The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer’s disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood–brain barrier, differentially impact Alzheimer’s disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer’s disease.

载脂蛋白 E ( APOE ) 基因的 ε4 等位基因是阿尔茨海默病的遗传危险因素，在大脑和外周细胞中大量表达。在这里，我们提出的证据表明，通过血脑屏障与大脑中的外周 apoE 同工型分开，对阿尔茨海默病的发病机制和认知产生不同的影响。为了评估外周apoE的功能，我们开发了在肝脏中表达人APOE3或APOE4但在大脑中未检测到apoE的条件小鼠模型。肝脏表达的 apoE4 通过损害脑血管功能来损害突触可塑性和认知能力。血浆蛋白质组分析揭示了 apoE 同工型依赖性功能途径，突出了细胞粘附、脂蛋白代谢和补体激活。当将年轻小鼠的 ApoE3 血浆输注到老年小鼠体内时，可以改善认知能力并减少血管相关神经胶质增生，而 apoE4 则损害了年轻小鼠血浆的有益作用。人诱导多能干细胞衍生的内皮细胞模型重现了血浆 apoE 异构体对内皮完整性的特异性影响，进一步支持了血管相关机制。与淀粉样蛋白模型小鼠繁殖后，肝脏表达的 apoE4 加剧了大脑淀粉样蛋白病理，而 apoE3 则减轻了这种病理。我们的研究结果证明了外周apoE4的致病作用，为靶向外周apoE治疗阿尔茨海默病提供了强有力的理论依据。