One of the primary genetic risk factors for Alzheimer's disease (AD) is the presence of the Ɛ4 allele of apolipoprotein E (APOE). APOE is a polymorphic lipoprotein that is a major cholesterol carrier in the brain. It is also involved in various cellular functions such as neuronal signaling, neuroinflammation and glucose metabolism. Humans predominantly possess three different allelic variants of APOE, termed E2, E3, and E4, with the E3 allele being the most common. The presence of the E4 allele is associated with increased risk of AD whereas E2 reduces the risk. To understand the molecular mechanisms that underlie APOE-related genetic risk, considerable effort has been devoted towards developing cellular and animal models. Data from these models indicate that APOE4 exacerbates amyloid β plaque burden in a dose-dependent manner. and may also enhance tau pathogenesis in an isoform-dependent manner. Other studies have suggested APOE4 increases the risk of AD by mechanisms that are distinct from modulation of Aβ or tau pathology. Further, whether plasma APOE, by influencing systemic metabolic pathways, can also possibly alter CNS function indirectly is not complete;y understood. Collectively, the available studies suggest that APOE may impact multiple signaling pathways and thus investigators have sought therapeutics that would disrupt pathological functions of APOE while preserving or enhancing beneficial functions. This review will highlight some of the therapeutic strategies that are currently being pursued to target APOE4 towards preventing or treating AD and we will discuss additional strategies that holds promise for the future.

中文翻译：

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针对阿尔茨海默病中载脂蛋白 E 功能的治疗方法。

阿尔茨海默病 (AD) 的主要遗传风险因素之一是载脂蛋白 E (APOE) Ɛ4 等位基因的存在。APOE是一种多态性脂蛋白，是大脑中主要的胆固醇载体。它还参与各种细胞功能，例如神经元信号传导、神经炎症和葡萄糖代谢。人类主要拥有三种不同的 APOE 等位基因变体，称为 E2、E3 和 E4，其中 E3 等位基因是最常见的。E4 等位基因的存在与 AD 风险增加有关，而 E2 降低风险。为了了解构成 APOE 相关遗传风险的分子机制，已经投入了大量精力来开发细胞和动物模型。来自这些模型的数据表明，APOE4 以剂量依赖性方式加剧了淀粉样蛋白 β 斑块的负担。并且还可能以异构体依赖性方式增强 tau 发病机制。其他研究表明，APOE4 通过不同于 Aβ 或 tau 病理学调节的机制增加了 AD 的风险。此外，血浆 APOE 是否通过影响全身代谢途径也可​​能间接改变 CNS 功能尚不完整；您了解。总的来说，现有研究表明 APOE 可能会影响多种信号通路，因此研究人员已经寻求能够破坏 APOE 病理功能同时保留或增强有益功能的治疗方法。这篇综述将重点介绍目前针对 APOE4 预防或治疗 AD 的一些治疗策略，我们将讨论未来有希望的其他策略。