Abstract Age-related macular degeneration (AMD) is a disease of aging that presently has very limited therapeutic resources. Soft drusen are deposits of protein and lipid between the retinal pigment epithelium (RPE) and choroidal capillaries in the Bruch's membrane. These deposits are visible in fundus photography as white to yellow patches in the macula. Their presence is a diagnostic feature of early asymptomatic AMD and a risk factor for developing late, symptomatic AMD. It was suggested over 25 years ago that drusen interfere with the flow of water and metabolites between the choroid capillaries and RPE cells and cause RPE cells either to die as in geographic atrophy and to initiate neovascularization as in wet AMD. However, the source of druse lipid has remained unknown. At various times, it was proposed that RPE plasma membrane vesicles or apolipoprotein B-lipoprotein secreted by the RPE was the source of these lesions. Recent genome-wide association studies pointed to an unexpected culprit: high-density lipoprotein (HDL). It had been known that apolipoprotein E (apo E) isoform ε4 is protective for AMD. This is the same isoform that does not mediate cell cholesterol efflux well and is a risk factor in atherosclerosis and Alzheimer's disease. But in AMD it is protective. The genome-wide association studies additionally implicated ATP-binding cassette transporter subfamily A member 1 (ABCA1) in AMD. ABCA1 mediates synthesis of HDL from lipid and apoE. ABCA1 alleles that increase plasma HDL cholesterol levels are a risk factor for AMD. Thus, increased production of HDL is an AMD rick factor. We outline reasons from druse composition and our preliminary data for the RPE and not plasma origins of HDL that is deposited in drusen. We then propose to test the hypothesis that hyperactive synthesis of HDL by the RPE contributes to druse formation. The hypothesis is tested in a mouse model of ABCA1 overexpression in the RPE in Aim 1. The hypothesis is also tested in polarized RPE monolayer cultures derived from human induced pluripotent stem cells either expressing or missing ABCA1 in Aim 2. Results of this exploratory project will provide evidence for a larger project into the role of HDL in AMD pathology.