Given the low prevalence of APOE2 and APOE4 alleles in the general populace, these data support the multiple hit model of AMD pathogenesis in which the presence of other genetic (e.g., CFH, HTRA1/ARMS2, C3) or environmental (e.g., smoking, high HDL) risks (7, 8, 10, 69) could drive ApoE3 phase separation and drusen nucleation. This evidence concerns the gene HTRA1 and age-related macular degeneration.