This study presents a proteomic analysis of drusen, which are extracellular deposits beneath the retinal pigment epithelium on Bruch's membrane and are risk factors for age-related macular degeneration (AMD). The research aimed to understand the molecular composition of drusen and their role in AMD pathogenesis. Using a method to isolate microgram quantities of drusen and Bruch's membrane, the researchers identified 129 proteins in drusen from 18 normal and 5 AMD donors. Immunocytochemical studies localized approximately 16% of these proteins in drusen. Common proteins in normal donor drusen included tissue metalloproteinase inhibitor 3, clusterin, vitronectin, and serum albumin, while crystallin was more frequently detected in AMD donor drusen. Oxidative protein modifications, such as carboxyethyl pyrrole adducts and carboxymethyllysine, were also observed, with carboxyethyl pyrrole adducts being more abundant in AMD than in normal Bruch's membrane. These findings support the hypothesis that oxidative injury contributes to AMD pathogenesis and suggest that oxidative protein modifications may play a critical role in drusen formation. AMD is the most common cause of legal blindness in the elderly population of developed countries. It is characterized by the breakdown of the macula, the central part of the retina responsible for high-acuity vision. Genetic studies have shown that AMD has a strong genetic component, with identical twins exhibiting 100% concordance. Late-onset AMD is usually defined as either "dry" or "wet" and is a slow, progressive disease with genetic and environmental risk factors. The wet form of AMD is characterized by abnormal blood vessels growing from the choriocapillaris through the retinal pigment epithelium, leading to hemorrhage, exudation, scarring, and/or serous retinal detachment. The dry form is more common, affecting approximately 90% of AMD patients, and is characterized by atrophy of the RPE and loss of macular photoreceptors. Currently, there is no cure for AMD, although some success has been achieved in attenuating choroidal neovascularization with photodynamic therapy. The study's findings suggest that oxidative protein modifications may be a key factor in drusen formation and AMD pathogenesis. The research highlights the importance of understanding the molecular composition of drusen to develop potential therapeutic targets for preventing AMD. The study also underscores the role of oxidative stress in the progression of AMD, with evidence suggesting that oxidative modifications of proteins may contribute to the formation and progression of drusen. The results provide important insights into the molecular mechanisms underlying AMD and highlight the potential of oxidative protein modifications as therapeutic targets.This study presents a proteomic analysis of drusen, which are extracellular deposits beneath the retinal pigment epithelium on Bruch's membrane and are risk factors for age-related macular degeneration (AMD). The research aimed to understand the molecular composition of drusen and their role in AMD pathogenesis. Using a method to isolate microgram quantities of drusen and Bruch's membrane, the researchers identified 129 proteins in drusen from 18 normal and 5 AMD donors. Immunocytochemical studies localized approximately 16% of these proteins in drusen. Common proteins in normal donor drusen included tissue metalloproteinase inhibitor 3, clusterin, vitronectin, and serum albumin, while crystallin was more frequently detected in AMD donor drusen. Oxidative protein modifications, such as carboxyethyl pyrrole adducts and carboxymethyllysine, were also observed, with carboxyethyl pyrrole adducts being more abundant in AMD than in normal Bruch's membrane. These findings support the hypothesis that oxidative injury contributes to AMD pathogenesis and suggest that oxidative protein modifications may play a critical role in drusen formation. AMD is the most common cause of legal blindness in the elderly population of developed countries. It is characterized by the breakdown of the macula, the central part of the retina responsible for high-acuity vision. Genetic studies have shown that AMD has a strong genetic component, with identical twins exhibiting 100% concordance. Late-onset AMD is usually defined as either "dry" or "wet" and is a slow, progressive disease with genetic and environmental risk factors. The wet form of AMD is characterized by abnormal blood vessels growing from the choriocapillaris through the retinal pigment epithelium, leading to hemorrhage, exudation, scarring, and/or serous retinal detachment. The dry form is more common, affecting approximately 90% of AMD patients, and is characterized by atrophy of the RPE and loss of macular photoreceptors. Currently, there is no cure for AMD, although some success has been achieved in attenuating choroidal neovascularization with photodynamic therapy. The study's findings suggest that oxidative protein modifications may be a key factor in drusen formation and AMD pathogenesis. The research highlights the importance of understanding the molecular composition of drusen to develop potential therapeutic targets for preventing AMD. The study also underscores the role of oxidative stress in the progression of AMD, with evidence suggesting that oxidative modifications of proteins may contribute to the formation and progression of drusen. The results provide important insights into the molecular mechanisms underlying AMD and highlight the potential of oxidative protein modifications as therapeutic targets.