Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss, especially among adults over 60 years old1 2. This eye disease primarily affects the macula, the central part of the retina responsible for sharp, detailed vision needed for reading, driving, and recognizing faces3 4. The prevalence of AMD is increasing globally due to aging populations, making understanding its causes and risk factors critical for prevention and management5 6.
Age-Related Macular Degeneration
AMD is an aging-related ocular disease characterized by progressive damage to the macula, leading to loss of central vision7 4. Early AMD is marked by the formation of drusen—lipoprotein-rich deposits beneath the retinal pigment epithelium (RPE)—and pigmentary changes in the macula8 1. These changes cause mild to moderate vision loss9 . The disease progresses to advanced stages, which include geographic atrophy (dry AMD) and choroidal neovascularization (wet AMD) 110.
The pathogenesis of AMD is multifactorial, involving complex interactions among metabolic, functional, genetic, and environmental factors11 12. Dysfunction and degeneration of the RPE layer play a central role in both dry and wet forms of AMD13 . Geographic atrophy is characterized by gradual degeneration and progressive atrophy affecting the RPE, choriocapillaris, and photoreceptor cells, leading to severe vision loss10 . A growing body of evidence implicates components of the innate immune system in AMD pathophysiology, suggesting inflammation contributes to disease progression14 8.
Abnormal Blood Vessels in AMD
The neovascular or wet form of AMD is defined by choroidal neovascularization, where abnormal blood vessels grow from the choroid into the subretinal space3 15. These vessels leak blood and fluid, causing hemorrhage, exudation, and rapid vision loss3 15. The leakage leads to fluid accumulation near the macula, damaging photoreceptors and causing vision distortion15 .
Vascular endothelial growth factor (VEGF) is a key protein driving this abnormal blood vessel growth and leakage15 . VEGF promotes angiogenesis, and its overexpression triggers the development of these harmful vessels, which can also cause retinal detachment15 . Although wet AMD is less common than dry AMD, it accounts for approximately 90% of acute vision loss cases related to AMD9 .
Anti-VEGF therapy is the mainstay treatment for wet AMD, effectively stabilizing vision in over 95% of patients within two years in clinical trials3 . However, real-world outcomes may be less favorable due to adherence challenges3 . Other treatments such as photodynamic therapy and laser photocoagulation are less commonly used today but may be considered in some cases16 .
Wet age-related macular degeneration develops when abnormal blood vessels grow into the macula. These vessels leak blood or fluid, leading to scarring of the macula and rapid loss of central vision. Wet AMD can develop suddenly but can be treated if caught early17 .
Genetic Factors in Macular Degeneration
AMD is a complex trait disease with a strong genetic component18 12. Genome-wide association studies have identified over 30 genetic loci linked to AMD risk, with the complement factor H (CFH) gene and the ARMS2/HTRA1 locus being the most significant19 2018. The CFH gene encodes a major inhibitor of the complement alternative pathway, implicating immune dysregulation in AMD pathogenesis19 .
Family history is a well-established risk factor, but AMD does not follow a simple Mendelian inheritance pattern; it is polygenic and multifactorial12 18. Increasing evidence suggests interactions between genetic, environmental, and therapeutic factors influence disease onset and progression12 . While genetic testing is not currently routine for AMD management, ongoing research aims to develop gene-targeted therapies21 .
Genetic background has long been established as a major risk factor for the development of AMD18 .
Macular Degeneration Demographics
AMD predominantly affects individuals over 60 years old, with prevalence and severity increasing with age1 2. It is more common among people of European ancestry compared to Africans, Hispanics, and Asians, although all ethnic groups can be affected2 . No consistent sex predilection has been established in large population studies2 .
With the global aging population, AMD is projected to become an increasingly important cause of visual impairment worldwide5 6. It is currently the leading cause of irreversible central vision loss in developed countries and a significant cause of blindness globally5 12.
Key Risk Factors
Several modifiable and non-modifiable risk factors contribute to AMD development and progression. Understanding these factors can help guide prevention and management strategies.
Smoking
Smoking is a well-established and significant risk factor for AMD, associated with a 2- to 3-fold increased risk22 . Tobacco smoke exposure contributes to oxidative stress and inflammation, accelerating retinal damage22 . Smoking cessation is strongly recommended to reduce AMD risk and slow progression23 .
Having Obesity
Obesity is linked to the development and progression of AMD24 . It is a significant public health concern associated with various ocular diseases, including AMD24 . Obesity-related metabolic disturbances may exacerbate retinal degeneration and increase the likelihood of transitioning from early to advanced AMD24 25.
High Blood Pressure
Hypertension is a recognized risk factor for progression to advanced AMD26 . Elevated blood pressure may impair choroidal circulation, contributing to retinal ischemia and promoting disease advancement22 .
Cardiovascular Disease
Cardiovascular risk factors, including atherosclerosis and heart disease, are associated with AMD22 . Vascular health influences retinal perfusion and may affect AMD pathogenesis22 . Managing cardiovascular health is important in AMD risk reduction.
Macular Degeneration in the Other Eye
Having AMD in one eye increases the risk of developing the disease in the other eye, reflecting shared genetic and environmental influences12 .
Dietary Factors
Low dietary intake of antioxidants and omega-3 fatty acids may increase AMD risk22 . Diets rich in fruits, vegetables, and fish containing these nutrients are associated with reduced risk and slower progression27 .
Sedentary Lifestyle
A sedentary lifestyle contributes indirectly to AMD risk by promoting obesity, cardiovascular disease, and poor metabolic health24 22. Regular physical activity supports vascular and overall health, potentially lowering AMD risk.
- Major modifiable risk factors for AMD include smoking, obesity, hypertension, cardiovascular disease, and poor diet22 26.
- Non-modifiable risk factors include age, family history, and genetic predisposition22 12.
Age-related macular degeneration is a complex disease whose etiology is associated with both genetic and environmental risk factors5 .
Summary of Macular Degeneration Causes
Age-related macular degeneration is a complex, multifactorial disease primarily affecting older adults. It involves progressive degeneration of the macula due to aging, genetic susceptibility, and environmental influences. Early AMD is characterized by drusen deposits and pigmentary changes, while advanced stages include geographic atrophy and neovascularization.
Abnormal growth of blood vessels in wet AMD leads to rapid vision loss, driven largely by VEGF-mediated angiogenesis. Genetic factors, especially variants in CFH and ARMS2/HTRA1, significantly influence disease risk and progression. Smoking, obesity, hypertension, cardiovascular disease, and poor diet are key modifiable risk factors that contribute to AMD development and worsening.
Preventive strategies focusing on lifestyle modifications and early detection are essential to reduce the burden of AMD and preserve vision in aging populations.
