Model organisms of human diseases are invaluable tools for unraveling pathogenic mechanisms, identifying potential targets for drug development, and evaluating the therapeutic efficacy of candidates in preclinical trials. The utility of model organisms hinges upon their ability to faithfully replicate the underlying pathogenic mechanisms of the human disease. For rodent models of Alzheimer's disease (AD) and AD-related dementias (ADRD), the limited translatability to human disease raises concerns about their overall utility. What factors contribute to this limitation? Is AD inherently too complex to be accurately modeled in nonhumans? Is the divergence between rodent brains and the human brain so pronounced that rodents are unsuitable as model organisms for AD? Or is it plausible that the commonly used rodent models don't capture the genuine pathogenic mechanisms underlying these diseases? This editorial discusses the challenges associated with transgenic models of AD and ADRD and offers some alternative approaches.

中文翻译：

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转基因技术令人着迷：病理学假设如何减缓阿尔茨海默病和相关痴呆症研究的进展


人类疾病的模型生物是揭示致病机制、确定药物开发的潜在靶点以及评估临床前试验中候选药物的治疗效果的宝贵工具。模型生物的效用取决于它们忠实复制人类疾病潜在致病机制的能力。对于阿尔茨海默病 (AD) 和 AD 相关痴呆 (ADRD) 的啮齿动物模型来说，其对人类疾病的有限转化性引起了人们对其整体效用的担忧。哪些因素导致了这种限制？ AD 本质上是否太复杂而无法在非人类身上准确建模？啮齿动物大脑和人类大脑之间的差异是否如此明显以至于啮齿动物不适合作为 AD 的模型生物？或者，常用的啮齿动物模型是否有可能无法捕捉到这些疾病的真正致病机制？这篇社论讨论了与 AD 和 ADRD 转基因模型相关的挑战，并提供了一些替代方法。