A large number of mouse models have been engineered, characterized and used to advance biomedical research in Alzheimer disease (AD). Early models simply damaged the rodent brain through toxins or lesions. Later, the spread of genetic engineering technology enabled investigators to develop models of familial AD by overexpressing human genes such as those encoding amyloid precursor protein (APP) or presenilins (PSEN1 or PSEN2) carrying mutations linked to early-onset AD. Recently, more complex models have sought to explore the impact of multiple genetic risk factors in the context of different biological challenges. Although none of these models has proven to be a fully faithful reproduction of the human disease, models remain essential as tools to improve our understanding of AD biology, conduct thorough pharmacokinetic and pharmacodynamic analyses, discover translatable biomarkers and evaluate specific therapeutic approaches. To realize the full potential of animal models as new technologies and knowledge become available, it is critical to define an optimal strategy for their use. Here, we review progress and challenges in the use of AD mouse models, highlight emerging scientific innovations in model development, and introduce a conceptual framework for use of preclinical models for therapeutic development.

已经设计，表征和使用了大量的小鼠模型来推进阿尔茨海默病（AD）的生物医学研究。早期的模型只是通过毒素或病变破坏了啮齿动物的大脑。后来，基因工程技术的普及使研究人员能够通过过表达人类基因（例如编码携带早期AD突变的淀粉样前体蛋白（APP）或早老素（PSEN1或PSEN2）的人类基因）来开发家族性AD模型。近来，更复杂的模型试图探索在不同生物学挑战的背景下多种遗传危险因素的影响。尽管这些模型都没有被证明能完全忠实地复制人类疾病，但是模型仍然是必不可少的工具，可以增进我们对AD生物学的理解，进行彻底的药代动力学和药效学分析，发现可翻译的生物标记并评估特定的治疗方法。为了在获得新技术和知识后充分发挥动物模型的潜力，至关重要的是确定一种最佳使用方法。在这里，我们回顾了使用AD小鼠模型的进展和挑战，突出了模型开发中新兴的科学创新，并介绍了使用临床前模型进行治疗开发的概念框架。