We analyzed Apolipoprotein A-1 (ApoA-1) containing lipoproteins isolated from Bruch’s membrane (BrM) of elderly human donor eyes and found a unique proteome, quite different from HDL isolated from donor plasma of the same individuals. The most striking difference is higher concentrations of ApoB and ApoE, which bind to glycosaminoglycans (GAGs). We hypothesize that this interaction promotes lipoprotein deposition onto BrM GAGs, initiating downstream effects that contribute to RPE dysfunction/death. We tested this hypothesis using two therapeutic strategies to alter the lipoprotein/protein profile of these extracellular deposits. First, we used short, heparan sulfate oligosaccharides to remove lipoproteins already deposited in both the extracellular matrix of RPE cells and in aged, donor BrM tissue. Second, we used an ApoA-1 mimetic, 5A peptide, which modulates the relative amounts of cholesterol and ApoA-1, ApoB, and ApoE secreted both apically and basolaterally from primary porcine RPE cells. Significantly, the 5A peptide altered the proteomic profile of circulating HDL and ameliorated some of the potentially harmful changes in protein composition seen with a high fat, high cholesterol diet in a mouse model of AMD. Together, these results indicate that HDL interactions with BrM represent a viable target to slow AMD progression in humans