Does ABO Blood Group Contribute to Glial Function?

Background/Objectives: Interindividual variability in responses to physiological and pathological perturbations remains a fundamental challenge in neuroscience. Astrocytes and microglia are dynamic regulators of brain homeostasis, immune surveillance, neurovascular function, and tissue repair, yet the biological factors contributing to their functional variability remain incompletely understood. The ABO blood group system influences glycobiology, endothelial function, haemostasis, inflammation, and host–environment interactions, but its potential contribution to glial function has received little attention. This Perspective examines whether ABO-associated biology could represent an overlooked modifier of glial functional adaptation. Methods: Evidence and concepts from glycobiology, vascular biology, immunology, and neuroscience are integrated to examine potential links between ABO-associated glycosylation and glial biology, with particular consideration of intrinsic cellular mechanisms, neurovascular interactions, and systemic conditioning. Results: The available evidence does not establish that ABO blood group directly determines astrocyte or microglial function. However, several biological processes influenced by ABO, including glycosylation, endothelial and haemostatic regulation, immune signalling, and host–environment interactions, converge with established regulators of glial function. On this basis, the ABO–Glia Functional Adaptation Framework is proposed as a testable model in which ABO-associated biology may modify glial responses to physiological and pathological perturbations through direct and/or indirect mechanisms. Conclusions: ABO blood group should be regarded as a candidate biological modifier of glial adaptation rather than a determinant of fixed glial phenotypes. Testing this hypothesis through mechanistic and longitudinal studies may clarify whether ABO contributes to interindividual variability in neurobiological responses and whether its inclusion as a stratification variable has value in precision neuroscience.