FIGURE 10.

Hypothesis-generating model of the potential relationship among APOE-associated lipid pathways, macrophage lipid handling, and disease manifestations in IEM. The model integrates the bioinformatics findings of the present study with mechanisms proposed in previously published literature. APOE was prioritized at the intersection of lipid metabolism and macrophage-related reference signatures, whereas the clinical cases demonstrated macrophage activation and vacuolated macrophage morphology. The proposed relationships among altered APOE-related lipid handling, macrophage dysfunction, lysosomal stress, inflammation, fibrosis, thrombosis, and multi-organ involvement were not directly tested in the twin patients. The model should therefore be interpreted as a framework for future experimental investigation rather than an established causal pathway.