Spontaneous animal models of Alzheimer’s disease (AD) offer the potential to bridge the translational gulf between promising rodent studies and failed human clinical trials. In this review, the relationship between cell biology, neuropathology, clinical phenotype and biomarker progression in human AD is summarized. Genetically altered animals have provided key insights into the cell biology of AD and, together with emerging stem cell systems, remain the most effective means to disentangle the entwined mechanisms that underlie AD. Translating therapeutic success from these models of familial AD to late onset human AD has been challenging. Spontaneous models of AD do not harbor AD-associated mutations and could potentially be used to demonstrate greater generalizability of new therapies to late onset AD. The value of such models has been advanced primarily on the basis of similar amyloid (and far less frequent, tangle) neuropathology. While these models are promising, this alone is insufficient for use of these models to assess efficacy of potential therapies. The correlation between progression of neuropathology and cognitive phenotype and the association of these with biomarker progression in these models is discussed, with an emphasis on the dog and non-human primates. Currently, interventional studies using these models are hampered by use of a variety of outcomes that are not easily comparable with those used in human trials and do not permit longitudinal assessment. Additional studies aimed at closing the gap between neuropathology and usable outcome measures would support more accurate subject selection, assessment of target engagement and evaluation of therapeutic efficacy.

中文翻译：

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自发性阿尔茨海默病动物模型在临床前疗效研究中的应用

自发性阿尔茨海默病 (AD) 动物模型提供了弥合有希望的啮齿动物研究和失败的人类临床试验之间的转化鸿沟的潜力。在这篇综述中，总结了人类 AD 中细胞生物学、神经病理学、临​​床表型和生物标志物进展之间的关系。基因改造动物为 AD 的细胞生物学提供了关键见解，并且与新兴的干细胞系统一起，仍然是解开 AD 背后交织机制的最有效手段。将这些家族性 AD 模型的治疗成功转化为晚发性人类 AD 一直具有挑战性。AD 的自发模型不包含 AD 相关突变，并且有可能用于证明新疗法对晚发性 AD 的更大普遍性。此类模型的价值主要基于类似的淀粉样蛋白（以及频率低得多的缠结）神经病理学。虽然这些模型很有前景，但仅凭这一点不足以使用这些模型来评估潜在疗法的疗效。讨论了神经病理学进展与认知表型之间的相关性以及这些与这些模型中生物标志物进展的关联，重点是狗和非人类灵长类动物。目前，使用这些模型的介入研究受到各种结果的阻碍，这些结果不易与人体试验中使用的结果进行比较，并且不允许纵向评估。旨在缩小神经病理学和可用结果测量之间差距的其他研究将支持更准确的受试者选择，