Gene Variants That Protect Against Alzheimer Disease Could Increase Risk of AMD

The risk of age-related macular degeneration (AMD) could be linked to structural variations in the APOE gene that were previously found to be associated with protection against Alzheimer disease.

A study published in JAMA Ophthalmology found that the risk of age-related macular degeneration (AMD) could be connected to structural variation in the APOE gene, which determines apolipoprotein E (apoE) levels, beyond the ε2/ε3/ε4 variants in a population of people with European ancestry.

The leading cause of blindness in high-income countries is AMD, and patients with AMD tend to have deposits of apoE in the macula. A recent study found an association of protection against Alzheimer disease with a variation in APOE, but the development of drugs that aim to mimic this function must account for the known association of the APOE ε2/ε3/ε4 variant with a risk of AMD. As such, this study aimed to assess the association between the entire spectrum of variations in the APOE gene and the risk of AMD in the general population.

The study used 2 cohort populations from the Danish general population: the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS). No participants were enrolled in both cohorts, and only participants of European descent were included due to the differing allelic frequency of APOE in other populations. The participants were all from the central part of Copenhagen or the suburbs surrounding the city.

Participants in the cohorts filled out a questionnaire, underwent a physical examination, and gave blood samples for DNA and biochemical analyses. The national Danish Patient Registry yielded information on diagnoses of AMD. Participants with a history of neovascular and/or nonneovascular AMD were included in the analysis.

There were 105,546 participants included in this study, with a mean (SD) age of 57.7 (13.4) years and a slightly larger female population (55%). There were 164 participants who developed AMD in the 10,369 participants of the CCHS, including 87 with nonneovascular AMD and 123 with neovascular AMD. There were 1575 participants who developed AMD in the 95,177 participants of the CGPS, of whom 911 had nonneovascular AMD and 1109 had neovascular AMD.

There were 27 rare variants identified by sequencing the APOE gene. Increased risk for any AMD, nonneovascular AMD, and neovascular AMD was observed from ε4 to ε3 to ε2. Participants who had ε44 (multifactorially adjusted HR [aHR], 0.66; 95% CI, 0.45-0.96) and ε43 (aHR, 0.80; 95% CI, 0.71-0.90) had a lower risk of any AMD compared with the ε33 variant; risk of AMD was higher in those with the ε32 variant (aHR, 1.15; 95% CI, 1.00-1.31) compared with the ε33 variant. Risks were similar for nonneovascular AMD and neovascular AMD and were similar after adjustment.

Values of plasma apoE levels were increased in participants with Gly145Asp and Arg154Cys and decreased in in participants with Leu46Pro compared with noncarriers. There was an increased risk of AMD (aHR, 3.53; 95% CI, 1.14-10.96), nonneovascular AMD (aHR, 4.20; 95% CI, 1.05-16.85), and neovascular AMD (aHR, 1.46; 95% CI, 0.21-10.39) in participants who were heterozygous for Gly145Asp compared with noncarriers.

An increased risk of AMD (aHR, 4.52; 95% CI, 1.13-18.13) and nonneovascular AMD (aHR, 7.88; 95% CI, 1.96-31.67) in participants who were heterozygous for Arg154Cys.

After multifactorial adjustment, the researchers found a higher risk of any AMD per 1-mg/dL genetic increase of plasma apoE (aHR, 1.12; 95% CI, 1.05-1.19); a further adjustment for APOE ε2/ε3/ε4 (aHR, 1.82; 95% CI, 1.20-2.76) and a model with ε33 only (aHR, 1.77; 95% CI, 1.14-2.75) found that risk was also higher.

Similar risks associated with genetic increase of plasma apoE were found for nonneovascular AMD in the multifactorially adjusted model (aHR, 1.14; 95% CI, 1.05-1.23), after adjustment for APOE ε2/ε3/ε4 (aHR, 2.24; 95% CI, 1.47-3.42), and in participants with only ε33 (aHR, 2.10; 95% CI, 1.13-3.38). There was a higher risk of neovascular AMD in the multifactorially adjusted model (aHR, 1.09; 95% CI, 1.02-1.18) but not in either of the other adjusted models.

There were some limitations to this study. Its findings may not be generalizable, as the population was composed entirely of White participants of European ancestry. There was risk of overfitting due to the weights generated for the variants. Diagnostic information was limited in availability and completeness, which means milder cases of AMD may not have been included. There was a lower response rate at 45%, which could limit the interpretation of results. Plasma apoE is also temporal, so levels could be affected by different covariates.

The researchers concluded that the APOE ε2/ε3/ε4 variant was associated with an increasing trend for risk of AMD. Rare variations were also found to be associated with a reduced risk of AMD.

They noted that certain “APOE variants have previously been reported to have protective associations for Alzheimer disease, but our findings show a simultaneous high risk of AMD. This limits the drug target potential of mechanisms resembling these variants.”


Ramussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Associations of Alzheimer disease–protective APOE variants with age-related macular degeneration. JAMA Ophthalmol. Published online November 17, 2022. doi:10.1001/jamaophthalmol.2022.4602

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