点来重新审视NSAIDs在AD治疗中的情况：（i）AD唯一的一级预防试验ADAPT的最新报告，该试验虽不完整，但表明长期服用萘普生的使用者有显著的保护作用；（ii）最近提出的AD演变动态模型。该模型认为，AD存在一个长达20年的临床无症状期，其持续时间取决于生活方式习惯、遗传因素或认知储备。许多所谓的疾病修饰药物在AD临床试验中失败，这促使人们认为只有在临床前给药治疗才会有效。在此，我们将论证NSAIDs在临床试验中失败是因为它们是疾病修饰药物，应该在疾病早期给药。因此，需要在认知正常个体中进行完整的预防试验。此外，抗炎治疗向早期阶段的转变揭示了关于NSAIDs在无症状个体中的靶点的知识空白。AD研究人员大多依赖对痴呆患者或动物模型中充满Aβ斑块的大脑进行尸检分析，从而根据晚期症状得出关于AD发病机制的结论。我们将讨论支持以下观点的证据：有缺陷而非过度的炎症是AD发病机制的基础；NSAIDs是作用于炎症和非炎症靶点的多功能药物；星形胶质细胞和小胶质细胞在疾病进展中可能发挥不同作用，重点强调载脂蛋白Eε4是NSAIDs的一个关键但未得到充分重视的靶点。根据流行病学数据的荟萃分析，NSAIDs平均提供58%的保护作用。如果这个数字是真实的，并转化为患者数量，NSAID治疗可能会重新成为一种值得追求的策略，以显著减轻AD带来的社会经济负担。
