Geographic Atrophy in Age-Related Macular Degeneration: A Tale of Two Stages

To examine disease progression in age-related macular degeneration (AMD) at 2 distinct stages, progression to geographic atrophy (GA) versus GA expansion, by comparison of the risk and protective factors at each stage.

Perspective.

Individuals at risk of GA or with GA.

Progression to GA and GA expansion rate.

Critical synthesis of the literature on risk and protective factors, both environmental and genetic, for progression to GA versus GA expansion in AMD.

Comparison of the risk and protective factors demonstrates partially overlapping but partially distinct risk and protective factors for progression to GA versus GA expansion. Some factors are shared (i.e., operating in the same direction at both stages), others are not shared, and others seem to operate in different directions at each stage. Risk variants at ARMS2/HTRA1 increase both risk of progression to GA and GA expansion rate, presumably through the same mechanism. By contrast, risk and protective variants at CFH/CFHR alter risk of GA but not GA expansion rate. A risk variant at C3 increases risk of GA but is associated with slower GA expansion. In environmental factors, cigarette smoking is associated with increased risk of GA and faster GA expansion, whereas increased age is associated with the former but not the latter. The Mediterranean diet is associated with decreased progression at both stages, although the food components with the largest contributions seem to differ between the 2 stages. Some phenotypic features, such as reticular pseudodrusen and hyperreflective foci, are associated with increased progression at both stages.

Analysis of the risk and protective factors for progression to GA and GA expansion demonstrates partially overlapping but partially distinct elements at each stage: some are shared, some are relevant to 1 stage only, and some even seem active in opposite directions at each stage. Aside from ARMS2/HTRA1, the overlap between the genetic risk factors for the 2 stages is minimal. This suggests that the biologic mechanisms differ at least partially between the 2 disease stages. This has implications for therapeutic approaches and suggests that treatment aimed at the underlying disease processes may need to be tailored by stage.

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