Apolipoprotein E (ApoE) is a key genetic and biochemical biomarker implicated in lipid metabolism, neurodegeneration, and cardiovascular diseases, most notably Alzheimer’s disease (AD). The three common isoforms ApoE E2, E3, and E4 differ in their influence on disease risk, with ApoE E4 strongly associated with increased susceptibility to late-onset AD. Accurate and early detection of ApoE protein isoforms is therefore critical for risk assessment, clinical monitoring, and therapeutic development. Immunosensors, a class of biosensors based on antibody–antigen interactions, have emerged as powerful tools for the rapid, sensitive, and specific detection of ApoE in various biological matrices. This review highlights recent advances in electrochemical, optical, and nanomaterial-based immunosensor platforms designed to detect ApoE, emphasizing their analytical performance, fabrication techniques, and clinical relevance. Additionally, challenges in isoform-specific detection, sensitivity optimization, and real-world sample analysis are discussed. The integration of ApoE-targeted immunosensors into diagnostic pipelines holds significant promise for precision medicine approaches in neurodegenerative and metabolic disease management.