Williams Michael
Northwestern University, Feinberg School of Medicine, Department of Molecular Pharmacology and Biological Chemistry, Chicago, IL 60611, USA.
Curr Opin Investig Drugs. 2009 Jan;10(1):23-34.
While Alzheimer's disease (AD) represents a major healthcare challenge, with 25 to 34 million individuals currently affected worldwide and triple this number of patients projected by 2050, the drugs currently approved for the palliative treatment of AD, the cholinesterase inhibitors and the NMDA antagonist memantine, have demonstrated questionable efficacy, highlighting an urgent need for new therapies. Efforts in targeting the removal of amyloid plaques from the brain of patients with AD have been disappointing, with neither plaque-removing vaccines nor the gamma-secretase modulator, tarenflurbil demonstrating clinical benefit, thus questioning the validity of the amyloid cascade hypothesis that has driven AD research for the past decade. The lack of progress in mechanistic approaches (the amyloid and tau hypotheses) to developing new AD drugs indicates that some of the basic assumptions of AD causality and the search for effective drugs are probably in need of major reassessment and redirection.
虽然阿尔茨海默病（AD）是一项重大的医疗保健挑战，目前全球有2500万至3400万人受其影响，预计到2050年患者数量将增至三倍，但目前批准用于AD姑息治疗的药物，即胆碱酯酶抑制剂和N-甲基-D-天冬氨酸（NMDA）拮抗剂美金刚，其疗效存疑，凸显了对新疗法的迫切需求。针对从AD患者大脑中清除淀粉样斑块的研究努力令人失望，去除斑块的疫苗和γ-分泌酶调节剂tarenflurbil均未显示出临床益处，因此对过去十年推动AD研究的淀粉样蛋白级联假说的有效性提出了质疑。在开发新的AD药物的机制方法（淀粉样蛋白和tau假说）方面缺乏进展，这表明AD病因学的一些基本假设以及寻找有效药物的方向可能需要进行重大重新评估和调整。
