Fang, H.; Liao, X.; Bullen, C. K.; Pu, R.; Wang, H.; Condoleo, J.; Cheat, S.; Chen, X.; Zhang, Y.; Zhang, S.; Huo, D.; Lissit, K.; Yang, A.; Jarvis, K.; Neifert, S.; Huang, Y.; Bishai, W.; Jain, S. K.; Dawson, T.; Dawson, V. L.; Xu, J.

The APOE gene is a major genetic determinant of neurovascular and immune function, yet the mechanisms by which its isoforms modulate brain vulnerability to pathogenic stress remain incompletely understood. Here, we employ isogenic human iPSC-derived immune vascularized Forebrain Organoid-based Multicellular Assembled Cerebral Organoids (FORMA COs) to dissect isoform-specific responses to a clinically relevant viral challenge. We find that APOE2 and APOE4 FORMA-COs exhibit heightened viral RNA burden and distinct neuroinflammatory profiles compared to APOE3. Specifically, APOE4 promotes IL-1 and VEGFA induction, whereas APOE2 leads to elevated TNF{beta} and VEGFA protein accumulation, indicating divergent pathways of injury. Integrated transcriptomic analyses, combined with known and predicted APOE protein protein interaction networks, reveal genotype dependent enrichment of cytokine signaling, angiogenic remodeling, and immune dysregulation. In vivo validation using humanized mouse models corroborates APOE genotype specific vascular remodeling, microglial activation, and oligodendrocyte perturbation. These findings demonstrate that APOE genotype confers context-specific susceptibility to neuroimmune and vascular injury, providing insight into genetic risk mechanisms underlying infection-related and neurodegenerative brain disorders.