The focus on amyloid plaques and neurofibrillary tangles has yielded no Alzheimer's disease (AD) modifying treatments in the past several decades, despite successful studies in preclinical mouse models. This inconsistency has caused a renewed focus on improving the fidelity and reliability of AD mouse models, with disparate views on how this improvement can be accomplished. However, the interactive effects of the universal biological variables of AD, which include age, APOE genotype, and sex, are often overlooked. Age is the greatest risk factor for AD, while the ε4 allele of the human APOE gene, encoding apolipoprotein E, is the greatest genetic risk factor. Sex is the final universal biological variable of AD, as females develop AD at almost twice the rate of males and, importantly, female sex exacerbates the effects of APOE4 on AD risk and rate of cognitive decline. Therefore, this review evaluates the importance of context for understanding the role of APOE in preclinical mouse models. Specifically, we detail how human AD pathology is mirrored in current transgenic mouse models ("What") and describe the critical need for introducing human APOE into these mouse models ("Who"). We next outline different methods for introducing human APOE into mice ("How") and highlight efforts to develop temporally defined and location-specific human apoE expression models ("When" and "Where"). We conclude with the importance of choosing the human APOE mouse model relevant to the question being addressed, using the selection of transgenic models for testing apoE-targeted therapeutics as an example ("Why").

中文翻译：

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APOE转基因小鼠模型中的阿尔茨海默氏病病理：谁，什么，何时，何地，为什么和如何。

尽管在临床前小鼠模型中进行了成功的研究，但在过去的几十年中，对淀粉样蛋白斑块和神经原纤维缠结的关注并未产生改变阿尔茨海默氏病（AD）的治疗方法。这种不一致导致人们重新集中精力改进AD鼠标模型的保真度和可靠性，但对如何实现这种改进的看法却截然不同。但是，AD的通用生物学变量（包括年龄，APOE基因型和性别）的交互作用常常被忽略。年龄是AD的最大危险因素，而编码载脂蛋白E的人APOE基因的ε4等位基因是最大的遗传危险因素。性别是AD的最终普遍生物学变量，因为女性发展AD的速度几乎是男性的两倍，而且重要的是，女性性行为会加剧APOE4对AD风险和认知能力下降的影响。因此，这篇综述评估了情境对于理解APOE在临床前小鼠模型中的作用的重要性。具体而言，我们详细介绍了如何在当前的转基因小鼠模型（“ What”）中反映出人类AD病理，并描述了将人类APOE引入这些小鼠模型（“ Who”）的关键需求。接下来，我们概述了将人类APOE引入小鼠的不同方法（“如何”），并重点介绍了开发时间定义和特定位置的人类apoE表达模型（“何时”和“何处”）的努力。我们得出结论，选择与要解决的问题相关的人类APOE小鼠模型非常重要，