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Importance: Low dietary nitrate intake has previously been suggested to be a risk factor for age-related macular degeneration (AMD) progression; however, this finding has not been replicated in other cohorts or adjusted for dietary patterns., Objective: To determine whether there is an association between dietary nitrate intake and AMD progression., Design, Setting, and Participants: This cohort study analyzed data from the prospective Age-Related Eye Disease Study (AREDS) and AREDS2 randomized clinical trial cohorts and their extended follow-up studies, which were conducted in multicenter outpatient retinal practices. Participants in both trials had non-late AMD in at least 1 eye. Data were analyzed from March 1, 2020, to September 30, 2022., Exposure: Dietary nitrate intake., Main Outcomes and Measures: Association between dietary nitrate intake and development of late AMD (neovascular AMD [nAMD] or geographic atrophy [GA]) or large drusen. The interactions of dietary patterns, with common at-risk single-nucleotide polymorphisms, were also assessed., Results: In the combined AREDS/AREDS2 cohort of 7788 participants (4288 AREDS participants and 3610 AREDS2 participants [110 of whom participated in both studies]), there were 13 511 eligible eyes. The combined cohort comprised 4396 women (56%) and 3392 men (44%), and the combined mean (SD) age was 71.1 (6.6) years. Dietary nitrate intake was associated with a decreased risk of progression to late AMD in the combined AREDS/AREDS2 cohort (hazard ratio [HR], 0.77 [95% CI, 0.69-0.86] for quartile 4 vs quartile 1 of intake) and a decreased risk of GA (HR, 0.71 [95% CI, 0.61-0.83]) and nAMD (HR, 0.85 [95% CI, 0.73-0.99]). In AREDS, increased nitrate intake (quartile 4 vs quartile 1) was associated with a decreased risk of late AMD (HR, 0.77 [95% CI, 0.65-0.91]) and GA (HR, 0.80 [95% CI, 0.65-0.97]) but not nAMD; in AREDS2, there was no association between nitrate intake (quartile 4 vs quartile 1) and late AMD (HR, 0.90 [95% CI, 0.80-1.02]) or nAMD (HR, 0.93 [95% CI, 0.78-1.11]). There was a correlation between Mediterranean dietary patterns and dietary nitrate intake (r = 0.52, P < .001)., Conclusions and Relevance: The findings of this cohort study suggest that dietary nitrate intake was associated with lower AMD risk. However, this association disappeared after adjusting for Mediterranean dietary patterns. These results are subject to potential bias and are hypothesis-generating in nature; therefore, they are insufficient to support new clinical recommendations. Previously described associations between dietary nitrate intake and AMD may in fact represent overall dietary patterns. Further research is needed before dietary nitrate intake can be recommended as a therapy for AMD.

Importance: After the Age-Related Eye Disease Study 2 (AREDS2) study, the beta carotene component was replaced by lutein/zeaxanthin for the development of the revised AREDS supplement. However, it is unknown if the increased risk of lung cancer observed in those assigned beta carotene persists beyond the conclusion of the AREDS2 trial and if there is a benefit of adding lutein/zeaxanthin to the original AREDS supplement that can be observed with long-term follow-up., Objective: To assess 10-year risk of developing lung cancer and late age-related macular degeneration (AMD)., Design, Setting, and Participants: This was a multicenter epidemiologic follow-up study of the AREDS2 clinical trial, conducted from December 1, 2012, to December 31, 2018. Included in the analysis were participants with bilateral or unilateral intermediate AMD for an additional 5 years after clinical trial. Eyes/participants were censored at the time of late AMD development, death, or loss to follow-up. Data were analyzed from November 2019 to March 2022., Interventions: During the clinical trial, participants were randomly assigned primarily to lutein/zeaxanthin and/or ω-3 fatty acids or placebo and secondarily to no beta carotene vs beta carotene and low vs high doses of zinc. In the epidemiologic follow-up study, all participants received AREDS2 supplements with lutein/zeaxanthin, vitamins C and E, and zinc plus copper. Outcomes were assessed at 6-month telephone calls. Analyses of AMD progression and lung cancer development were conducted using proportional hazards regression and logistic regression, respectively., Main Outcomes and Measures: Self-reported lung cancer and late AMD validated with medical records., Results: This study included 3882 participants (mean [SD] baseline age, 72.0 [7.7] years; 2240 women [57.7%]) and 6351 eyes. At 10 years, the odds ratio (OR) of having lung cancer was 1.82 (95% CI, 1.06-3.12; P = .02) for those randomly assigned to beta carotene and 1.15 (95% CI, 0.79-1.66; P = .46) for lutein/zeaxanthin. The hazard ratio (HR) for progression to late AMD comparing lutein/zeaxanthin with no lutein/zeaxanthin was 0.91 (95% CI, 0.84-0.99; P = .02) and comparing ω-3 fatty acids with no ω-3 fatty acids was 1.01 (95% CI, 0.93-1.09; P = .91). When the lutein/zeaxanthin main effects analysis was restricted to those randomly assigned to beta carotene, the HR was 0.80 (95% CI, 0.68-0.92; P = .002). A direct analysis of lutein/zeaxanthin vs beta carotene showed the HR for late AMD was 0.85 (95% CI, 0.73-0.98; P = .02). The HR for low vs high zinc was 1.04 (95% CI, 0.94-1.14; P = .49), and the HR for no beta carotene vs beta carotene was 1.04 (95% CI, 0.94-1.15; P = .48)., Conclusions and Relevance: Results of this long-term epidemiologic follow-up study of the AREDS2 cohort suggest that lutein/zeaxanthin was an appropriate replacement for beta carotene in AREDS2 supplements. Beta carotene usage nearly doubled the risk of lung cancer, whereas there was no statistically significant increased risk with lutein/zeaxanthin. When compared with beta carotene, lutein/zeaxanthin had a potential beneficial association with late AMD progression.

Importance: Age-related macular degeneration (AMD) is a common cause of irreversible vision loss among individuals older than 50 years. Although considerable advances have been made in our understanding of AMD genetics, the differential effects of major associated loci on disease manifestation and progression may not be well characterized., Objective: To elucidate the specific associations of the 2 most common genetic risk loci for AMD, the CFH-CFHR5 locus on chromosome 1q32 (Chr1) and the ARMS2/HTRA1 locus on chromosome 10q26 (Chr10)-independent of one another and in combination-with time to conversion to late-stage disease and to visual acuity loss., Design, Setting, and Participants: This case series study included 502 individuals who were homozygous for risk variants at both Chr1 and Chr10 (termed Chr1&10-risk) or at either Chr1 (Chr1-risk) or Chr10 (Chr10-risk) and who had enrolled in Genetic and Molecular Studies of Eye Diseases at the Sharon Eccles Steele Center for Translational Medicine between September 2009 and March 2020. Multimodal imaging data were reviewed for AMD staging, including grading of incomplete and complete retinal pigment epithelium and outer retinal atrophy., Main Outcomes and Measures: Hazard ratios and survival times for conversion to any late-stage AMD, atrophic or neovascular, and associated vision loss of 2 or more lines., Results: In total, 317 participants in the Chr1-risk group (median [IQR] age at first visit, 75.6 [69.5-81.7] years; 193 women [60.9%]), 93 participants in the Chr10-risk group (median [IQR] age at first visit, 77.5 [72.2-84.2] years; 62 women [66.7%]), and 92 participants in the Chr1&10-risk group (median [IQR] age at first visit, 71.7 [68.0-76.3] years; 62 women [67.4%]) were included in the analyses. After adjusting for age and AMD grade at first visit, compared with 257 participants in the Chr1-risk group, 56 participants in the Chr1&10-risk group (factor of 3.3 [95% CI, 1.6-6.8]; P < .001) and 58 participants in the Chr10-risk group (factor of 2.6 [95% CI, 1.3-5.2]; P = .007) were more likely to convert to a late-stage phenotype during follow-up. This difference was mostly associated with conversion to macular neovascularization, which occurred earlier in participants with Chr1&10-risk and Chr10-risk. Eyes in the Chr1&10-risk group (median [IQR] survival, 5.7 [2.1-11.1] years) were 2.1 (95% CI, 1.1-3.9; P = .03) times as likely and eyes in the Chr10-risk group (median [IQR] survival, 6.3 [2.7-11.3] years) were 1.8 (95% CI, 1.0-3.1; P = .05) times as likely to experience a visual acuity loss of 2 or more lines compared with eyes of the Chr1-risk group (median [IQR] survival, 9.4 [4.1-* (asterisk indicates event rate did not reach 75%)] years)., Conclusions and Relevance: These findings suggest differential associations of the 2 major AMD-related risk loci with structural and functional disease progression and suggest distinct underlying biological mechanisms associated with these 2 loci. These genotype-phenotype associations may warrant consideration when designing and interpreting AMD research studies and clinical trials.

Importance: The Age-Related Eye Disease Study age-related macular degeneration (AREDS AMD) scale is designed to classify AMD severity. The present cohort study explored whether 2-year progression along this scale was useful for estimating the risk of future progression to late AMD or best-corrected visual acuity (BCVA) loss., Objective: To assess whether 2-year progression along the AREDS AMD scale can be used to estimate the probability of long-term clinically meaningful outcome measures for clinical trials or epidemiologic studies., Design, Setting, and Participants: Age-Related Eye Disease Study participants enrolled in a clinical trial of oral micronutrient supplements had annual color fundus photographs graded centrally using the AREDS AMD scale. Two-year progression (≥2-step and ≥3-step increases in AMD score between baseline and the 2-year study visit) was evaluated as a method of estimating the risk of long-term progression to late AMD or BCVA loss. The AREDS (1992-2001) was a randomized, placebo-controlled clinical trial based at 11 retinal specialty clinics in the United States. The dates of analysis in the present cohort study were November 1992 through November 2005., Main Outcomes and Measures: Development of neovascular (NV) AMD, central geographic atrophy (CGA), any geographic atrophy (GA), or BCVA loss of at least 2 lines or at least 3 lines., Results: Among 3868 participants in the AREDS free of late AMD at baseline, the mean (SD) age was 68.3 (5.0) years, and 2180 of 3868 (56.4%) were women. In the first 2 years after randomization to the AREDS, 669 of 7458 (9.0%) of eyes had at least 2-step 2-year progression, and 275 of 7458 (3.7%) of eyes had at least 3-step 2-year progression. In the 5-year follow-up period (years 2-7), 486 of 7223 (6.7%) of eyes developed NV AMD, 339 of 7253 (4.7%) developed CGA, 726 of 7246 (10.0%) developed any GA, 2622 of 7095 (37.0%) had at least 2-line BCVA loss, and 1494 of 7155 (20.9%) had at least 3-line BCVA loss. After adjusting for demographic and clinical confounders and stratifying by baseline AMD score, statistically significant associations were observed between at least 2-step and at least 3-step 2-year progression of AMD score and subsequent 5-year development of NV AMD: hazard ratios (HRs) ranged from 3.6 (99% CI, 2.4-5.2) to 19.4 (99% CI, 7.7-48.9). For CGA, HRs ranged from 2.6 (99% CI, 1.7-4.0) to 4.7 (99% CI, 2.5-8.9); the results were similar for any GA. For at least 2-line and at least 3-line BCVA loss, HRs ranged from 1.3 (99% CI, 1.0-1.7) to 2.8 (99% CI, 1.8-4.3). For all outcomes, at least 3-step 2-year progression had stronger associations than at least 2-step 2-year progression. These findings were also validated in the AREDS2 cohort., Conclusions and Relevance: Two-year progression of AMD score was associated with progression to clinically meaningful anatomic (late AMD) and vision (≥2-line or ≥3-line loss) outcomes, suggesting that this scale may be useful for future clinical trials designed to slow the progression of AMD.

Importance: Previous studies of the role of dietary and supplementary calcium in age-related macular degeneration (AMD) have produced mixed results, suggesting that supplementation and decreased dietary intake are both harmful., Objective: To evaluate the association of baseline dietary and supplementary calcium intake with progression of AMD., Design, Setting, and Participants: This study involved secondary analyses of participants enrolled in the Age-Related Eye Disease Study (AREDS). The AREDS study (1992-2001) enrolled patients from academic and community-based retinal practices in the United States. Men and women with varying severity of AMD were included. Data analysis for this article occurred from September 2015 to December 2018., Exposures: Baseline self-reported dietary or supplementary calcium intake., Main Outcomes and Measures: Development of late AMD, geographic atrophy (central or noncentral), or neovascular AMD detected on centrally graded baseline and annual fundus photographs., Results: A total of 4751 participants were included (mean [SD] age, 69.4 [5.1] years); 4543 (95.6%) were white, and 2655 (55.9%) were female. Compared with those who were in the lowest quintile, the participants in the highest quintile of dietary calcium intake had a lower risk of developing late AMD (hazard ratio [HR], 0.73 [95% CI, 0.59-0.90]), central geographic atrophy (HR, 0.64 [95% CI, 0.48-0.86]), and any geographic atrophy (HR, 0.80 [95% CI, 0.64-1.00]). The participants in the highest tertile of supplementary calcium intake had a lower risk of developing neovascular AMD (HR, 0.70 [95% CI, 0.50-0.97]) compared with those who did not take calcium supplements. When stratified by sex, women in the highest quintile of dietary calcium intake had a lower risk of developing late AMD (HR, 0.73 [95% CI, 0.56-0.97]) compared with those in the lowest quintile. Women in the highest tertile of calcium supplementation had a lower risk of progression to neovascular AMD (HR, 0.67 [95% CI, 0.48-0.94]) compared with those who did not take calcium supplements. Similar findings were found in men for dietary calcium. Too few men took calcium supplements to allow for analyses., Conclusions and Relevance: In this secondary analysis, higher levels of dietary and supplementary calcium intake were associated with lower incidence of progression to late AMD in AREDS participants. The results may be owing to uncontrolled confounding or chance and should be considered hypothesis development requiring additional study.

Importance: To test potential treatments for age-related macular degeneration (AMD), clinical trials need standardized outcome measures that are valid for predicting AMD progression in different study populations., Objective: To evaluate the validity of the Age-Related Eye Disease Study (AREDS) detailed and simple AMD severity scales by comparing rates of development of late AMD (neovascular AMD and/or central geographic atrophy) between AREDS and AREDS2 participants., Design, Setting, and Participants: Both AREDS (1992-2001) and AREDS2 (2006-2012) enrolled patients from academic and community-based retinal practices across the United States. In AREDS (n = 4519), participants with varying severity of AMD-from no AMD to late AMD in 1 eye-were enrolled. In AREDS2 (n = 4203), participants with bilateral large drusen or large drusen in the study eye and late AMD in the fellow eye were enrolled., Main Outcomes and Measures: Five-year incidence of late AMD, assessed by annual masked centralized fundus photograph grading., Results: In AREDS, the mean (SD) age of the patients was 69.3 (5.7) years, and 2519 (55.7%) were female. In AREDS2, the mean (SD) age of the patients was 73.1 (7.7) years, and 2388 (56.8%) were female. The 5-year rates of late AMD did not differ between AREDS2 and AREDS participants within nearly all baseline AMD detailed severity scale levels: levels 1 to 3: 2.4% vs 0.5% (difference, 1.9%; 95% CI, -0.2% to 4.0%; P < .001); level 4: 6.5% vs 4.9% (difference, 1.6%; 95% CI, -1.7% to 4.8%; P = .34); level 5: 8.0% vs 5.6% (difference, 2.4%; 95% CI, -1.2% to 5.9%; P = .22); level 6: 12.8% vs 13.7% (difference, -0.9%; 95% CI, -4.8% to 3.1%; P = .66); level 7: 26.2% vs 27.8% (difference, -1.5%; 95% CI, -6.6% to 3.5%; P = .54); and level 8: 46.4% vs 44.7% (difference, 1.7%; 95% CI, -7.5% to 10.9%; P = .72). Within simple scale levels, AREDS2 and AREDS 5-year rates did not differ significantly except for level 1 (9.4% vs 3.1%, P = .02; level 2: 12.8% vs 11.8%, P = .65; level 3: 26.3% vs 25.9%, P = .90; and level 4: 45.6% vs 47.3%, P = .57)., Conclusions and Relevance: The AREDS detailed and simple AMD severity scales were useful measures for assessing the risk of developing late AMD in the AREDS2 population; these data suggest that they should be useful tools for clinical trials of AMD treatments.

Importance: Providing long-term follow-up of the natural history of age-related macular degeneration (AMD) and associated risk factors will facilitate future epidemiologic studies and clinical trials., Objective: To describe 10-year progression rates to intermediate or advanced AMD., Design, Setting, and Participants: We observed the Age-Related Eye Disease Study (AREDS) participants for an additional 5 years after a randomized clinical trial of antioxidant vitamins and minerals was completed. Observation occurred at 11 clinical sites of medical retinal practices from academic institutions and community medical centers. Participants aged 55 to 80 years with no AMD or AMD of varying severity (n = 4757) were followed up in the AREDS trial for a median duration of 6.5 years. When the trial ended, 3549 of the 4203 surviving participants were followed for 5 additional years., Exposure: Treatment with antioxidant vitamins and minerals., Main Outcomes and Measures: Development of varying stages of AMD and changes in visual acuity. The rates of progression to large drusen and advanced AMD (neovascular AMD or central geographic atrophy) were evaluated using annual fundus photographs assessed centrally. Best-corrected visual acuity was measured at annual study visits., Results: The risk of progression to advanced AMD increased with increasing age (P = .01) and severity of drusen. Women (P = .005) and current smokers (P < .001) were at increased risk of neovascular AMD. In the oldest participants with the most severe AMD status at baseline, the risks of developing neovascular AMD and central geographic atrophy by 10 years were 48.1% and 26.0%, respectively. Similarly, rates of progression to large drusen increased with increasing severity of drusen at baseline, with 70.9% of participants with bilateral medium drusen progressing to large drusen and 13.8% to advanced AMD in 10 years. Median visual acuity at 10 years in eyes that had large drusen at baseline but never developed advanced AMD was 20/25; eyes that developed advanced AMD had a median visual acuity of 20/200., Conclusions and Relevance: The natural history of AMD demonstrates relentless loss of vision in persons who developed advanced AMD. These progression data and the risk factor analyses may be helpful to investigators conducting research in clinic populations.

Importance: The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina., Objective: To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD., Design, Setting, Participants: The Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye., Interventions: In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination., Main Outcomes and Measure: S Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy., Conclusion and Relevance: The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements., Trial Registration: clinicaltrials.gov Identifier: NCT00345176.