Abstract
Geographic atrophy is an advanced form of age-related macular degeneration (AMD) characterized by progressive loss of retinal pigment epithelium (RPE), overlying photoreceptors, and choriocapillaris in well-demarcated areas of the macula.(1,2) It accounts for a substantial proportion of legal blindness in older adults and is increasingly recognized as a distinct therapeutic target rather than an inevitable end-stage of non-neovascular AMD.(1,3) Clinically, geographic atrophy presents with paracentral scotomas that often progress toward the fovea, leading to central vision loss, reduced reading speed, and impaired contrast sensitivity, while peripheral vision is relatively preserved.(2–4) Multimodal retinal imaging—particularly fundus autofluorescence, optical coherence tomography, and near-infrared reflectance—has enabled precise phenotyping of lesion morphology and growth, which is now central both to prognostication and to endpoint selection in interventional trials.(3–5)
Pathophysiologically, geographic atrophy reflects a multifactorial process involving chronic oxidative stress, lipofuscin accumulation, complement system dysregulation, mitochondrial dysfunction, and impaired autophagy within the RPE, with secondary degeneration of photoreceptors and choroidal vasculature.(6–9) Genetic studies implicate variants in complement factor H and other complement components, supporting the role of chronic low-grade inflammation in disease initiation and progression.(7,10) Until recently, management was limited to risk-factor modification, nutritional supplementation based on Age-Related Eye Disease Study (AREDS) formulations, and low-vision rehabilitation.(11,12) Randomized controlled trials of intravitreal complement inhibitors have now demonstrated the first disease-modifying therapies capable of slowing geographic atrophy lesion growth, although functional benefits and long-term safety remain under evaluation.(13–16)
This review synthesizes current knowledge regarding the epidemiology, imaging characteristics, and molecular mechanisms of geographic atrophy, summarizes evidence from key clinical trials of complement-targeted and other investigational therapies, and highlights emerging research directions including gene therapy, regenerative approaches, and combined structural–functional endpoints. Geographic atrophy has transitioned from an untreatable condition to a rapidly evolving therapeutic area, yet substantial unmet needs remain in preserving visual function, personalizing treatment, and preventing progression from intermediate AMD.
Introduction
Age-related macular degeneration is a leading cause of irreversible visual impairment in individuals over 60 years of age in high-income countries.(1,3) While neovascular (exudative) AMD has become increasingly treatable with anti–vascular endothelial growth factor (VEGF) agents, geographic atrophy—representing the advanced non-neovascular form of AMD—has historically lacked approved therapies and contributes significantly to AMD-related blindness.(1,11) Geographic atrophy is defined by sharply demarcated areas of partial or complete loss of RPE, photoreceptors, and choriocapillaris, typically beginning in the parafoveal region and enlarging over time.(2,4)
Epidemiological data suggest that geographic atrophy affects approximately 0.5–1% of individuals over 75 years, with prevalence increasing with age and varying by ethnicity and genetic background.(1,3,10) Patients commonly report difficulty reading, recognizing faces, and adapting to low luminance, often years before Snellen acuity significantly declines.(4,5,17) With population ageing and improved survival, the burden of geographic atrophy is expected to increase, making it an important focus for both clinical practice and health policy.
Advances in imaging and molecular genetics over the last two decades have transformed understanding of geographic atrophy pathogenesis. Complement dysregulation, oxidative damage to the RPE, chronic inflammation, and mitochondrial dysfunction are recognized as central drivers of disease progression, acting on a background of aging-related susceptibility and environmental exposures such as smoking.(6–10,18) These insights have catalyzed the development of targeted therapies, particularly agents modulating the complement cascade, some of which have recently gained regulatory approvals for slowing lesion expansion.(13–16)
The aims of this article are to: (1) describe the clinical and imaging characteristics of geographic atrophy; (2) summarize current knowledge of underlying mechanisms; (3) review the contemporary clinical trial landscape; and (4) discuss emerging directions for prevention and treatment.
Mechanistic Basis of Geographic Atrophy
Retinal Pigment Epithelium Dysfunction and Photoreceptor Loss
The RPE performs essential functions including phagocytosis of photoreceptor outer segments, recycling of visual pigment, maintenance of the outer blood–retina barrier, and regulation of oxidative stress.(6,18) In geographic atrophy, RPE cells exhibit structural and functional abnormalities such as accumulation of lipofuscin granules, mitochondrial damage, impaired autophagy, and increased susceptibility to apoptosis.(6,8,9)
Lipofuscin, a complex aggregate of oxidized proteins and lipids that accumulates in RPE lysosomes, contains the fluorophore N-retinylidene-N-retinylethanolamine (A2E), which has phototoxic properties and can induce complement activation and apoptosis under blue light exposure.(6,8) Excessive lipofuscin contributes to RPE dysfunction and is a major source of hyperautofluorescence signals that often precede atrophic lesion formation on fundus autofluorescence imaging.(5,19)
Degeneration of RPE cells leads to secondary loss of overlying photoreceptors, particularly cone photoreceptors responsible for high-resolution central vision.(4,6,9) Histological studies show thinning of the outer nuclear layer and disruption of the photoreceptor inner/outer segment junction at the borders of geographic atrophy, consistent with progressive centrifugal cell loss.(4,20) Choriocapillaris dropout is also observed beneath areas of atrophy, indicating a complex interplay between the RPE, photoreceptors, and choroidal vasculature.(7,9,20)
Oxidative Stress, Mitochondrial Dysfunction, and Aging
The macula is exposed to high levels of visible light and has substantial metabolic demand, making it particularly vulnerable to oxidative damage.(6,18) Reactive oxygen species (ROS) generated by mitochondrial respiration, photo-oxidation of visual cycle intermediates, and inflammation can damage cellular components, leading to RPE senescence and apoptosis.(6,18,21) Aging-associated decline in antioxidant defenses and mitochondrial quality control further amplifies susceptibility.
Studies of donor eyes with geographic atrophy reveal mitochondrial DNA damage, reduced mitochondrial mass, and altered expression of genes involved in oxidative phosphorylation and antioxidant pathways in RPE cells.(9,21) Experimental models suggest that mitochondrial dysfunction can trigger inflammasome activation, complement activation, and cell death pathways, linking metabolic stress to inflammatory mechanisms observed in AMD.(9,18,21)
Complement System Dysregulation and Inflammation
Genetic and biochemical evidence strongly implicates the complement system—a central component of innate immunity—in the pathogenesis of geographic atrophy.(7,10,22) Genome-wide association studies have identified risk variants in complement factor H (CFH), complement component 3 (C3), complement factor B (CFB), complement factor I (CFI), and other complement regulators that increase susceptibility to advanced AMD including geographic atrophy.(10,22)
Complement activation products such as C3a, C5a, and membrane attack complex (MAC, C5b-9) have been detected in drusen, Bruch’s membrane, and choriocapillaris in AMD eyes, suggesting chronic local complement activation at the RPE–choroid interface.(7,22,23) Dysregulated complement activity can promote inflammation, microglial activation, and endothelial damage, potentially accelerating RPE and choriocapillaris degeneration.(7,22,23)
The central role of complement has motivated the development of intravitreal agents targeting C3, C5, and complement factor D as strategies to slow geographic atrophy progression.(13–16,24) Outcomes of these trials provide both proof-of-concept for complement modulation and insights into the complex balance between protective and detrimental complement functions in the eye.
Drusen, Subretinal Drusenoid Deposits, and Bruch’s Membrane Changes
Clinically, geographic atrophy often arises from eyes with intermediate AMD characterized by large drusen and pigmentary abnormalities.(2,3) Drusen are extracellular deposits composed of lipids, proteins, and complement components located between the RPE and Bruch’s membrane.(6,22) Subretinal drusenoid deposits (reticular pseudodrusen), located above the RPE, are also associated with increased risk of progression to geographic atrophy.(25,26)
Structural alterations of Bruch’s membrane, including thickening, lipid accumulation, and reduced hydraulic conductivity, may impair nutrient and waste exchange between the choroid and RPE.(6,18) These changes, together with drusen and subretinal deposits, likely contribute to chronic metabolic and inflammatory stress that predisposes to RPE atrophy.
Clinical and Imaging Features
Symptoms and Functional Impact
Patients with geographic atrophy often present with difficulty reading, needing more light, impaired dark adaptation, and paracentral scotomas that can be detected with microperimetry or Amsler grid testing.(4,17,27) Central visual acuity may remain relatively preserved until atrophy encroaches on the fovea, meaning that substantial functional impairment may exist even when Snellen acuity appears adequate.(4,17)
Reduced contrast sensitivity, impaired low-luminance visual acuity, and prolonged dark adaptation have been documented and may predict future progression.(17,27,28) These functional deficits have important implications for quality of life and should be considered alongside structural endpoints in clinical trials.
Fundus Autofluorescence
Fundus autofluorescence (FAF) imaging, which detects lipofuscin-related fluorescence from the RPE, is a key modality for assessing geographic atrophy.(5,19) Atrophic areas appear as regions of markedly reduced autofluorescence corresponding to loss or thinning of RPE, while surrounding zones frequently show increased autofluorescence that may reflect stressed RPE at risk of future atrophy.(5,19)
Classification schemes based on FAF patterns, such as banded or diffuse hyperautofluorescence, have been associated with differing rates and directions of lesion growth.(5,19,29) Measurement of geographic atrophy area on FAF has become a standard structural endpoint in clinical trials and observational studies.(3,5,13)
Optical Coherence Tomography
Spectral-domain and swept-source optical coherence tomography (OCT) provide high-resolution cross-sectional images of retinal architecture, enabling detailed characterization of geographic atrophy.(4,20,30) OCT features include RPE atrophy with increased choroidal signal transmission, loss of the ellipsoid zone and outer nuclear layer, and thinning of the outer retina.(4,20,30)
At the junctional zone between atrophic and intact retina, OCT may show subsidence of the outer plexiform and inner nuclear layers towards Bruch’s membrane, known as the “OCT island” or “collapse” sign, which correlates with photoreceptor loss.(20,30) OCT angiography has revealed attenuation or absence of the choriocapillaris beneath geographic atrophy and may provide additional insight into vascular contributions to disease progression.(31)
Lesion Growth and Risk Factors
Longitudinal cohort studies have shown that geographic atrophy lesions enlarge at an average rate of approximately 1.5–2.0 mm² per year, although growth rates vary widely between individuals.(2,3,32) Baseline lesion size, multifocality, proximity to the fovea, FAF pattern, and presence of reticular pseudodrusen have all been associated with faster progression.(2,5,26,29,32)
Smoking, low macular pigment optical density, and genetic risk alleles in CFH and ARMS2/HTRA1 have also been linked to increased risk of geographic atrophy development and faster growth, underscoring the multifactorial nature of disease progression.(10,25,33)
Clinical Research and Current Treatment Landscape
Risk-Factor Modification and Nutritional Supplementation
Before the advent of targeted therapies, management of geographic atrophy focused on modifying systemic and ocular risk factors and optimizing visual function.(11,12) Smoking cessation, control of cardiovascular risk factors, and dietary patterns rich in leafy greens and omega-3 fatty acids are generally recommended, although direct evidence for geographic atrophy-specific benefits is limited.(11,18,34)
The original Age-Related Eye Disease Study (AREDS) demonstrated that high-dose antioxidant vitamins (vitamin C, vitamin E, beta-carotene) plus zinc reduced the risk of progression from intermediate AMD to advanced AMD (geographic atrophy or neovascular AMD) in high-risk eyes.(11) AREDS2 subsequently modified the formulation by replacing beta-carotene with lutein and zeaxanthin and evaluating omega-3 fatty acids; long-term follow-up confirmed a modest risk reduction in AMD progression, with lutein/zeaxanthin particularly beneficial in individuals with low dietary intake.(12,35,36) These supplements do not reverse established geographic atrophy but may modestly reduce progression from earlier AMD stages.
Low-Vision Rehabilitation
As geographic atrophy progresses, low-vision services including optical and electronic magnification, contrast enhancement, and orientation and mobility training are important to maintain independence and quality of life.(37) Evidence suggests that early referral to low-vision rehabilitation improves functional outcomes and psychosocial adjustment, although robust randomized trials are limited.(37)
Complement Inhibition: C3 and C5 Targeting
Recent randomized controlled trials targeting the complement cascade represent a major advance in geographic atrophy management. Intravitreal pegcetacoplan, a complement C3 inhibitor, has been evaluated in the phase 3 OAKS and DERBY trials.(13,14) In OAKS, monthly and every-other-month injections significantly reduced geographic atrophy lesion growth by approximately 22% and 16%, respectively, at 24 months compared with sham, while DERBY showed more modest but directionally similar effects.(13,14) Pooled analyses demonstrated a dose-dependent slowing of lesion expansion, though the effect on visual function endpoints such as best-corrected visual acuity and reading speed was less clear.(13,14)
Intravitreal avacincaptad pegol, a C5 inhibitor, demonstrated similar structural benefits in the GATHER1 and GATHER2 trials, with around 14–18% reduction in geographic atrophy growth at 12 months relative to sham.(15,16) Based on these data, regulatory agencies have approved both agents for slowing geographic atrophy progression in certain regions, marking the first disease-modifying treatments for this condition.(13–16)
A notable safety consideration with complement inhibition is an increased incidence of exudative (neovascular) AMD in treated eyes compared with sham, possibly related to altered immunologic balance or unmasking of pre-existing choroidal neovascularization.(13–16,24) In OAKS and DERBY, new-onset neovascular AMD occurred in up to 13% of eyes receiving monthly pegcetacoplan, compared with approximately 3% in sham-treated eyes.(13,14) Similarly, GATHER trials reported higher conversion rates to neovascular AMD with avacincaptad pegol.(15,16) These findings underscore the need for careful monitoring and integrated management with anti-VEGF therapy when necessary.
Other Investigational Therapies
In addition to complement inhibitors, several other mechanistic approaches have been investigated:
• Neuroprotective agents and visual cycle modulators. Emixustat hydrochloride, a visual cycle modulator intended to reduce accumulation of toxic retinoid byproducts, did not demonstrate efficacy in slowing geographic atrophy expansion in a phase 2/3 trial.(38) Ciliary neurotrophic factor delivered via encapsulated cell technology showed structural and functional signals in early studies but did not progress to widespread clinical use.(39)
• Cell-based therapies. Subretinal transplantation of RPE cells derived from human embryonic stem cells or induced pluripotent stem cells has been explored in early-phase trials, demonstrating feasibility and short-term safety, though long-term efficacy and optimal delivery methods remain uncertain.(40,41)
• Gene therapy. Experimental gene therapies aim to modify complement regulation or deliver neuroprotective factors to the retina, but human data in geographic atrophy are still limited to early-phase safety studies.(42)
Emerging Research Directions
Refining Endpoints: Structural–Functional Correlation
Current trials predominantly use geographic atrophy area enlargement as the primary endpoint, yet structural slowing does not always translate into measurable short-term visual acuity benefits.(13–16,32) Emerging research emphasizes endpoints that better capture functional preservation, such as microperimetry-derived retinal sensitivity maps, low-luminance visual acuity, reading speed, and patient-reported outcomes.(27,28,43) Integrating these measures with high-resolution imaging may improve assessment of clinically meaningful benefit.
Personalized Risk Stratification and Treatment Selection
Genetic profiling, imaging biomarkers (including reticular pseudodrusen, FAF patterns, and choriocapillaris flow deficits), and systemic factors may enable more precise stratification of patients at highest risk of rapid progression.(10,25,26,29,31–33) Future work may clarify which subgroups derive the greatest benefit from complement inhibition or other therapies, potentially informing personalized dosing regimens and combination approaches.
Combination Therapies and Earlier Intervention
Given the multifactorial nature of geographic atrophy, combination strategies targeting complementary pathways—such as complement inhibition plus antioxidant or mitochondrial support—are conceptually attractive.(6–10,18,21) Early intervention at the stage of intermediate AMD, before overt geographic atrophy develops, is another key area of investigation, with ongoing trials assessing whether complement or other modulators can delay onset of atrophy in high-risk eyes.(24,44)
Regenerative and Restorative Approaches
Stem cell–derived RPE transplantation, photoreceptor replacement, and optogenetic therapies aim not only to slow degeneration but also to restore lost function.(40–42,45) Advances in biomaterials, surgical techniques, and gene-editing technologies may enhance the feasibility of such interventions. However, challenges related to immune rejection, long-term survival of transplanted cells, and integration with host neural circuits remain substantial.(40–42,45)
Conclusion
Geographic atrophy represents a major cause of vision loss in older adults and a distinct advanced stage of age-related macular degeneration characterized by progressive degeneration of the RPE, photoreceptors, and choriocapillaris.(1–4) Pathogenesis involves a complex interplay between oxidative stress, mitochondrial dysfunction, lipofuscin accumulation, complement system dysregulation, and age-related structural changes in Bruch’s membrane.(6–10,18,21–23) Advances in multimodal imaging have substantially improved the ability to characterize lesion morphology, monitor progression, and select endpoints for clinical trials.(3–5,20,30)
For many years, management of geographic atrophy was limited to risk-factor modification, AREDS-based nutritional supplementation, and low-vision rehabilitation.(11,12,37) Recent randomized trials of intravitreal complement inhibitors have established the first disease-modifying therapies capable of slowing lesion enlargement, although functional benefits, optimal dosing, and long-term safety—particularly regarding neovascular AMD risk—remain areas of active investigation.(13–16,24) Ongoing research into combination strategies, gene and cell-based therapies, and earlier-stage interventions offers the prospect of more comprehensive disease control and functional preservation.(24,40–42,44,45)
As therapeutic options expand, clinicians will increasingly face decisions regarding initiation, continuation, and sequencing of treatments in the context of patient preferences, comorbidities, and healthcare resource constraints. Continued integration of mechanistic insights, imaging biomarkers, and functional outcome measures will be essential to optimize care for individuals with geographic atrophy and to prevent progression from earlier AMD stages.
This article is for educational purposes only and reflects current scientific literature at the time of writing.
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