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.

Participants: 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 before glaucoma were excluded.

Methods: A 1:4 cohort of participants with glaucoma and control participants was created using a propensity score-matching design that considered age, race, ethnicity, and sex. Participants with whole-genome sequencing data were stratified by APOE genotype for sub-analyses. A multivariable Cox regression model was used to adjust for residual imbalance in comorbidities.

Main outcome measures: Incidence of dementia and its subtypes.

Results: Among the 393 497 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 37 776 matched controls without glaucoma. During the observation period (median, 6.5 years; interquartile range, 3.3-10.7 years), dementia was diagnosed in 1127 individuals (2.39%). Glaucoma was associated with a significantly increased risk of all-cause dementia (adjusted hazard ratio [aHR], 1.23; 95% confidence interval [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) were linked to an 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), whereas 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, (ε2ε3 > ε3ε3 > ε3ε4).

Conclusions: Glaucoma was associated with a higher risk of dementia across APOE genotypes, with varying associations among glaucoma and dementia subtypes. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.