Abstract
Geographic atrophy (GA) is a vision-threatening late manifestation of age-related macular degeneration (AMD) and is increasingly recognized as the atrophic endpoint toward which advanced dry and neovascular AMD may converge. This review examines the clinical and translational progression from early AMD to GA, focusing on the key pathogenic factors, affected tissues, and stage-specific therapeutic approaches. We performed a mechanism-oriented synthesis of clinical, translational, and preclinical evidence identified through search of Medline, Web of Science Core Collection, and Scopus conducted from February to September 2026. Aging, genetic susceptibility, oxidative stress, mitochondrial dysfunction, impaired heterophagy and autophagy, retinoid by-product accumulation, complement dysregulation, and Bruch’s membrane remodeling progressively disrupt outer-retinal homeostasis. Drusen and subretinal pigment epithelium deposits represent structural markers of this imbalance and contribute to a self-amplifying microenvironment of impaired transport, local inflammation, and tissue remodeling. As reparative capacity fails, regulated cell-death programs including ferroptosis, necroptosis, apoptosis, pyroptosis, and inflammation-associated injury, promote lesion formation and expansion of atrophic areas. Current therapies remain stage-specific: anti-vascular endothelial growth factor agents control exudation in neovascular AMD, whereas complement inhibitors slow GA enlargement without restoring lost RPE-photoreceptor architecture. GA should therefore be regarded as the final expression of cumulative metabolic, immune, vascular, and extracellular matrix failure, supporting earlier multifaceted therapeutic strategies.