Apolipoprotein E (ApoE) is a multifunctional protein involved in lipid transport and lipoprotein metabolism, mediating lipid distribution/redistribution in tissues and cells. It can also regulate inflammation and immune function, maintain cytoskeleton stability, and improve neural tissue Function. Due to genetic polymorphisms of ApoE (ε2, ε3, and ε4), its three common structural isoforms (ApoE2, ApoE3, ApoE4) are also associated with the risk of many diseases, especially degenerative diseases, such as vascular degenerative diseases including atherosclerosis (AS), coronary heart disease (CHD), and neurodegenerative disease like Alzheimer's disease (AD). The frequency of the ε4 allele and APOE variants were significantly higher than that of the ε2 and ε3 alleles in the patients with CHD or AD. In recent years, ApoE has frequently appeared in tumor research and become a tumor biomarker gradually. It has been found that ApoE is highly expressed in most solid tumor tissues, such as glioblastoma, gastric cancer, pancreatic ductal cell carcinoma, etc. Studies illustrated that ApoE could regulate the polarization changes of macrophages, participate in the construction of tumor immune microenvironment, regulate tumor inflammation and immune response and play a role in tumor progression, invasion, and metastasis. Of course, many functions of ApoE and its relationship with diseases are still under research. By reviewing the structure and function of ApoE from degeneration diseases to tumor neoplasms, we hope to better understand such a biomarker and further explore the value of ApoE in later studies.