Glaucoma and Neurodegenerative Disease Risk: A 10-Year Assessment of Real-World Global Data.

Abstract

To evaluate 10-year risk trajectories of newly diagnosed neurodegenerative diseases among glaucoma patients across age-stratified cohorts and clinical subtypes. Retrospective cohort study. Using TriNetX data (2005-2025), glaucoma patients were propensity-matched 1:1 to controls based on baseline demographics, comorbidities, medications, and laboratory metrics. Outcomes were defined using International Classification of Diseases, Tenth Revision codes. Risks for mild cognitive impairment (MCI), Alzheimer's disease (AD), vascular dementia (VD), unspecified dementias, and Parkinson's disease (PD) were assessed. Cohorts were stratified by age (<45 vs >65 years) and subtype (primary open-angle [POAG], primary angle-closure [PACG], and normal-tension [NTG] glaucoma). 1-, 3-, 5-, and 10-year hazard ratios (HRs) and 95% confidence intervals (CIs). Among 384,256 matched pairs, glaucoma correlated with elevated 10-year risks for AD (HR = 1.485; 95% CI,1.427-1.546; P < .001), VD (HR = 1.213; 95%CI, 1.159-1.27; P < .001), and a delayed PD risk peaking at 10 years (HR = 1.115; 95%CI, 1.066-1.167; P < .001). AD and VD risks emerged early in late-onset glaucoma but showed delayed emergence in early-onset patients, where AD risk peaked at 10 years (HR = 2.320; P = .03). Subtype analysis revealed no significant AD associations for POAG (HR = 1.044; P = .10), PACG (HR = 1.096; P = .13), or NTG (HR = 1.097; P = .19). However, VD risk was elevated in POAG (HR = 1.203; 95% CI, 1.129-1.281; P < .001) and PACG (HR = 1.224; 95% CI, 1.056-1.419; P = .007), but not NTG (P = .08). MCI risk increased in POAG (HR = 1.201; 95% CI, 1.120-1.288; P < .001) and NTG (HR = 1.235; 95% CI, 1.089-1.401; P = .001). NTG demonstrated the only significant PD association (HR = 1.283; 95% CI, 1.043-1.577; P = .018), while POAG (P = .05) and PACG (P = .58) showed no correlation. All 3 subtypes maintained significant associations with unspecified dementia (all P < .05). Glaucoma is observationally associated with subsequent neurodegenerative diagnoses, with statistical trajectories varying by onset age and clinical subtype. These findings indicate population-level correlations rather than causal mechanistic linkages.