Apolipoprotein E (apoE) plays an important role in cholesterol metabolism and repair after injury. In humans, there are three major isoforms, (apoE2, 3, and 4) encoded by the APOEε2, ε3, and ε4 alleles, whereof the latter is a well-known risk factor for the development of cardiovascular and Alzheimer’s disease, and cognitive injury following various environmental challenges. Outside of the brain, the major source of circulating apoE is the liver. As liver-secreted apoE cannot pass the blood-brain-barrier, historically apoE and other liver-generated factors secreted into the blood were assumed not to affect brain function. However, increasing evidence supports the role of the liver and liver-generated factors on brain function. Translational studies of how the liver and its function might affect the brain are inherently difficult due to the species-specific differences in key processes, like lipid metabolism, between mouse and man. Chimeric models like humanized liver mice offer unprecedented opportunities to study the role of the liver and liver-generated factors including apoE in a close-to-human environment, albeit not without challenges. In addition to humanized liver mice, in vitro models including human primary hepatocytes and hepatoma cell lines are being used to define and increase our understanding of apoE isoform-dependent effects on liver function. Albeit the use of well-developed liver organoid models to study hepatic functions and diseases, studies aiming to elucidate APOE/apoE biology in these models are yet to be established. In this chapter, humanized liver mice and in vitro models to study the role of APOE genotype and apoE isoforms on liver and brain function are discussed. These models are not only relevant to brain function of human liver transplant recipients, but also for the development of therapeutic strategies to improve brain function in those at risk to develop neurodegenerative diseases and cognitive impairment.