Exploring Molecular and Clinical Dimensions of Glaucoma as a Neurodegenerative Disease

Glaucoma is traditionally defined as an ocular disease characterized by progressive retinal ganglion cell degeneration, in some cases with elevated intraocular pressure (IOP), and optic nerve damage. However, growing evidence indicates that glaucoma shares critical features with neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. This study aimed to explore the systemic nature of primary open-angle glaucoma (POAG) by integrating visual function, cognitive performance, and transcriptomic profiling. We conducted a multidimensional assessment of POAG patients and age-matched controls, accounting for demographic factors. Structural parameters included retinal nerve fiber layer (RNFL) thickness, measured using optical coherence tomography (OCT), and visual field indices mean deviation (MD) and pattern standard deviation (PSD). Cognitive function was evaluated across multiple domains, encompassing visual memory, executive function, processing speed, and verbal fluency. Additionally, transcriptomic analysis was performed from conjunctival samples to identify differentially expressed genes (DEGs) and enriched pathways. POAG patients exhibited significant RNFL thinning, which correlated with both visual field loss and cognitive impairments, particularly in terms of visual memory and executive function. Transcriptomic profiling revealed a distinct gene expression signature in POAG, including upregulation of TTBK1 and CCN2 (CTGF), genes associated with tau phosphorylation and extracellular matrix remodeling. Functional enrichment analysis indicated the involvement of neurodegenerative pathways, such as glutamate signaling, calcium signaling, and cell adhesion. Our findings support the reclassification of glaucoma as a neurodegenerative disease with both ocular and cognitive manifestations. Furthermore, biomarkers such as TTBK1 and CCN2 may serve as potential targets for early detection and neuroprotective therapy.