The cholesterol transporting protein apolipoprotein E (ApoE) occurs in three 
allelic variants in humans unlike in other species. The resulting protein 
isoforms E2, E3 and E4 exhibit differences in lipid binding, integrating into 
lipoprotein particles and affinity for lipoprotein receptors. ApoE isoforms 
confer genetic risk for several diseases of aging including atherosclerosis, 
Alzheimer's disease, and age-related macular degeneration (AMD). A single E4 
allele increases the risk of developing Alzheimer's disease, whereas the E2 
allele is protective. Intriguingly, the E4 allele is protective in AMD. Current 
thinking about different functions of ApoE isoforms comes largely from studies 
on Alzheimer's disease. These data cannot be directly extrapolated to AMD since 
the primary cells affected in these diseases (neurons vs. retinal pigment 
epithelium) are so different. 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.