Abstract
Glaucoma has conventionally been characterized as an optic neuropathy resulting from the degeneration of retinal ganglion cells (RGCs) and axonal loss of the optic nerve head (ONH). However, accumulating data suggest that glaucoma extends beyond ocular effects and encompasses widespread alterations in the brain anatomy, connectivity, and energy metabolism. Therefore, this review aimed to consolidate the current understanding of altered brain metabolism in glaucoma and situate it within the broader context of bioenergetic susceptibility. We investigated the role of mitochondrial malfunction, oxidative stress, glial activation, and impaired axonal transport in the development of energy insufficiency along the retinocerebral axis. Additionally, this review examined the mechanisms by which metabolic deficiencies disrupt synaptic homeostasis and functional connections, potentially leading to neurodegeneration. Notably, this review does not argue for a single causal hierarchy by which metabolic failure universally initiates glaucoma. Rather, we frame bioenergetic insufficiency as a convergent vulnerability state and a downstream amplifier that can interact bidirectionally with established upstream stressors such as intraocular pressure (IOP)–related mechanical strain and neurovascular dysregulation. Particularly, we focused on the bidirectional relationship between mechanical stress associated with IOP and brain metabolic failure, along with evidence that metabolic abnormalities can emerge early and, in longitudinal experimental models, may be detectable before overt structural degeneration; however, the temporal sequence remains unclear because much of the evidence is cross-sectional. Accordingly, mechanistic causality in this review was primarily grounded in experimental/preclinical studies. In contrast, human neuroimaging and metabolomic findings are interpreted primarily as associative biomarkers that support but do not by themselves contribute to glaucomatous neurodegeneration. We also investigated novel diagnostic instruments such as metabolic imaging, cerebrospinal fluid (CSF) biomarkers, and plasma-derived metabolomic signatures, which could facilitate the preclinical identification of glaucomatous neurodegeneration. Furthermore, this review discusses the innovative therapeutic strategies aimed at brain metabolism, including mitochondrial stabilizers, ketone-based therapies, neurovascular modulators, and activity-oriented neurorehabilitation. Collectively, these insights provide an integrative framework in which glaucoma is viewed as an ocular neurodegenerative disease with measurable systemic and cerebral metabolic correlates that may modulate susceptibility and progression, without implying that metabolic failure is a universal primary trigger.