Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a progressive macular disorder and a leading cause of visual impairment in patients aged 50 and older, with an estimated 200 million people affected worldwide and a projected 288 million by 2040.² It threatens the central, high-acuity vision needed for reading, driving, and recognizing faces.¹ Disease is staged as early, intermediate, or late, with late AMD split into two forms: neovascular ("wet") AMD, driven by abnormal choroidal blood vessel growth, and geographic atrophy ("dry"/atrophic AMD), driven by progressive retinal pigment epithelium (RPE) atrophy.³¹

The main risk factor is advancing age — in patients over 75, roughly a 25% risk of early AMD and an 8% risk of late AMD has been reported — alongside smoking, nutritional factors, cardiovascular disease, and genetic markers in complement, lipid, angiogenic, and extracellular matrix pathways.⁴³ Retinal aging in AMD involves drusen accumulation, alterations in Bruch's membrane and the extracellular matrix, vascular inflammation, mitochondrial dysfunction, oxidative stress, and RPE cell senescence.⁵

Vision loss ranges from mild to severe, with progressive impairment of central high-acuity vision interfering with reading, driving, and facial recognition; advanced disease causes substantial functional disability.⁴

Key differentials: diabetic macular edema, retinal vein occlusion, central serous chorioretinopathy, macular hole, epiretinal membrane, and other macular dystrophies causing central vision loss in older adults.

Diagnosis combines dilated fundus exam with retinal photography, fluorescein/indocyanine green angiography, and optical coherence tomography, which has also identified imaging biomarkers that help predict progression to late disease.³¹ Accurate diagnosis requires combining clinical examination with these investigations rather than clinical impression alone.³

For earlier-stage disease, dietary antioxidant supplementation is used with the goal of slowing progression, though the degree of benefit depends on disease stage.³ This practice traces back to the NIH-sponsored AREDS2 trial, which refined the original AREDS antioxidant/zinc formulation by substituting beta-carotene (linked to lung cancer risk in smokers) with lutein and zeaxanthin; today's standard AREDS2 formulation (vitamin C, vitamin E, lutein, zeaxanthin, zinc, copper) is the basis for supplements recommended in intermediate AMD (Age-Related Eye Disease Study Research Group, JAMA 2013; see the Landmark Trials page).

The advent of anti-VEGF therapy has revolutionized treatment of neovascular AMD, with ranibizumab and bevacizumab showing similar efficacy in head-to-head evidence, though systemic safety differences remain hard to fully characterize.⁶³ Newer agents aim to extend the interval between injections: brolucizumab (HAWK and HARRIER trials) and faricimab (TENAYA and LUCERNE) have both shown visual outcomes non-inferior to standard aflibercept dosing while allowing many patients to be maintained on longer treatment intervals, reducing injection burden without sacrificing efficacy (Dugel et al., Ophthalmology 2020; Heier et al., Lancet 2022).¹

Management of dry AMD/geographic atrophy has historically lagged behind wet AMD, but that is changing: complement pathway inhibitors, visual cycle modulators, antioxidative and neuroprotective agents, and gene/stem-cell therapies are all in active trials, and two intravitreal anti-complement agents (pegcetacoplan and avacincaptad pegol) have shown phase 3 evidence of slowing geographic atrophy growth.⁶ Still, an effective intervention to prevent progression to late AMD in the first place remains elusive.¹

• Dilated fundus examination is required for diagnosis but should be supplemented with imaging including OCT^4,3
• Advances in retinal imaging have identified biomarkers that help predict progression to late AMD¹
• Anti-VEGF therapy has transformed outcomes in neovascular AMD, with newer agents offering potentially longer dosing intervals^1,6
• Two intravitreal anti-complement agents have shown phase 3 evidence of slowing geographic atrophy, a meaningful shift for previously untreatable dry AMD⁶
• Common pitfall: failing to obtain dilated fundus exam in older patients with visual complaints, delaying diagnosis⁴
• Common pitfall: assuming no treatment options exist for dry AMD, when complement inhibitors have recently shown efficacy in geographic atrophy⁶
• Common pitfall: delaying anti-VEGF treatment in neovascular AMD, which can result in irreversible vision loss³