Apolipoprotein E (APOE) is a lipid transport protein encoded by a polymorphic gene with three common isoforms (ε2, ε3, and ε4). While APOE ε4 is widely recognized as the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), proteomic studies have revealed broader immunobiological consequences of APOE variation across tissues and diseases. This chapter examines how current proteomic technologies, including mass spectrometry, SomaScan, Olink, and NULISA, are used to investigate the inflammatory functions of APOE, with an emphasis on platform-specific capabilities, limitations, and cross-platform comparability. Proteomic studies across plasma, cerebrospinal fluid (CSF), brain tissue, induced pluripotent stem cell (iPSC)-derived models, and liver reveal consistent differences in immune signaling associated with APOE genotype. APOE ε4 is linked to widespread upregulation of inflammatory pathways, including cytokine signaling, interferon responses, complement activation, and MHC class I-mediated antigen presentation. These changes are detectable even in cognitively unimpaired individuals lacking classical AD biomarkers, indicating that APOE ε4 modifies baseline immune signaling prior to overt pathology. In iPSC-derived models, APOE ε4 intrinsically activates glial and neuronal inflammatory pathways, including STAT3 and TGF-β signaling, independent of amyloid-β or tau accumulation. Similar inflammatory signatures are observed in peripheral tissues such as the liver, highlighting the systemic nature of APOE ε4’s immunomodulatory effects. In contrast, APOE ε2 is associated with increased expression of neutrophil granule proteins and antimicrobial peptides, suggesting an immune profile skewed toward enhanced innate defense. These findings underscore the pleiotropic role of APOE in shaping both central and peripheral immune environments. Taken together, these findings position APOE as a key modulator of immune network topology, acting through tissue-specific and cell-autonomous mechanisms. Current limitations, such as single-platform reliance and underrepresentation of non-AD phenotypes, highlight the need for multi-platform validation, longitudinal sampling, and integrative multi-omics approaches. A broader investigation of APOE’s immunoregulatory functions will be critical for identifying novel biomarkers and informing genotype-specific therapeutic strategies across neurodegenerative and systemic inflammatory disorders.