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Genetic Risk Factor for Alzheimer's Disease Linked to Reduced Glaucoma Risk

Journal

Originally published on Investigative Ophthalmology & Visual Science

Key findings

  • This study used data from two genome-wide association studies to examine whether APOE alleles are associated with primary open-angle glaucoma
  • The APOE e4 allele, the strongest known genetic risk factor for Alzheimer's disease, was associated with reduced risk of primary open-angle glaucoma (OR, 0.83; 95% CI, 0.74–0.94; P=0.002)
  • These findings imply a mechanistic difference between neurodegenerative diseases of the eye and those of the brain

Prior research has demonstrated that some of the genes associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis, also increase the risk of glaucoma—a group of disorders resulting in loss of retinal and optic nerve cells that is the third leading cause of blindness worldwide. However, Milica A. Margeta, MD, PhD, assistant professor of Ophthalmology at Harvard Medical School, and Janey L. Wiggs, MD, PhD, Paul Austin Chandler professor of Ophthalmology at Harvard Medical School and associate chief of Ophthalmology Clinical Research at Massachusetts Eye and Ear, and colleagues have found this isn't true across the board.

In Investigative Ophthalmology & Visual Science, the researchers report that the apolipoprotein E (APOE) ε4 allele, the strongest known genetic risk factor for late-onset Alzheimer's disease (AD), is associated with reduced risk of primary open-angle glaucoma (POAG). This finding suggests a mechanistic difference between neurodegenerative diseases of the eye and brain.

Study Methods

The researchers analyzed data from two case–control genome-wide association studies:

  • The Mass Eye and Ear component of the Glaucoma Genes and Environment study—486 POAG cases and 344 controls
  • The National Eye Institute Glaucoma Human Genetics Collaboration—2,120 POAG cases and 2,262 controls

The team tested the following for their associations with glaucoma:

  • APOE ε3, the most common APOE allele and considered the baseline for AD risk
  • APOE ε4, which raises the risk of AD relative to ε3
  • APOE ε2, which is protective against AD

APOE Results

In the combined dataset, APOE ε4 was inversely associated with POAG overall, and in both the high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) subgroups:

  • POAG overall—OR, 0.83; 95% CI, 0.74–0.94; P=0.002
  • HTG—OR, 0.81; 95% CI, 0.70–0.94; P=0.005
  • NTG—OR, 0.71; 95% CI, 0.58–0.87; P=0.001

The largest effect of APOE genotype was observed for NTG cases versus controls (P=0.008). This implies that APOE could directly regulate retinal ganglion cell degeneration rather than indirectly through regulation of intraocular pressure.

17%
lower risk of primary open-angle glaucoma overall in cases with APOE ε4 than controls

19%
lower risk of high-tension glaucoma in cases with APOE ε4 than controls

29%
lower risk of normal-tension glaucoma in cases with APOE ε4 than controls

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