While age-related macular degeneration (AMD) has long been recognized as a multifactorial disease, the relative weight of genetics versus modifiable lifestyle factors in determining progression risk has remained uncertain. In a new study conducted by the Massachusetts Eye and Ear / Harvard Ophthalmology Department, researchers used longitudinal modeling to show that healthy lifestyle changes can substantially reduce the risk of progression to advanced AMD, even among individuals with the highest genetic susceptibility.
The findings, derived from large-scale prospective cohorts, underscore the importance of integrating genomic risk profiling with behavioral intervention in AMD management — an emerging frontier in precision ophthalmology.
The analysis combined data from AREDS, AREDS2, and UK Biobank cohorts, encompassing over 17,000 individuals with detailed phenotypic, genetic, and lifestyle information. Participants were genotyped for AMD-associated variants across the CFH, ARMS2/HTRA1, C3, and CFI loci, among others, and stratified into genetic risk quintiles.
Lifestyle variables included smoking status, body mass index (BMI), physical activity, and dietary adherence (assessed via Mediterranean diet scores). The primary outcome was progression to advanced AMD — defined as neovascular AMD or geographic atrophy — over a mean follow-up of 10 years.
Using a multivariable Cox proportional hazards model adjusted for age, sex, and ancestry, the authors quantified the independent and combined effects of genetic and lifestyle factors on AMD progression.
As expected, genetic risk strongly predicted AMD progression, with individuals in the top 20% of polygenic risk having a fivefold greater chance of reaching advanced disease compared with the lowest quintile. However, healthy lifestyle factors significantly mitigated this risk.
Among participants in the highest genetic risk group, those who were nonsmokers, maintained a BMI <25, and adhered to a Mediterranean-style diet had a 45–50% lower risk of advanced AMD compared to their counterparts with poor lifestyle profiles.
Smoking was the single strongest modifiable risk factor — current smokers with high genetic risk faced nearly tenfold higher odds of progression compared with nonsmoking, low-risk individuals. Conversely, regular physical activity and higher dietary intake of omega-3 fatty acids, leafy greens, and antioxidants provided measurable protection.
Notably, the study’s modeling predicted that up to one-third of advanced AMD cases among genetically susceptible individuals could be prevented through combined lifestyle modification.
The findings reinforce that genetic determinism for AMD does not equal inevitability of disease progression. Even in patients carrying high-risk variants, clinical counseling on smoking cessation, weight management, and nutrition remains crucial. As the authors conclude, their results "underscore the importance of targeted lifestyle interventions in individuals with heightened risk, to reduce progression from early and intermediate AMD to advanced debilitating stages."
The findings, derived from large-scale prospective cohorts, underscore the importance of integrating genomic risk profiling with behavioral intervention in AMD management — an emerging frontier in precision ophthalmology.
The analysis combined data from AREDS, AREDS2, and UK Biobank cohorts, encompassing over 17,000 individuals with detailed phenotypic, genetic, and lifestyle information. Participants were genotyped for AMD-associated variants across the CFH, ARMS2/HTRA1, C3, and CFI loci, among others, and stratified into genetic risk quintiles.
Lifestyle variables included smoking status, body mass index (BMI), physical activity, and dietary adherence (assessed via Mediterranean diet scores). The primary outcome was progression to advanced AMD — defined as neovascular AMD or geographic atrophy — over a mean follow-up of 10 years.
Using a multivariable Cox proportional hazards model adjusted for age, sex, and ancestry, the authors quantified the independent and combined effects of genetic and lifestyle factors on AMD progression.
As expected, genetic risk strongly predicted AMD progression, with individuals in the top 20% of polygenic risk having a fivefold greater chance of reaching advanced disease compared with the lowest quintile. However, healthy lifestyle factors significantly mitigated this risk.
Among participants in the highest genetic risk group, those who were nonsmokers, maintained a BMI <25, and adhered to a Mediterranean-style diet had a 45–50% lower risk of advanced AMD compared to their counterparts with poor lifestyle profiles.
Smoking was the single strongest modifiable risk factor — current smokers with high genetic risk faced nearly tenfold higher odds of progression compared with nonsmoking, low-risk individuals. Conversely, regular physical activity and higher dietary intake of omega-3 fatty acids, leafy greens, and antioxidants provided measurable protection.
Notably, the study’s modeling predicted that up to one-third of advanced AMD cases among genetically susceptible individuals could be prevented through combined lifestyle modification.
The findings reinforce that genetic determinism for AMD does not equal inevitability of disease progression. Even in patients carrying high-risk variants, clinical counseling on smoking cessation, weight management, and nutrition remains crucial. As the authors conclude, their results "underscore the importance of targeted lifestyle interventions in individuals with heightened risk, to reduce progression from early and intermediate AMD to advanced debilitating stages."
