In recent decades, the human APOE gene has emerged as an intricate and fascinating genetic entity. From its genomic landscape to its gene products, it is rich with layers of complexity that expand beyond traditional notions of genes. The significance of APOE in human health is underscored by its associations with various disorders, prompting an in-depth exploration of its molecular features and biological implications. APOE’s crucial genetic variations not only produce distinct apoE protein isoforms but also impact the gene’s epigenetic signature. This interaction between genetics and epigenetics likely governs the expression and biological effects of APOE. Recent progress in epigenetics suggests a sophisticated hierarchy of epigenetic mechanisms within the APOE locus, involving both APOE and its neighboring genes. This indicates the potential for coregulation of APOE with its flanking genes within a three-dimensional genomic framework. Consequently, the genetic associations observed with various phenotypes and disorders in the APOE locus are likely a result of the combined biological effects of multiple genes within that locus. Comprehending the genetic and epigenetic mechanisms of APOE is vital for understanding its diverse functions and biological impacts. This understanding could potentially pave the way for innovative therapeutic approaches tailored to tackle APOE-associated health challenges.