What the Research Says About Age-Related Macular Degeneration: A Comprehensive Review

Editorial note: We only cite studies published in peer-reviewed journals. We summarize findings without overstating conclusions.

Published in JAMA (the Journal of the American Medical Association) in January 2024, this review by researchers at the John A. Moran Eye Center at the University of Utah, the University of Bonn in Germany, and Queens University of Belfast synthesizes current evidence on age-related macular degeneration — covering how the disease develops, who is at risk, how it is diagnosed and staged, and what treatments are currently available. The authors reviewed 58 studies published between 2018 and 2023, including randomized clinical trials, meta-analyses, systematic reviews, and prospective cohort studies. The full study is available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC12935482/

The Scale of the Problem

Age-related macular degeneration (AMD) is a progressive disease of the macula — the small central zone of the retina responsible for the sharp, detailed vision used for reading, recognizing faces, and driving. It is a leading cause of severe vision impairment in people over 55 years of age across countries at all income levels, accounting for 6 to 9 percent of all legal blindness worldwide.

Approximately 20 million people in the United States were living with AMD in 2019, of whom roughly 1.5 million had late-stage disease. Globally, an estimated 196 million people had AMD in 2020. That number is projected to reach 288 million by 2040 — an increase driven primarily by aging populations rather than any change in individual risk.

The annual incidence of AMD rises sharply with age: from 0.3 cases per 1,000 people aged 55 to 59 years, to 5.7 per 1,000 in those aged 75 to 79, to 36.7 per 1,000 in those aged 90 and older. AMD is not equally distributed across ethnic groups. Prevalence among people of European origin is approximately 12.3 percent for the 45-to-85 age range, compared with about 10.4 percent in those of Hispanic origin, 7.5 percent in those of African origin, and 7.4 percent in those of Asian origin.

What AMD Is and How It Develops

AMD is fundamentally a disease of aging — specifically, of the aging support system that sustains the photoreceptors, the light-sensing cells of the retina. Four structures bear the brunt of the disease: the photoreceptors themselves; the retinal pigment epithelium (RPE), a single layer of cells that nourishes and maintains the photoreceptors; the Bruch membrane, a thin collagenous layer separating the RPE from the blood supply beneath it; and the choriocapillaris, the fine network of capillaries that supplies blood to the outer retina.

As part of normal aging, blood vessels in this region lose density, the Bruch membrane accumulates lipids and other deposits, and photoreceptor populations thin. In people who develop AMD, these aging changes are compounded by four additional pathological processes: chronic low-grade inflammation; abnormal deposition of lipids and lipoproteins; increased oxidative stress; and impaired maintenance of the extracellular matrix — the structural scaffolding between cells. Together, these processes produce extracellular deposits in and around the retinal layers. These deposits, collectively known as drusen, are the defining hallmark of early AMD.

Drusen are composed of lipids, minerals, and proteins. Their presence and growth reflect ongoing disruption of normal retinal housekeeping. The review notes that genetic studies have linked AMD to genes involved in inflammation and immunity, lipid metabolism and transport, cellular stress management, and extracellular matrix maintenance — a finding that helps explain why the disease follows the pattern it does.

The Four Stages of AMD

The review uses the following clinical classification, adapted from the international Beckman Initiative for Macular Research:

Early-Stage AMD

Defined by the presence of medium-sized drusen (between 63 and 125 micrometers in diameter) without pigmentary changes in the RPE. People at this stage typically have no symptoms and normal visual acuity. The 5-year rate of progression to late-stage disease is less than 1.3 percent, which is why nutritional supplementation is not recommended at this stage.

Intermediate-Stage AMD

Characterized by large drusen (over 125 micrometers) and/or pigmentary abnormalities — changes in the coloration and position of RPE cells, which begin migrating away from their normal attachment at the Bruch membrane into inner retinal layers. People at this stage may notice difficulty in low-light conditions and low-contrast surroundings, though visual acuity often remains measurably normal. This is the stage at which nutritional supplementation with the AREDS2 formula is recommended (see Treatment section below).

Late-Stage Geographic Atrophy (Dry AMD)

Geographic atrophy (GA) represents the slow, progressive death of photoreceptors and RPE cells in confluent patches. As these patches enlarge over time, they encroach on central vision. Symptoms include gradual distortion, declining visual acuity, and eventual central visual field loss. Within a two-year period, roughly half of people with geographic atrophy will experience moderate vision loss (defined as loss of 15 letters on a standardized vision chart), and one quarter will experience severe loss (30 letters). Until 2023, no approved treatment existed for geographic atrophy.

Late-Stage Exudative Neovascular (Wet) AMD

In this form, abnormal blood vessels grow beneath or into the retina in response to a signaling protein called vascular endothelial growth factor A (VEGF-A), which is released as the oxygen-deprived retina attempts to generate new blood supply. These new vessels are fragile and leaky, causing fluid to accumulate in and beneath the retinal layers — producing rapid, sometimes sudden distortion and vision loss, along with hemorrhages and eventual scarring. Wet AMD progresses more quickly than geographic atrophy and, if untreated, causes more severe acute vision loss. However, it is also the form for which the most effective treatments exist.

Risk Factors

Age

Age is the dominant risk factor, with incidence rising dramatically after 75. The steep age-related increase in risk is consistent across all populations studied.

Genetics

The estimated heritability of late-stage AMD is approximately 71 percent — meaning that genetic factors account for about 71 percent of the variation in who develops the disease. Genome-wide association studies have identified two major genetic loci strongly linked to AMD: variants in the CFH (complement factor H) gene, which is involved in regulating inflammation, and variants in the ARMS2-HTRA1 region on chromosome 10. Individuals carrying high-risk variants at these loci face substantially elevated lifetime risk.

Smoking

Cigarette smoking is the most consistently documented environmental risk factor for AMD across multiple large prospective studies. One study of more than 61,000 women found that AMD developed in 1 out of every 1,708 person-years among women currently smoking 25 or more cigarettes per day, compared with 1 out of every 3,740 person-years in women who had never smoked. A parallel study in more than 21,000 men found that approximately 2 percent of men smoking 20 or more cigarettes per day developed AMD during follow-up, compared with less than 1 percent of non-smokers.

Diet and Lifestyle

A prospective study of more than 4,200 adults found that consuming fish twice per week was associated with a reduced AMD risk (hazard ratio 0.76). Adherence to recommended daily amounts of vegetables, fruit, and fish together was associated with a substantially lower risk (hazard ratio 0.58). Lower physical activity levels have also been associated with higher AMD prevalence, though causation cannot be inferred from largely cross-sectional data on this point.

Existing AMD Features

The presence of advanced AMD features in one eye greatly increases the risk in the other. In the AREDS trial, 53.1 percent of participants who already had late-stage AMD in one eye and had large drusen and pigmentary changes in the other eye developed late-stage AMD in that second eye within five years.

Symptoms and Clinical Presentation

Early AMD typically produces no symptoms. The first symptoms most patients notice at intermediate stage are difficulty seeing in low-light conditions — a dimly lit restaurant, reading in low light — and in low-contrast surroundings. These subtle changes often go unreported because patients adapt their behavior without recognizing them as disease symptoms.

By the time patients seek medical evaluation, most report either visual distortion (straight lines appearing curved or wavy — a symptom called metamorphopsia) or more obvious blurring and declining visual acuity. A survey of 217 AMD patients found that roughly 40 percent initially sought help due to visual distortion, while about 38 percent presented with a more general decline in vision quality. When AMD becomes symptomatic in both eyes, patients report more functionally significant impairments: difficulty reading, inability to drive, trouble recognizing faces.

The review emphasizes an important practical point: AMD does not typically cause complete blindness in which vision becomes entirely black. It causes central vision loss while peripheral vision is usually preserved. This distinction matters for patient counseling and quality-of-life expectations.

Diagnosis and Imaging

Clinical diagnosis begins with dilated fundus examination using a slit lamp and a special focusing lens, which allows direct visualization of drusen, pigmentary changes, atrophic areas, hemorrhages, and fluid. Several imaging technologies extend and refine this examination:

Optical coherence tomography (OCT) is the most widely used tool in routine clinical practice, providing three-dimensional cross-sectional images of the retinal layers down to micrometer resolution. It is particularly valuable for detecting intraretinal and subretinal fluid in wet AMD and for monitoring treatment response. Its sensitivity for detecting exudative neovascular AMD is 91.7 percent — substantially higher than visual acuity testing (30.0 percent) or clinical biomicroscopy alone (53.8 percent).

Fundus autofluorescence images the natural fluorescence of lipofuscin and other molecules in the RPE, and is especially useful for identifying and tracking the progression of geographic atrophy. Regulatory agencies have accepted fundus autofluorescence as a primary outcome measure in clinical trials for geographic atrophy.

Fluorescein angiography involves intravenous injection of a fluorescent dye to visualize leaking blood vessels. It remains the gold standard for identifying the neovascularization of wet AMD, but carries risks including allergic reactions and, rarely, anaphylaxis.

OCT angiography is a newer, noninvasive technique that visualizes retinal microvasculature by detecting the motion of blood cells without requiring a dye injection. The review notes it has potential to eventually replace fluorescein angiography for neovascular AMD detection, though it remains primarily a research tool at the time of publication.

Treatment: Nutritional Supplementation (AREDS and AREDS2)

The landmark Age-Related Eye Disease Study (AREDS), a randomized clinical trial of 3,640 participants conducted by the National Eye Institute, established the foundation of nutritional supplementation for AMD. Participants with intermediate to advanced AMD were randomized to receive antioxidant vitamins (vitamin C, vitamin E, and beta carotene), zinc, both, or placebo. At five years, the estimated probability of progression to late-stage AMD was 28 percent for placebo, 23 percent for antioxidants alone, 22 percent for zinc alone, and 20 percent for the combination — a meaningful reduction in risk for people already showing significant AMD features.

Importantly, because the five-year progression rate for early AMD is only about 1.3 percent, AREDS supplementation is specifically recommended only for people who have already progressed to intermediate or late-stage AMD in at least one eye. It is not recommended for people with early AMD or no AMD.

AREDS2 subsequently refined the formula by replacing beta carotene — which was found to elevate lung cancer risk in current and former smokers — with lutein (10 mg) and zeaxanthin (2 mg). The current recommended AREDS2 formula consists of: 500 mg vitamin C, 400 IU vitamin E, 10 mg lutein, 2 mg zeaxanthin, 80 mg zinc oxide, and 2 mg cupric oxide. Beta carotene-containing versions of the formula should not be used by anyone who currently or previously smoked.

Clinicians should be aware that exceeding recommended doses of these supplements can produce adverse effects. Vitamin C in high doses may contribute to kidney stones; high-dose vitamin E has been linked to muscle weakness, reduced thyroid function, and elevated hemorrhagic stroke risk; and excess zinc can cause sideroblastic anemia through copper depletion and genitourinary symptoms. These risks are uncommon at the AREDS2 doses but warrant awareness in clinical monitoring.

Treatment: Anti-VEGF Therapy for Wet AMD

For exudative neovascular (wet) AMD, the development of anti-VEGF treatments delivered by injection into the eye (intravitreal injection) has been one of medicine’s significant advances of the past two decades. These drugs block vascular endothelial growth factor, the protein driving the growth of the abnormal, leaky blood vessels that cause vision loss in wet AMD.

The pivotal MARINA trial enrolled 716 patients and randomized them to receive monthly intravitreal injections of ranibizumab (at one of two doses) or monthly sham injections. At 12 months, 94.5 to 94.6 percent of patients in the ranibizumab groups lost fewer than 15 letters of visual acuity, compared with 62.2 percent in the sham group. Very few ranibizumab-treated patients experienced severe vision loss (30 letters or more) at 12 months — 0.8 to 1.2 percent versus 14.3 percent in the sham group. These results were practice-changing: for the first time, a treatment not only slowed vision loss but produced actual improvements in average visual acuity.

A subsequent systematic review of six trials confirmed that at one year, 17.9 percent of anti-VEGF-treated patients gained 15 or more letters of visual acuity compared with 4.3 percent of untreated patients — a more than fourfold difference.

In clinical practice, injections are not always given monthly. Two individualized approaches — treat-and-extend (injecting at every visit while gradually extending the interval between visits) and pro re nata (injecting only when signs of active disease are seen at monthly monitoring visits) — reduce the number of injections without substantially sacrificing visual outcomes. The treat-and-extend approach in particular has become widely used.

Newer anti-VEGF agents and delivery systems have extended the time between required treatments to as long as 24 weeks for some patients. Biosimilar versions of the original agents — drugs that closely replicate the approved biologics — now offer cost-effective alternatives with comparable safety and efficacy.

Serious ocular adverse events from intravitreal anti-VEGF injection — including endophthalmitis (infection inside the eye), retinal detachment, and traumatic lens injury — occur but are infrequent across the clinical trial literature. Endophthalmitis rates in major trials have ranged from 0.06 to 0.16 percent per injection.

Long-Term Outcomes

Approximately 7.3 years after initiating anti-VEGF treatment in the ANCHOR and MARINA trials, 43 percent of treated eyes had maintained or improved their visual acuity compared with baseline, while 34 percent had lost 15 or more letters. A clinically important finding from long-term follow-up studies is that many eyes treated for wet AMD develop macular atrophy over time — in one cohort study, 98 percent of eyes showed macular atrophy at a mean of 7.3 years after treatment initiation. This underscores that anti-VEGF therapy controls the exudative disease but does not halt the underlying degenerative process.

Treatment: New Drugs for Geographic Atrophy

Until 2023, there were no approved treatments for geographic atrophy — the dry, slowly progressive form of late AMD. In 2023, the U.S. Food and Drug Administration approved two drugs that target the complement system, a branch of the immune system that has been implicated in AMD pathogenesis: pegcetacoplan and avacincaptad pegol, both delivered by intravitreal injection.

In the OAKS and DERBY phase 3 trials, monthly pegcetacoplan reduced geographic atrophy progression by 21 percent at 12 months in OAKS (statistically significant) and by 12 percent in DERBY (not statistically significant at 12 months, though both trials reached significance at 24 months). In the GATHER2 trial, monthly avacincaptad pegol reduced the rate of geographic atrophy growth from 0.392 mm per year with sham injections to 0.336 mm per year — a 14 percent reduction.

The review is candid about the limitations of these results: neither drug demonstrated statistically significant benefits on prespecified visual function outcomes (i.e., measurable improvements in what patients could actually see) during the reported study periods. Additionally, both drugs were associated with increased rates of new-onset exudative neovascular AMD — the more acute, leaky form of the disease. The review cites expert commentary characterizing the risk-benefit profile of these drugs as uncertain, and notes there is no general recommendation for their routine use at this time.

Practical Guidance: What Patients and Clinicians Should Know

The review includes several practical points relevant to both patients and the general practitioners who often see AMD patients first:

Treatment delays for wet AMD cause measurable harm. A prospective study of 185 patients found that those treated within 7 weeks of diagnosis had a 38 percent improvement in vision at 6 months, while those with delays of 21 weeks or more had improvement in only 20 percent of cases. Ideally, treatment for wet AMD should begin within 14 days of diagnosis.

AMD does not cause total blindness, but it causes severe functional impairment. A retrospective analysis found that 71 percent of patients with bilateral geographic atrophy were unable to drive at initial diagnosis, and 66.7 percent of those eligible to drive at baseline had lost that eligibility within a median of 1.6 years.

Patients who smoke should be strongly advised to stop — smoking is the most modifiable environmental risk factor for AMD, and the relationship is dose-dependent and well-established. Dietary guidance emphasizing vegetables, fruit, and fatty fish is appropriate for all AMD patients. Former and current smokers who use AREDS supplements must use the AREDS2 formula (without beta carotene), not the original AREDS formulation.

Anticoagulation therapy does not need to be withheld before intravitreal injections. A retrospective analysis found no statistically significant difference in intraocular hemorrhage rates between patients taking anticoagulants and those not taking them at the time of injection.

Summary of Key Takeaways

• AMD affects 196 million people worldwide and is projected to reach 288 million by 2040, driven primarily by aging populations. It is a leading cause of legal blindness in people over 55 across all income levels.
• AMD develops through four interacting mechanisms: chronic inflammation, abnormal lipid deposition, oxidative stress, and impaired extracellular matrix maintenance — all acting on the photoreceptors, retinal pigment epithelium, Bruch membrane, and choriocapillaris of the macula.
• Age is the primary risk factor. Genetic factors account for approximately 71 percent of the variation in AMD risk, with CFH and ARMS2-HTRA1 gene variants having the strongest established associations. Cigarette smoking is the most important modifiable risk factor.
• AMD progresses through early, intermediate, and late stages. Late-stage AMD takes two forms: geographic atrophy (slow, progressive photoreceptor death) and exudative neovascular AMD (abnormal blood vessel growth causing rapid fluid leakage and vision loss).
• Optical coherence tomography is the most sensitive non-invasive tool for detecting and monitoring AMD, with 91.7 percent sensitivity for exudative neovascular disease — far exceeding visual acuity testing or clinical examination alone.
• The AREDS2 nutritional supplement formula (vitamin C, vitamin E, lutein, zeaxanthin, zinc, and copper) reduces five-year progression to late-stage AMD from 28 percent to approximately 20 percent in people with intermediate or advanced AMD. It is not recommended for early AMD.
• Anti-VEGF intravitreal injections are first-line therapy for wet AMD and have transformed its prognosis — preventing severe vision loss in approximately 95 percent of treated patients at 12 months in major trials. Long-term data show that macular atrophy often develops in treated eyes over time despite disease control.
• Two complement-inhibiting drugs (pegcetacoplan and avacincaptad pegol) were approved in 2023 for geographic atrophy and modestly slow lesion growth, but neither has yet demonstrated significant improvements in visual function, and both increase the risk of developing wet AMD. Their role in routine clinical practice remains uncertain.

Source: Fleckenstein M, Schmitz-Valckenberg S, Chakravarthy U. Age-Related Macular Degeneration: A Review. JAMA. 2024 Jan 9;331(2):147-157. doi: 10.1001/jama.2023.26074. Full text available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC12935482/