The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.

载脂蛋白 E ε4 ( APOE4 ) 是阿尔茨海默病 (AD) 最强的遗传风险因素，对人脑细胞功能的影响仍不清楚。在这里，我们研究了APOE4对来自群体和同基因人类诱导多能干细胞、死后大脑和APOE靶向替代小鼠的脑细胞类型的影响。群体和等基因模型表明APOE4局部单倍型而不是单一风险等位基因会导致风险。全球转录组分析揭示了星形胶质细胞和小胶质细胞中人类特异性、APOE4驱动的脂质代谢失调。APOE4增强de novo尽管由于星形胶质细胞中溶酶体胆固醇隔离导致细胞内胆固醇升高，但胆固醇合成仍然存在。此外，基质体失调与与神经元共培养的星形胶质细胞中趋化性、胶质细胞活化和脂质生物合成的上调有关，这概括了人脑中星形胶质细胞基质体信号传导的改变。因此，APOE4启动神经胶质细胞特异性细胞和非细胞自主失调，可能导致 AD 风险增加。