Is there a role for apolipoprotein E in perinatal brain injury?

Perinatal brain injury remains a major cause of neonatal morbidity and lifelong neurological disability. Despite advances in neonatal care, the molecular determinants that modulate vulnerability and recovery in the immature brain remain poorly defined. Genetic variation is increasingly recognized as a contributor to the heterogeneous susceptibility observed among affected infants. Among the genes implicated in neurodevelopmental outcomes, apolipoprotein E (ApoE) has emerged as a key regulator of lipid metabolism, neuroinflammatory signaling, and neuronal repair in the central nervous system. This systematic review examines clinical studies linking APOE genotype to the occurrence, severity, and outcome of perinatal brain injury, including intraventricular hemorrhage, hypoxic–ischemic encephalopathy, and perinatal stroke, and integrates these findings with a narrative synthesis of experimental and mechanistic literature. Available human data remain limited and heterogeneous. While some studies suggest that the ε2 and ε4 alleles may be associated with increased susceptibility to severe injury and poorer outcomes, findings are inconsistent and require independent replication. Preclinical studies further demonstrate that ApoE modulates glial activation, lipid and cholesterol transport, blood–brain barrier integrity, and neuronal survival following hypoxic–ischemic and inflammatory insults. Isoform-specific effects, especially associated with ApoE4, appear to exacerbate neuroinflammatory and vascular dysfunction. However, despite converging evidence from animal models and adult neurological disease, ApoE-dependent mechanisms in the developing brain remain insufficiently explored. Overall, this review highlights APOE genotype as a plausible contributor to vulnerability following perinatal brain injury and underscores the need for large, well-characterized neonatal cohorts and developmentally appropriate mechanistic studies to inform future neuroprotective strategies.