Although the biochemical and pathological hallmarks of Alzheimer's disease (AD), such as axonal transport defects, synaptic loss, and selective neuronal death, are well characterized, the underlying mechanisms that cause AD are largely unknown, thereby making it difficult to design effective therapeutic interventions. Genome-wide association studies (GWAS) studies have identified several factors associated with increased AD risk. Of these genetic factors, polymorphisms in the Apolipoprotein E (APOE) gene are the strongest and most prevalent. While it has been established that the ApoE protein modulates the formation of amyloid plaques and neurofibrillary tangles, the precise molecular mechanisms by which various ApoE isoforms enhance or mitigate AD onset and progression in aging adults are yet to be elucidated. Advances in cellular reprogramming to generate disease-in-a-dish models now provide a simplified and accessible system that complements animal and primary cell models to study ApoE in the context of AD. In this review, we will describe the use and manipulation of human induced pluripotent stem cells (hiPSCs) in dissecting the interaction between ApoE and AD. First, we will provide an overview of the proposed roles that ApoE plays in modulating pathophysiology of AD. Next, we will summarize the recent studies that have employed hiPSCs to model familial and sporadic AD. Lastly, we will speculate on how current advances in genome editing technologies and organoid culture systems can be used to improve hiPSC-based tools to investigate ApoE-dependent modulation of AD onset and progression.

中文翻译：

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使用人类诱导多能干细胞 (hiPSC) 研究载脂蛋白 E (APOE) 导致阿尔茨海默病 (AD) 风险的机制。

尽管阿尔茨海默病 (AD) 的生化和病理特征，例如轴突运输缺陷、突触损失和选择性神经元死亡，已得到充分表征，但导致 AD 的潜在机制在很大程度上尚不清楚，因此很难设计有效的治疗干预措施。全基因组关联研究 (GWAS) 研究确定了与 AD 风险增加相关的几个因素。在这些遗传因素中，载脂蛋白 E (APOE) 基因的多态性最强且最普遍。虽然已经确定 ApoE 蛋白调节淀粉样蛋白斑和神经原纤维缠结的形成，但各种 ApoE 亚型增强或减轻老年人 AD 发病和进展的精确分子机制尚未阐明。用于生成培养皿中疾病模型的细胞重编程的进展现在提供了一个简化且易于使用的系统，该系统补充了动物和原代细胞模型，以研究 AD 背景下的 ApoE。在这篇综述中，我们将描述人类诱导多能干细胞 (hiPSC) 在剖析 ApoE 和 AD 之间相互作用时的使用和操作。首先，我们将概述 ApoE 在调节 AD 病理生理学中所发挥的作用。接下来，我们将总结最近使用 hiPSC 来模拟家族性和散发性 AD 的研究。最后，我们将推测如何利用基因组编辑技术和类器官培养系统的当前进展来改进基于 hiPSC 的工具，以研究 AD 发病和进展的 ApoE 依赖性调节。