The Role of the APOE Gene in Age-Related Macular Degeneration

APOE gene variants that protect against Alzheimer’s disease may put people at risk for age-related macular degeneration (AMD), according to the results of a new cohort study in JAMA Ophthalmology.

The APOE gene provides instructions for making a protein called apolipoprotein E, which is involved in lipid metabolism and transportation of cholesterol in the body. It is present in the central nervous system and in drusen (yellow deposits) and basal laminar deposits in the macula, which are early signs of age-related macular degeneration.

The role of APOE in Alzheimer’s disease is well known. One variation, the E4 allele, is a risk factor for Alzheimer’s disease and plays a role in vascular dementia and cerebrovascular disease. Other variations, such as the E2 allele and high plasma apolipoprotein E, have a protective effect for Alzheimer’s disease. Some studies have suggested that the variant E2 and high plasma apolipoprotein E may be associated with a higher risk of age-related macular degeneration.

Investigators in the JAMA Ophthalmology study wanted to understand the full range of APOE variations with risk of age-related macular degeneration. Led by Katrine L. Rasmussen, M.D., Ph.D., in the department of Clinical Biochemistry at Copenhagen University Hospital–Rigshospitalet in Denmark, they used two large general population cohorts — the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS) — and performed population-based sequencing of white people with European ancestry. They performed population-based sequencing of 10,369 people from the Copenhagen City Heart Study, which included 164 peopled who developed any AMD, and 95,177 people from the Copenhagen General Population Study, which included 1,575 who developed AMD.

They found that APOE E2, E3, E4 and rare variations with low plasma apoE E4 were associated with a reduced risk of age-related macular degeneration but rare variations with high plasma apoE E2 were associated with increased risk of AMD.

Investigators also found that APOE variations in the low-density lipoprotein (LDL) receptor binding site may protect for Alzheimer’s disease because of less tau protein in the brain. At the same time, these APOE variations are associated with severe adverse reactions, such as elevated serum cholesterol and triglyceride levels and age-related macular degeneration.

A strength of the study is the large population cohort design, but investigators said a limitation was the population of white people of European ancestry only.

Michelle Grunin, Ph.D., and her colleagues argued for expanding complex disease studies to include more globally diverse samples in a recent commentary in JAMA Ophthalmology.

In an accompanying commentary, Michelle Grunin, Ph.D., a postdoctoral fellow at The Hebrew University of Jerusalem, and her colleagues, discuss the complex relationship between APOE variation, Alzheimer’s disease, and age-related macular degeneration. As they point out in the commentary, Alzheimer’s disease and age-related macular degeneration risk, as well as APOE-risk, varies across ancestry. They point to one study in people of African ancestry where the effect of the APOE E4 allele was modified at a second point upstream of the gene, which reduced the risk for Alzheimer’s.

“Given the role of APOE in AD, AMD, and other diseases, the detection of an APOE-modifying variation in populations that are not primarily of European descent emphasizes the nes,” Grunin and colleagues wrote. “Data from groups historically underrepresented in research are important, even in AMD, for which risk is lowest among populations of primarily African ancestry.”