The Apolipoprotein E (APOE)locus has garnered significant clinical interest because of its association with Alzheimer’s disease (AD) and longevity. This genetic association appears across multiple genes in theAPOElocus. Despite the apparent differences between AD and longevity, both conditions share a commonality of aging-related changes in mitochondrial function. This commonality is likely due to accumulative biological effects partly exerted by theAPOElocus. In this study, we investigated changes in mitochondrial structure/function-related markers using oxidative stress-induced human cellular models and postmortem brains (PMBs) from individuals with AD and normal controls. Our results reveal a range of expressional alterations, either upregulated or downregulated, in these genes in response to oxidative stress. In contrast, we consistently observed an upregulation of multipleAPOElocus genes in all cellular models and AD PMBs. Additionally, the effects of AD status on mitochondrial DNA copy number (mtDNA CN) varied depending onAPOEgenotype. Our findings imply a potential coregulation ofAPOElocus genes possibly occurring within the same topologically associating domain (TAD) of the 3D chromosome conformation. The coordinated expression ofAPOElocus genes could impact mitochondrial function, contributing to the development of AD or longevity. Our study underscores the significant role of theAPOElocus in modulating mitochondrial function and provides valuable insights into the underlying mechanisms of AD and aging, emphasizing the importance of this locus in clinical research.