Specific apolipoprotein E variants demonstrate distinct mechanisms for protecting neurons from oxidative death. ApoE2 and the rare ApoE3 Christchurch variant actively extract oxidized unsaturated lipids from neurons through the ABCA7 transporter, preventing ferroptosis—a form of iron-dependent cell death increasingly linked to neurodegeneration. Conversely, ApoE4 particles worsen oxidized lipid accumulation, triggering endolysosomal dysfunction that impairs cellular waste processing. This mechanistic insight explains why ApoE2 carriers show reduced Alzheimer's risk while ApoE4 carriers face elevated risk. The protective variants essentially function as molecular vacuum cleaners, removing lipid toxins before they can damage critical neuronal machinery. This represents a paradigm shift from viewing ApoE primarily as a cholesterol transport protein to recognizing its role as an oxidative stress defense system. The findings suggest therapeutic strategies could focus on enhancing oxidized lipid clearance or mimicking protective ApoE variant functions. However, the research utilized cultured neurons and mouse models, requiring validation in human brain tissue and clinical populations before translation to therapies.