The ε4 allele of the apolipoprotein E gene (APOE4) represents the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), prompting growing interest in allele-specific therapeutic strategies. This chapter examines the emerging potential of CRISPR-based gene editing—specifically cytosine base editing (CBE) and prime editing (PE)—to convert APOE4 to lower-risk alleles such as APOE3, APOE2, and rare protective variants including APOE3-Christchurch, APOE3-Jacksonville, and APOE4-R251G. Advances in delivery technologies, particularly lipid nanoparticles (LNPs), synthetic exosomes (SEs), and adeno-associated viral vectors (AAV), are addressing the formidable challenge of delivering gene editing tools across the blood-brain barrier. Studies using isogenic human induced pluripotent stem cell (iPSC) models have demonstrated phenotypic rescue following APOE editing, and recent in vivo studies have confirmed functional editing in the brains of APOE4-knockin mice after intravenous administration. Key challenges remain, including optimization of editing efficiency, cell-type targeting, durability of editing, and determination of optimal therapeutic timing. APOE gene editing thus represents a promising precision medicine approach, with potential both for therapeutic intervention and for mechanistic dissection of APOE4-driven pathophysiology in AD.