Geographic Atrophy Multifocality in the Age-Related Eye Disease Study 2

Importance: Geographic atrophy (GA) progression represents the combination of contiguous expansion and new lesion addition. Multifocal GA is associated with faster area-based progression and has been linked to faster decline in visual acuity, but the natural history and risk factors for new lesion addition are unknown. Objective: To examine, in eyes with preexisting GA, the natural history of new GA lesion incidence and identify risk factors for faster incidence. Design, Setting, and Participants: This was a post hoc analysis of the Age-Related Eye Disease Study 2 (AREDS2), which was a multicenter study based in retinal specialty clinics in the US. Included in the analysis were eyes with incident GA considered in 2 cohorts: (1) any-focality GA (eyes with unifocal or multifocal GA at incidence) and (2) unifocal GA (eyes with unifocal GA at incidence). Study data were analyzed from January to May 2025. Exposures: Demographic and dietary characteristics, genotype, GA characteristics, and macular features. Main Outcomes and Measures: The primary outcome was new GA lesion incidence rate, after GA incidence. Annual fundus photographs were graded for GA presence and characteristics and macular features. After GA incidence, new GA lesion incidence events were recorded. Univariable and multivariable analyses were performed by generalized estimating equations regression, with least absolute shrinkage and selection operator regression for variable screening. Results: A total of 689 eyes with incident GA of 570 participants (mean [SD] age, 74.5 [6.9] years; 332 female [58.2%]) were included in this study. Eyes constituted 2 main cohorts: (1) any-focality GA (ie, 689 eyes with unifocal or multifocal GA at incidence) and (2) unifocal GA (ie, 386 eyes with unifocal GA at incidence). Over a mean (SD) follow-up of 2.1 (0.9) years, the mean (SD) GA lesion incidence rate was 0.25 (0.50) lesions per year (range, 0-3 lesions per year) and 0.40 (0.70) lesions per year (range, 0-5 lesions per year) in the unifocal and any-focality cohorts, respectively. For the unifocal cohort, the multivariable model comprised 4 risk factors: reticular pseudodrusen (RPD), noncentral GA, lower nut intake, and higher calorie intake. For the any-focality cohort, the model comprised 7 risk factors: GA lesion number, noncentral GA, greater GA proximity to central macula, RPD, age, lower fish intake, and higher calorie intake. Conclusions and Relevance: In this post hoc analysis of the AREDS2 trial data, the natural history data and multivariable models may be helpful in clinical practice and trials. The models included a combination of GA characteristics and RPD status; the risk factors for first GA occurrence, subsequent lesion incidence rate, and area-based progression overlapped only partially. Their mechanisms may, therefore, be partially distinct, which has implications for therapeutic approaches.