The association between glaucoma and dementia in a national cohort of All of Us participants.

Purpose: To assess the association between glaucoma and its subtypes and incidence of dementia and its subtypes across APOE genotypes in the National Institutes of Health (NIH) All of Us Research Program.

Design: Retrospective longitudinal cohort study.

Subjects: A cohort of individuals with linked electronic health record (EHR) data in the All of Us dataset, with every individual with a glaucoma diagnosis matched with four control participants. Participants diagnosed with dementia prior to glaucoma were excluded.

Methods: A 1:4 cohort of participants with a glaucoma diagnosis and control participants was created using a propensity score matching design that considered age, race, ethnicity, and sex. Among participants with whole-genome sequencing data, APOE was genotyped to stratify for sub-analyses. Multivariable Cox regression model was used to adjust for residual imbalance in comorbidities: hypertension, obesity, depression, traumatic brain injury, type 2 diabetes, and hearing loss.

Main outcome measure: Incidence of dementia and its subtypes.

Results: Among the 393497 All of Us participants with linked EHRs, we identified 9444 individuals (2.40%) with glaucoma diagnoses (excluding participants with diagnoses of dementia before glaucoma) and 37776 matched controls without glaucoma. During the observation period (median: 6.5 years, inter-quartile range: 3.3 to 10.7 years), dementia was diagnosed in 1127 (2.39%) individuals. Glaucoma was associated with a significantly increased risk of all-cause dementia (adjusted HR (aHR): 1.23, 95% CI: 1.08-1.40), Alzheimer's disease (aHR: 1.60, 95% CI: 1.26-2.02), and vascular dementia (aHR: 1.38, 95% CI: 1.04-1.83). Among glaucoma subtypes, primary open-angle glaucoma (POAG, N=5756) and normal-tension glaucoma (NTG, N=1106) was linked to elevated risk of Alzheimer's disease (POAG: aHR: 1.48, 95% CI: 1.11-1.96; NTG: aHR: 1.87, 95% CI: 1.09-3.18), while angle-closure glaucoma (N=3150) showed no significant association (aHR=1.49, 95% CI: 0.91-2.27). Glaucoma was associated with an increased risk of all-cause dementia across the three APOE genotypes assessed, with the greatest increased risk observed in ε2ε3 (N=4965, aHR: 1.76, 95% CI: 1.11-2.79), followed by ε3ε3 (N=23667, aHR: 1.45, 95% CI: 1.19-1.75) and ε3ε4 (N=8544, aHR: 1.43, 95% CI: 1.09-1.87).

Conclusions: Glaucoma was associated with a higher risk of dementia with varying associations among glaucoma and dementia subtypes across APOE genotypes.