The ɛ4 allele of the apolipoprotein E gene (APOE), which translates to the APOE4 isoform, is the strongest genetic risk factor for late-onset Alzheimer disease (AD). Within the CNS, APOE is produced by a variety of cell types under different conditions, posing a challenge for studying its roles in AD pathogenesis. However, through powerful advances in research tools and the use of novel cell culture and animal models, researchers have recently begun to study the roles of APOE4 in AD in a cell type-specific manner and at a deeper and more mechanistic level than ever before. In particular, cutting-edge omics studies have enabled APOE4 to be studied at the single-cell level and have allowed the identification of critical APOE4 effects in AD-vulnerable cellular subtypes. Through these studies, it has become evident that APOE4 produced in various types of CNS cell — including astrocytes, neurons, microglia, oligodendrocytes and vascular cells — has diverse roles in AD pathogenesis. Here, we review these scientific advances and propose a cell type-specific APOE4 cascade model of AD. In this model, neuronal APOE4 emerges as a crucial pathological initiator and driver of AD pathogenesis, instigating glial responses and, ultimately, neurodegeneration. In addition, we provide perspectives on future directions for APOE4 research and related therapeutic developments in the context of AD.

载脂蛋白 E 基因 ( APOE ) 的ɛ4等位基因可翻译为 APOE4 同工型，是晚发性阿尔茨海默病 (AD) 最强的遗传风险因素。在中枢神经系统内，APOE 由多种细胞类型在不同条件下产生，这对研究其在 AD 发病机制中的作用提出了挑战。然而，通过研究工具的强大进步以及新型细胞培养和动物模型的使用，研究人员最近开始以细胞类型特异性的方式以及比以往更深入、更机制的水平研究 APOE4 在 AD 中的作用。特别是，尖端组学研究使得 APOE4 能够在单细胞水平上进行研究，并能够识别 APOE4 在 AD 易感细胞亚型中的关键作用。通过这些研究，很明显，各种类型的 CNS 细胞（包括星形胶质细胞、神经元、小胶质细胞、少突胶质细胞和血管细胞）中产生的 APOE4 在 AD 发病机制中发挥着不同的作用。在这里，我们回顾了这些科学进展，并提出了 AD 细胞类型特异性 APOE4 级联模型。在该模型中，神经元 APOE4 成为 AD 发病机制的关键病理启动子和驱动因素，引发神经胶质反应，最终引发神经退行性变。此外，我们还对 AD 背景下 APOE4 研究和相关治疗发展的未来方向提供了展望。