ApoE4 and Alzheimer’s Disease: Glial Cell Dysfunction, Metabolic Crosstalk, and Precision Medicine Perspectives

Introduction: Alzheimer’s disease (AD) remains one of the most challenging neurodegenerative disorders, and genetic factors play a major role in its development. Among them, the Apolipoprotein E (APOE) gene, especially the APOE4 variant, is strongly linked to higher disease risk. This review explores how understanding APOE’s role can open the door to precision therapies designed to slow or prevent AD. Methods: We reviewed recent studies and clinical data focused on APOE-targeted approaches. These included research on APOE genotyping, biomarker-based clinical trials, lifestyle interventions, small molecule modulators, gene-silencing methods, gene-editing tools, and APOE-directed immunotherapies. Evidence from preclinical and early clinical studies was analyzed to highlight emerging strategies. Results: Findings show that carrying the APOE4 variant accelerates amyloid build-up, increases brain inflammation, and weakens the blood–brain barrier, all of which contribute to earlier onset of AD. Several targeted strategies are showing promise, such as lifestyle changes tailored to APOE status, drugs that improve ApoE lipidation, antisense oligonucleotides that reduce APOE4 expression, CRISPR-based gene editing to correct the risk variant, and antibodies that neutralize harmful forms of ApoE. Discussion: These advances suggest that combining APOE genotyping with blood, CSF, and imaging biomarkers could help identify people at the highest risk and guide early, personalized treatment. While most of these approaches are still experimental, they mark an important shift toward precision medicine in AD. Conclusion: Targeting APOE-related pathways may become a powerful way to delay or prevent AD, especially in people with the APOE4 variant. Large, well-designed clinical trials are now needed to bring these promising strategies into practice.