Age-related macular degeneration (ARMD), characterized by drusen containing lipids, was reported to show a lower frequency of the ApoE epsilon4 allele than control subjects.
Apolipoprotein E is a common component of the extracellular plaques and deposits characteristic of these disorders, including drusen, which are a hallmark of age-related macular degeneration.
A logistic model for early AMD found a significant association with AD diagnosis (p < 0.0001), after adjusting for confounders (age, smoking, hypertension, high and low density lipoproteins, cataract surgery and APOE ε4 carrier status).
A spectrum of complement dysregulation was modeled on the APOE4AMD mouse model by crossing these mice to complement factor H knockout (cfh-/-) mice to test the impact of excess complement activation, and by crossing them to soluble-complement-receptor-1-related protein y (sCrry) mice, in which sCrry acts as a potent inhibitor of mouse complement acting in a manner similar to CFH.
A total of 24 variants from five genes (BCMO1, BCO2, NPCL1L1, ABCG8, and FADS2) not previously related to AMD and four genes related to AMD in previous studies (SCARB1, ABCA1, APOE, and ALDH3A2) were associated independently with AMD, after adjusting for age and ancestry.
After controlling for age, gender, race, cigarette smoking, and other factors, early ARM was not associated with APOE genotypes, with an odds ratio (OR) of 1.35 (95% confidence interval [CI], 0.54-3.38) for epsilon2/epsilon2 genotype, an OR of 1.06 (95% CI, 0.80-1.40) for epsilon2/epsilon3 genotype, an OR of 0.63 (95% CI, 0.32-1.24) for epsilon2/epsilon4 genotype, an OR of 0.99 (95% CI, 0.80-1.24) for epsilon3/epsilon4 genotype, and an OR of 0.88 (95% CI, 0.47-1.63) for epsilon4/epsilon4 genotype, as compared with epsilon3/epsilon3 genotype (reference).
Analysis of CFH, TLR4, and APOE polymorphism in India suggests the Tyr402His variant of CFH to be a global marker for age-related macular degeneration.
Cholesterol efflux genes (APOE and ABCA1) were identified as risk factors for AMD, although how cholesterol efflux influences accumulation of this lipid in sub-RPE deposits remains elusive.
Consistent with a pathogenic role for Aβ, we show here that a mouse model of AMD that invokes multiple factors that are known to modify AMD risk (aged human apolipoprotein E 4 targeted replacement mice on a high-fat, cholesterol-enriched diet) presents with Aβ-containing deposits basal to the retinal pigmented epithelium (RPE), histopathologic changes in the RPE, and a deficit in scotopic electroretinographic response, which is reflective of impaired visual function.
Consistent with previous studies, the APOE epsilon2 allele is associated with a significant increased risk of late ARM development, whereas the epsilon4 allele may confer some protection.
Despite extensive genetic screening of candidate genes only two associations have been identified with AMD (Adenosine triphosphate (ATP)-binding cassette rim (ABCR) protein and apolipoprotein E gene-ApoE).
GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD.
Here, we propose that ApoE serves a fundamentally different purpose in regulating cholesterol homeostasis in the retinal pigment epithelium and this could explain why allelic risk factors are flipped for AMD compared to Alzheimer's disease.