APOE4 is a strong genetic risk factor for Alzheimer’s disease and Dementia with Lewy bodies; however, how its expression impacts pathogenic pathways in a human-relevant system is not clear. Here using human iPSC-derived cerebral organoid models, we find that APOE deletion increases α-synuclein (αSyn) accumulation accompanied with synaptic loss, reduction of GBA levels, lipid droplet accumulation and dysregulation of intracellular organelles. These phenotypes are partially rescued by exogenous apoE2 and apoE3, but not apoE4. Lipidomics analysis detects the increased fatty acid utilization and cholesterol ester accumulation in apoE-deficient cerebral organoids. Furthermore, APOE4 cerebral organoids have increased αSyn accumulation compared to those with APOE3. Carrying APOE4 also increases apoE association with Lewy bodies in postmortem brains from patients with Lewy body disease. Our findings reveal the predominant role of apoE in lipid metabolism and αSyn pathology in iPSC-derived cerebral organoids, providing mechanistic insights into how APOE4 drives the risk for synucleinopathies.

APOE4是阿尔茨海默病和路易体痴呆的强遗传风险因素；然而，其表达如何影响人类相关系统中的致病途径尚不清楚。使用人类 iPSC 衍生的脑类器官模型，我们发现APOE缺失会增加 α-突触核蛋白 (αSyn) 的积累，并伴有突触损失、GBA 水平降低、脂滴积累和细胞内细胞器失调。这些表型部分被外源apoE2 和apoE3 拯救，但apoE4 不能。脂质组学分析检测到 apoE 缺陷的大脑类器官中脂肪酸利用率的增加和胆固醇酯的积累。此外，与APOE3相比， APOE4大脑类器官增加了 αSyn 积累。携带APOE4还会增加路易体病患者死后大脑中 apoE 与路易体的关联。我们的研究结果揭示了 apoE 在 iPSC 衍生的脑类器官的脂质代谢和 αSyn 病理学中的主要作用，为APOE4如何驱动突触核蛋白病风险提供了机制见解。