AGE-RELATED MACULAR DEGENERATION CURRENT INVESTIGATIONS AND TREATMENTS

agerelatedmaculardeg774enerationkapak

PATHOGENESIS AND GENETICS

Osman Özen

Kastamonu Training and Research Hospital, Department of Ophthalmology, Kastamonu, Türkiye

Özen O. Pathogenesis and Genetics. In: Çıtırık M, Şekeryapan Gediz B, editors. Age-Related Macular Degeneration: Current Investigations and Treatments. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.3-14.

ABSTRACT

Age-related macular degeneration (AMD) is one of the leading causes of irreversible vision loss in elderly individuals in developed countries. The disease is seen in two clinical forms: neovascular (wet or exudative) AMD, which accounts for approximately 10% of cases, and non-neovascular (dry or atrophic) AMD, which accounts for approximately 90% of cases. Histopathological evaluations and genetic linkage analyses in different populations have shown that interactions between factors such as aging, oxidative stress, chronic inflammation, lipofuscin accumulation, and angiogenesis play important roles in the pathogenesis of AMD. It is suggested that the basic mechanism in the development of AMD is pathological changes such as Bruch membrane (BM) thickening, lipofuscin accumulation in retinal pigment epithelium (RPE) cells, and decreased choroidal circulation, which occur due to the aging process. The oxidative stress process also interacts with genetic factors, the complement system, and inflammation. Excessive production of reactive oxygen species contributes to various pathological mechanisms at the RPE and photoreceptor cell levels. Chronic inflammation and the complement system play an important role in the pathogenesis of AMD. Histopathological examinations have revealed the presence of inflammatory cell infiltration between the RPE-BM complex during the AMD disease process. In addition, inflammation is a condition that triggers neovascularization by increasing the release of pro-angiogenic cytokines, such as vascular endothelial growth factor (VEGF). Lipofuscin material accumulation is observed in RPE cells as a result of dysfunction in the lysosome-mediated degradation mechanism, which leads to further accumulation of cellular waste and causes RPE and photoreceptor cell loss. Decreased choroidal blood flow and hemodynamic changes causing hypoxia also contribute to RPE and photoreceptor atrophy in this process. Factors such as VEGF and angiopoietin trigger the formation of new vessels (angiogenesis) and lead to neovascularization in the macula. The genetic basis of AMD has been found to be associated with variations in genes related to the complement system, retina-related genes, lipoprotein metabolism, and extracellular matrix. In particular, the Y402H polymorphism in the CFH gene is considered the most important variant for AMD risk. The ARMS2 and HTRA1 genes have also been found to be strongly associated with AMD. In conclusion, AMD is a multifactorial disease that results from the complex interaction of aging, oxidative stress, inflammation, and genetic factors. Understanding these factors is an important step for the treatment and prevention of the disease.

Keywords: Age-related macular degeneration; Etiology; Genetic factors; Oxidative stress; Inflammation; Retinal neovascularization

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