Post-hoc AREDS2 analysis highlights distinct mechanisms driving GA progression

A new post-hoc analysis of the Age-Related Eye Disease Study 2 showed that the natural history data and multivariable models may be helpful in clinical practice and trials. While the risk factors for the first development of GA lesions, the subsequent incidence rate of the lesions, and area-based progression overlapped only partially, the investigators reported that their mechanisms may be partially distinct, which has an impact on potential therapeutic approaches.

The investigators, led by Leon von der Emde, MD, reported their results in JAMA Ophthalmology. He is affiliated with the Multidisciplinary Retinal Research Unit, Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD, and the Department of Ophthalmology, University of Bonn, Bonn, Germany.

AREDS2 methodology

Many clinical trials have focused on progression, which is usually defined and measured in terms of area-based progression.^2,3 However, Emde and associates offered another consideration.

They noted that “area-based progression represents the combination of two distinct processes: contiguous expansion at the border of existing lesions and the addition of new lesions.⁴ Importantly, these may have different risk factors and biologic mechanisms. For example, it is unclear whether the risk factors for the first GA occurrence⁴ are different from those for subsequent lesions. Of note, drugs might address only one of these processes.”

They explained further, “All GA begins with a single atrophic lesion.⁵ Theoretically, given sufficient time, all GA might also end as a single lesion, occupying most of the macula. However, great heterogeneity between eyes may exist in the middle portion of this lifespan. At one extreme, some eyes may have only 1 incidence event, followed by contiguous expansion only, such that the GA always remains unifocal.⁴ At the other extreme, some eyes may have multiple ongoing incidence events, with highly multifocal GA in the middle years, before contiguous expansion and confluence events lead gradually back toward unifocality,” they said.

To date, no studies have reported such natural history data. This knowledge is important because multifocal GA exhibits much faster area-based progression because of its larger perimeter^2,3,6 and results in a more rapid decrease in visual acuity.⁷

In the study under discussion, the authors investigated the natural history of GA lesion incidence rates and analyzed potential risk factors for faster incidence of GA lesions.

The study included eyes with incident GA, which were divided as follows: eyes with unifocal or multifocal GA at incidence and eyes with unifocal GA at incidence. The authors considered demographic and dietary characteristics, genotype, GA characteristics, and macular features.

The main outcome was the incidence rate of new GA lesions following the GA incidence. Fundus photographs obtained annually were graded for the presence of GA and characteristics and macular features. After the GA incidence, new GA lesion incidence events were recorded.

What new information about GA was gleaned?

The study included 689 eyes of 570 patients with incident GA of 570 participants (mean age, 74.5 years; 332 women). Of the eyes, 689 eyes had unifocal or multifocal GA at incidence, and 386 eyes had unifocal GA at incidence.

“Over a mean follow-up of 2.1 ± 0.9 years, the mean GA lesion incidence rate was 0.25 ± 0.50 lesion per year (range, 0-3 lesions per year) and 0.40 ± 0.70 lesion per year (range, 0-5 lesions per year) in the unifocal and any-focality cohorts, respectively. For the unifocal cohort, the multivariable model comprised four risk factors: reticular pseudodrusen, noncentral GA, lower nut intake, and higher calorie intake. For the any-focality cohort, the model comprised seven risk factors: GA lesion number, noncentral GA, greater GA proximity to central macula, reticular pseudodrusen, age, lower fish intake, and higher calorie intake,” the investigators reported.

The authors reached the conclusions that “specific risk factors may help predict progression to more highly multifocal GA, which itself is associated with faster area-based progression; the risk factors for first GA occurrence, subsequent GA lesion incidence rate, and area-based progression overlapped partially. Their mechanisms may, therefore, be partially distinct, which has implications for therapeutic approaches."

References

1. von der Emde L, Hou J, Mukherjee S, et al. Geographic atrophy multifocality in the Age-Related Eye Disease Study 2. JAMA Ophthalmol. 2025; published online November 6. doi:10.1001/jamaophthalmol.2025.3979

2. Keenan TD, Agrón E, Domalpally A, et al. ; AREDS2 Research Group . Progression of geographic atrophy in age-related macular degeneration: AREDS2 report number 16. Ophthalmology. 2018;125(12):1913-1928. doi: 10.1016/j.ophtha.2018.05.028

3. Fleckenstein M, Mitchell P, Freund KB, et al. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2018;125(3):369-390. doi: 10.1016/j.ophtha.2017.08.038

4. Keenan TDL. Geographic atrophy in age-related macular degeneration: a tale of 2 stages. Ophthalmol Sci. 2023;3:100306. doi:10.1016/j.xops.2023.100306

5. Sadda SR, Guymer R, Holz FG, et al. Consensus definition for atrophy associated with age-related macular degeneration on OCT: classification of atrophy report 3. Ophthalmology. 2018;125:537-548. doi:10.1016/j.ophtha.2017.09.028

6. Shen LL, Sun M, Grossetta Nardini HK, Del Priore LV. Progression of unifocal versus multifocal geographic atrophy in age-related macular degeneration: a systematic review and meta-analysis. Ophthalmol Retina. 2020;4:899-910. doi:10.1016/j.oret.2020.03.020

7. Shen LL, Kaiser PK, Liu J, et al. Determinants of 4-year visual acuity loss in geographic atrophy: an analysis of Age-Related Eye Disease Study and Age-Related Eye Disease Study 2. Ophthalmology. 2025;132:785-798. doi:10.1016/j.ophtha.2025.01.028