APOE4 is the strongest genetic risk factor for Alzheimer’s disease^1,2,3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer’s disease^4,5,6,7,8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE^2,3,4,5,6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes—myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer’s disease.

APOE4 是阿尔茨海默病最强的遗传风险因素^1,2,3。然而，APOE4 对人脑的影响尚未完全了解，这限制了为携带APOE4和其他阿尔茨海默氏病危险因素的个体开发靶向疗法的机会^4,5,6,7,8。在这里，为了更全面地了解APOE4对人脑的影响，我们对APOE4携带者与非携带者的死后人脑进行了单细胞转录组学分析。这表明APOE4与人脑所有细胞类型的广泛基因表达变化有关。^{与 APOE 2,3,4,5,6}的生物学功能一致，APOE4 显着改变与胆固醇稳态和运输相关的信号传导途径。通过对死后人脑、诱导多能干细胞衍生细胞和靶向替代小鼠的组织学和脂质组学分析证实了这些发现，我们发现胆固醇异常沉积在少突胶质细胞中，少突胶质细胞负责绝缘和促进神经元的电活动。我们发现APOE4大脑中胆固醇定位的改变与髓鞘形成的减少同时发生。药理学上促进胆固醇转运可增加APOE4小鼠的轴突髓鞘形成并改善学习和记忆。我们提供了一个单细胞图谱，描述了 APOE4 对衰老人脑的转录作用，并建立了 APOE4、胆固醇、髓鞘形成和记忆之间的功能联系，为阿尔茨海默病提供了治疗机会。