For the past three decades, apolipoprotein E (APOE) has been known as the single greatest genetic modulator of sporadic Alzheimer disease (AD) risk, influencing both the average age of onset and the lifetime risk of developing AD. The APOEε4 allele significantly increases AD risk, whereas the ε2 allele is protective relative to the most common ε3 allele. However, large differences in effect size exist across ethnoracial groups that are likely to depend on both global genetic ancestry and local genetic ancestry, as well as gene–environment interactions. Although early studies linked APOE to amyloid-β — one of the two culprit aggregation-prone proteins that define AD — in the past decade, mounting work has associated APOE with other neurodegenerative proteinopathies and broader ageing-related brain changes, such as neuroinflammation, energy metabolism failure, loss of myelin integrity and increased blood–brain barrier permeability, with potential implications for longevity and resilience to pathological protein aggregates. Novel mouse models and other technological advances have also enabled a number of therapeutic approaches aimed at either attenuating the APOEε4-linked increased AD risk or enhancing the APOEε2-linked AD protection. This Review summarizes this progress and highlights areas for future research towards the development of APOE-directed therapeutics.

在过去的三十年里，载脂蛋白 E ( APOE ) 被认为是散发性阿尔茨海默病 (AD) 风险的单一最大遗传调节剂，影响着 AD 的平均发病年龄和终生患 AD 的风险。 APOE ε4 等位基因显着增加 AD 风险，而 ε2 等位基因相对于最常见的 ε3 等位基因具有保护作用。然而，不同种族群体之间的效应大小存在巨大差异，这可能取决于全球遗传祖先和当地遗传祖先，以及基因与环境的相互作用。尽管早期研究将 APOE 与淀粉样蛋白 - β 淀粉样蛋白（定义 AD 的两种罪魁祸首之一）联系起来，但在过去的十年中，越来越多的研究将 APOE 与其他神经退行性蛋白病和更广泛的与衰老相关的大脑变化联系起来，例如神经炎症、能量代谢失败、髓磷脂完整性丧失和血脑屏障通透性增加，对长寿和对病理性蛋白质聚集体的恢复能力具有潜在影响。新颖的小鼠模型和其他技术进步也使得许多治疗方法成为可能，旨在减轻APOE ε4 相关的 AD 风险增加或增强APOE ε2 相关的 AD 保护。本综述总结了这一进展，并重点介绍了 APOE 导向疗法的未来研究领域。