{"doi":"10.1016/j.exer.2025.110304","title":"Dissecting the biological complexity of age-related macular degeneration: Is it one disease, multiple separate diseases, or a spectrum?","abstract":"Clinicians recognize the heterogeneity of age-related macular degeneration (AMD) in presentation, progression, and treatment response, as well as the challenges in distinguishing it from other macular degenerations. As part of the 2024 Ryan Initiative for Macular Research meeting, a group of clinician-scientists and basic scientists were convened to consider the question of whether AMD should be classified as a single disorder or a spectrum of conditions. To answer this question, we reviewed research on several “dimensions” that constitute AMD risk or pathogenesis: genetics, ancestry, retinal imaging findings, diet and environment, aging, and outer retinal molecular and cellular pathways. The group reached a consensus that AMD represents a heterogeneous collection of disease states arising from the interplay of these dimensions. This heterogeneity can be conceived of as a “cloud” of AMD phenotypes. Defining subtypes within this “cloud” requires longitudinal cohorts of well-genotyped and phenotyped patients who progress from no AMD through late AMD, analyzed by unsupervised learning. Comparing the AMD subtypes that emerge from this analysis, especially -omics data from each subtype, will illuminate biology that is applicable to certain subtypes of AMD patients and molecular pathogenic mechanisms that universally apply to all AMD. This knowledge will, in turn, drive improved drug development. • Rather than being a single disease, AMD is either a continuous or discontinuous spectrum with varying presentations, progression rates, outcomes, and responses to treatment. • Multiple factors contribute to AMD, including genetics, ancestry, retinal imaging findings, diet/environment, aging, and outer retina biological pathways. • The factors that contribute to AMD can be conceived of as axes on a multi-dimensional coordinate system, with AMD occupying a cloud of points in this coordinate system. • Well-characterized longitudinal studies of AMD patients need to be combined with unsupervised learning to define disease subtypes that exist within the AMD “cloud”. • With AMD subtypes defined, comparing omics data between subtypes will identify biological pathways and therapeutic targets critical for specific AMD subtypes.","journal":"Experimental Eye Research","year":2025,"id":513693,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1376178,"name":"Benjamin R. 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Zouache","orcid":"0000-0003-3689-7748","position":10,"is_corresponding":false},{"id":490100,"name":"Burt T. Richards","orcid":"0000-0003-1789-2335","position":11,"is_corresponding":false},{"id":54647,"name":"Gregory S. Hageman","orcid":"0000-0001-6360-829X","position":12,"is_corresponding":false},{"id":1376179,"name":"Gerry Rodrigues","orcid":null,"position":13,"is_corresponding":false},{"id":277735,"name":"Kapil Bharti","orcid":"0000-0003-4884-3173","position":14,"is_corresponding":false},{"id":274377,"name":"John G. Flannery","orcid":"0000-0002-0720-8897","position":15,"is_corresponding":false},{"id":54651,"name":"Michael B. 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