No Strong Association between the Apolipoprotein E E4 Allele and Glaucoma: A Multicohort Study

Sean Mullany, Santiago Diaz-Torres, Joshua M. Schmidt, Daniel Thomson, Ayub Qassim, Henry N. Marshall, Lachlan S.W. Knight, Ella C. Berry, Antonia Kolovos, David Dimasi, Stewart Lake, Richard A. Mills, John Landers, Paul Mitchell, Paul R. Healey, Toby Commerford, Sonja Klebe, Emmanuelle Souzeau, Mark M. Hassall, Stuart MacGregorPuya Gharahkhani, Owen M. Siggs, Jamie E. Craig

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Purpose: To elucidate a potential association between the apolipoprotein E (APOE) E4 allele and glaucoma prevalence in large cohorts. 

Design: A cross-sectional analysis of baseline and prospectively collected cohort data. 

Participants: UK Biobank (UKBB) participants of genetically determined European ancestry (n = 438 711). Replication analyses were performed using clinical and genotyping data collected from European participants recruited to the Canadian Longitudinal Study of Aging (CLSA; n = 18 199), the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG; n = 1970), and the Blue Mountains Eye Study (BMES; n = 2440).

Methods: Apolipoprotein E alleles and genotypes were determined, and their distributions were compared on the basis of glaucoma status. Similar analyses were performed using positive control outcomes associated with the APOE E4 allele (death, dementia, age-related macular degeneration) and negative control outcomes not associated with the APOE E4 allele (cataract, diabetic eye disease). Outcome phenotypes were also correlated with Alzheimer's dementia (AD), a clinical outcome highly associated with the APOE E4 allele. 

Main Outcome Measures: Results of APOE E4 genotype-phenotype comparisons were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Replication analyses investigated APOE E4 associations in 2 replication cohorts (CLSA and ANZRAG/BMES).

Results: The APOE E4 allele was inversely associated with glaucoma (OR, 0.96; 95% CI, 0.93–0.99; P = 0.016) and both negative controls (cataract: OR, 0.98; 95% CI, 0.96–0.99; P = 0.015; diabetic eye disease: OR, 0.92; 95% CI, 0.87–0.97; P = 0.003) in the UKBB cohort. A paradoxical positive association was observed between AD and both glaucoma (OR, 1.30; 95% CI, 1.08–1.54; P < 0.01) and cataract (OR, 1.15; 1.04–1.28; P = 0.018). No association between the APOE E4 allele and glaucoma was observed in either replication cohort (CLSA: OR, 1.03; 95% CI, 0.89–1.19; P = 0.66; ANZRAG/BMES: OR, 0.97; 95% CI, 0.84–1.12; P = 0.65). 

Conclusions: A small negative association observed between APOE E4 and glaucoma within the UKBB was not evident in either replication cohort and may represent an artifact of glaucoma underdiagnosis in APOE E4 carriers. 

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Original languageEnglish
Article number100287
Number of pages13
JournalOphthalmology Science
Issue number3
Early online date13 Feb 2023
Publication statusPublished - Sept 2023


  • Alzheimer's dementia
  • APOE
  • Apolipoprotein E
  • Glaucoma
  • POAG


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