This article provides a systematic review of the epidemiology, pathogenesis, diagnosis, and current treatment of age-related macular degeneration (AMD), emphasizing disease heterogeneity and the importance of personalized therapeutic strategies, offering clear directions for future research.
Literature Overview
This article, 'Age-related macular degeneration,' published in Nature Reviews. Disease Primers, reviews and summarizes the latest research advances in age-related macular degeneration (AMD). It systematically outlines the disease's epidemiological characteristics, genetic and environmental risk factors, pathophysiological mechanisms, clinical diagnosis, and management strategies, while also discussing its impact on patients' quality of life. The authors emphasize that AMD is not a single disease but a spectrum encompassing multiple phenotypes, necessitating individualized treatment plans based on specific phenotypes and disease stages. Although anti-VEGF therapy has significantly improved the prognosis of neovascular AMD, effective interventions remain lacking for late-stage dry AMD—geographic atrophy (GA)—highlighting unmet clinical needs. The article further notes that advances in high-resolution imaging and genomics have facilitated precise phenotypic classification and risk prediction models, laying the theoretical foundation for future targeted therapies. The entire section is coherent and logical, ending with a Chinese period.Background Knowledge
Age-related macular degeneration (AMD) is the leading cause of blindness in individuals over 55 years old in developed countries, primarily affecting the central region of the retina—the macula—and leading to progressive loss of central vision. Its main pathological features include drusen deposition, retinal pigment epithelium (RPE) degeneration, choriocapillaris atrophy, and, in advanced stages, geographic atrophy (GA) or macular neovascularization (MNV). AMD is widely recognized as a multifactorial disease involving complex interactions among aging, genetic susceptibility (e.g., variants in CFH and ARMS2-HTRA1 genes), environmental factors (e.g., smoking, diet), and chronic inflammation. Current research focuses on understanding the roles of lipid metabolism dysregulation, aberrant complement activation, oxidative stress, extracellular matrix remodeling, and mitochondrial dysfunction in AMD pathogenesis. Although anti-VEGF drugs have significantly improved outcomes in neovascular AMD, the long-term treatment burden remains high, and they do not halt GA progression. Furthermore, no effective therapy exists for GA—the advanced form of dry AMD—posing a major challenge in current research. Additionally, the high heterogeneity of AMD suggests it may be driven by distinct molecular mechanisms, making traditional clinical classifications insufficient for precision medicine. Therefore, refined phenotyping based on high-resolution imaging (e.g., OCT, FRA) and genetic information, along with the development of combination therapies or stage-specific interventions targeting different pathways, has become a key focus of current research. This review systematically integrates epidemiological, genetic, pathophysiological, and clinical data, offering a comprehensive perspective on the complexity of AMD and identifying key directions for future translational research.
Research Methods and Experiments
This study is an authoritative review article based on a systematic review and integrative analysis of numerous published epidemiological studies, genome-wide association studies (GWAS), pathological investigations, clinical trials, and basic mechanistic research. The author team synthesized data from global multicenter population studies to assess the prevalence and incidence of AMD and analyze the impact of factors such as race, age, and lifestyle. At the mechanistic level, evidence from human ocular tissue samples, animal models, and in vitro cellular experiments was integrated to elucidate the roles of key pathways including lipid deposition, complement activation, oxidative stress, extracellular matrix alterations, and inflammatory responses. Additionally, studies combining high-resolution retinal imaging techniques (e.g., OCT, FRA) with genetic risk scores (GRS) were reviewed to explore genotype–phenotype associations across different phenotypes and to develop disease progression prediction models. The article also summarizes current clinical management strategies, particularly the efficacy and limitations of anti-VEGF therapy, and analyzes potential reasons for the failure of several phase III clinical trials, emphasizing the need to move beyond single-target strategies.Key Conclusions and Perspectives
Research Significance and Prospects
This review highlights the complexity of AMD as a disease spectrum, challenging the traditional single-mechanism model and offering a new paradigm for future research. By integrating genetic, imaging, and clinical data, it supports the necessity of refined phenotyping, advancing the shift from one-size-fits-all treatment to personalized precision medicine. The article points out that while anti-VEGF therapy represents a major breakthrough, its limitations underscore the urgent need to develop new therapies targeting GA and other non-vascular pathways. For example, drugs targeting the complement system, lipid metabolism, oxidative stress, or extracellular matrix remodeling are at various stages of development.
Future research should focus on building more accurate predictive models by integrating multi-omics data (genomics, epigenomics, radiomics) to identify high-risk individuals and rapid progressors. Additionally, developing combination therapies that simultaneously target multiple key pathways, or dynamically adjusting treatment regimens based on disease stage, may be key to achieving long-term vision preservation. Exploring non-invasive biomarkers to monitor treatment response and disease progression will also help optimize clinical trial design. Ultimately, achieving early intervention and delaying or even reversing disease progression will be central goals in improving patients’ quality of life.
Conclusion
This article provides a comprehensive review of the epidemiology, genetic basis, pathophysiological mechanisms, and current clinical management of age-related macular degeneration (AMD). As one of the leading causes of global blindness, AMD arises from complex interactions among aging, genetics, and environmental factors, resulting in progressive damage to the retina–pigment epithelium–choroid complex. Although anti-VEGF therapy has significantly improved outcomes in neovascular AMD, effective treatments for the advanced dry form—geographic atrophy (GA)—remain lacking, highlighting a substantial unmet clinical need. The study emphasizes that AMD is not a single disease but a spectrum with diverse molecular mechanisms and clinical phenotypes. Advances in high-resolution imaging and genomics are enabling refined phenotypic classification and individualized risk prediction. Future therapeutic strategies should move beyond single-target approaches, shifting toward precision interventions based on specific phenotypes and disease stages, potentially involving combination therapies that simultaneously target multiple pathways such as inflammation, lipid metabolism, oxidative stress, and extracellular matrix remodeling. By integrating multi-omics data with advanced imaging technologies, early prediction, precise phenotyping, and effective intervention may become possible, ultimately delaying or preventing central vision loss and significantly improving patients’ quality of life.
