Associations of Alzheimer Disease–Protective APOE Variants With Age-Related Macular Degeneration

Abstract

ImportanceThe association of major lipid genes with and their potential as drug targets for age-related macular degeneration (AMD) is unknown. These associations are important to study because AMD is the leading cause of irreversible late-onset blindness in high-income countries.ObjectiveTo determine whether the full range of structural genetic variation in apolipoprotein E (APOE), a master gene in peripheral and cerebral lipid metabolism, is associated with risk of AMD.Design, Setting, and ParticipantsThis cohort study used data from the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS) cohorts. Participants were followed from study inclusion at the time of blood sampling to occurrence of event, death, emigration, or December 7, 2018, whichever came first. For participants in CCHS, the APOE gene was sequenced, and 9 variants with a heterozygote frequency of at least 0.0002 were genotyped in the CGPS. Observers were masked to patient groupings. Data were analyzed from March to September 2021.ExposuresThe exposure was APOE status, and the direct gene product in plasma, apoE levels, was measured in all participants.Main Outcomes and MeasuresCox regression was applied to estimate risk of AMD associated with APOE genotype.ResultsA total of 105 546 participants (mean [SD] age, 57.7 [13.4] years; 58 140 [55%] female participants) were included. Compared with participants with the common ɛ33 genotype, risk of AMD was lower in participants with ε44 (multifactorially adjusted hazard ratio [aHR], 0.66; 95% CI, 0.45-0.96) and ε43 (aHR, 0.80; 95% CI, 0.71-0.90) genotypes and higher in the ε32 (aHR, 1.15; 95% CI, 1.00-1.31) genotype. Compared with noncarriers, risk of AMD was higher for participants with Gly145Asp (aHR, 3.53; 95% CI, 1.14-10.96) and Arg154Cys (aHR, 4.52; 95% CI, 1-13-18.13) heterozygotes. Results were similar after further adjustment for lipid traits and after adjustment for the APOE ε2/ε3/ε4 variant. Combining all common and rare structural variants in a weighted allele score, risk of AMD per 1-mg/dL genetically higher plasma apoE was increased in the adjusted model (aHR, 1.12; 95% CI, 1.05-1.19), the adjusted model plus APOE ɛ2/ɛ3/ɛ4 status (aHR, 1.82; 95% CI, 1.20-2.76), and the adjusted model in individuals with the ε33 genotype only (aHR, 1.77; 95% CI, 1.14-2.75).Conclusions and RelevanceThese findings highlight that structural variation in APOE beyond the ε2/ε3/ε4 variants may be important for risk of AMD in a population of European ancestry. Rare functional ɛ2-like variants in APOE have previously been reported to have protective associations for Alzheimer disease but the present findings suggest a simultaneous high risk of AMD. This would limit the drug target potential of mechanisms resembling these variants.

Genetic and molecular biomarkers for geographic atrophy

“…APOE is present in drusen (Klaver et al., 1998; Mahley, 2016) and cholesterol homeostasis in the RPE is dysregulated in AMD (Bowes Rickman et al., 2013; Pikuleva & Curcio, 2014). Combined with the genetic association to AMD risk and GA lesion growth, these data suggest a role for APOE in the regulation of lipoproteins in the retina leading to AMD pathogenesis (Rasmussen et al., 2023).…”

Alzheimer Disease Treatment With Acetylcholinesterase Inhibitors and Incident Age-Related Macular Degeneration

“…Importantly the E4 allele increases the odds of AD development but is protective for AMD in those with European ancestry. 44 However, the link between the E4 al-lele and AMD risk may vary over diverse patient populations as it does for AD. 45 Future studies should incorporate genetic predisposition for AMD to confirm the effect of AChEIs.…”

Note the Nuance—Examining the Association of Alzheimer-Protective APOE Variation With Risk for Age-Related Macular Degeneration

“…No linkage estimates for the association between the studied rare variants and the ε2/ε3/ε4 genotypes are available from Ensembl, 1KG, or GnomAD due to their rarity in worldwide populations (the authors show this in eTable 2 in the Supplement of their article). 4 Further, 18 other known nonmissense rare variants were not included in this study. Therefore, the impact of these other known rare variants on apoE function, apoE levels in plasma, AMD risk, and trans effects on the particular variants studied herein is unknown.…”

“…A contemporary debate on the influence of rare APOE variation on potential AD-focused drug targets in APOE highlights an area for concern . The complex relationship between apoE levels, APOE variation, AD risk, and AMD risk is the premise for the study presented in this issue of JAMA Ophthalmology by Rasmussen and colleagues, wherein the authors evaluate these factors in a large, longitudinal cohort of more than 100 000 Europeans.…”

“…Additionally, the authors make sweeping statements regarding testing the “full spectrum” of allelic variation in APOE ; however, it is impossible to know based on these analyses if there are other variants upstream, downstream, or completely outside the APOE locus that are in linkage or have trans impact on the current rare variants studied that would influence their effects, because the rare variants studied here in APOE are so very rare. No linkage estimates for the association between the studied rare variants and the ε2/ε3/ε4 genotypes are available from Ensembl, 1KG, or GnomAD due to their rarity in worldwide populations (the authors show this in eTable 2 in the Supplement of their article) . Further, 18 other known nonmissense rare variants were not included in this study.…”