Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss for Americans aged 65 years and older and is a multifactorial disease.1 It is characterized by complex interactions among aging, environmental risk factors, and genetic susceptibility.
The most significant risk factor is aging, and symptoms can range from being asymptomatic to experiencing vision impairment and blindness. AMD has also been associated with a decreased quality of life (QOL), a 15% increased risk of depression, reduced work productivity, and elevated all-cause mortality.1
The role of nutritional support in AMD progression
“When it comes to macular degeneration, the first thing to realize is just how prevalent it is, and that we should have about three times as many AMD patients in our practices as glaucoma," explains Jeffry Gerson, OD, FAAO. "And so with that in mind, I think we need to be thinking about it more proactively—not just in how we find it, but then how we educate our patients, and what we ask of them to do to reduce risk of progression.”
While anti-VEGF treatments are effective for the exudative form of AMD, the majority of patients actually have the non-exudative form. Therefore, it is crucial to incorporate dietary and nutritional preventive measures that specifically target non-exudative AMD. For example, a high dietary intake of lutein and zeaxanthin may help reduce the risk of progressing to late AMD.1
Dietary factors are increasingly being studied for their impact on AMD. Research indicates that oral supplements with specific nutrients may help prevent or delay the progression of AMD, especially in neovascular cases.
Pamela D. Theriot, OD, FAAO highlights, “Patients want to know what things they can do to prevent the disease from coming; now we've got the perfect solution with PreserVision AREDS3. They can utilize it as a preventative, and use it earlier in their disease cycle.”
Higher intakes of vitamins A, B6, B12, C, and E are associated with a lower risk of AMD. Additionally, a healthy diet rich in folate from leafy greens, fruits, and whole grains may reduce vision loss in advanced AMD.2
AMD diagnostic and monitoring techniques
Early AMD
Early AMD is often asymptomatic, but some individuals may experience mild central distortion and difficulty reading in low light. Drusen, small yellowish deposits between the retinal pigmented epithelium (RPE) and Bruch's membrane, are the first visible signs and key indicators of AMD. Their size and number increase the risk of progression to more severe AMD and loss of central vision.3
Intermediate AMD
Intermediate AMD is characterized by the presence of medium-sized drusen, at least one large drusen, and/or GA that does not involve the center of the macula. This condition may lead to mild metamorphopsia. The risk of progressing from intermediate to advanced AMD over 5 years is approximately 18%.3
Advanced AMD
There are two types of advanced AMD, neovascular AMD (nAMD) and geographic atrophy (GA). nAMD, the most common advanced form of AMD, involves the growth of new blood vessels into the sub-RPE and subretinal spaces. If untreated, it can cause fluid accumulation, hemorrhage, lipid exudates, RPE detachment, and ultimately irreversible vision loss and scarring.3
GA, the advanced form of dry AMD, leads to the loss of RPE, photoreceptors, and choriocapillaris. This results in a gradual, permanent loss of central vision that progresses more slowly than in nAMD. Sudden vision loss in a patient with GA may indicate new neovascularization and should prompt referral.3
For a deeper dive into grading AMD, check out How to Accurately Stage Age-Related Macular Degeneration with Cheat Sheet!
Imaging and functional testing
Patients aged 55 and older should have a dilated fundus examination to screen for ocular diseases such as age-related macular degeneration. A comprehensive ophthalmologic examination remains the gold standard for diagnosing AMD, with appropriate additional testing such as fundus photography and autofluorescence (FAF), fluorescein angiography (FA), indocyanine green angiography (ICGA), and optical coherence tomography (OCT).3
Fundus photography
Color fundus photography is a non-invasive, widely available, and cost-effective tool for assessing the macula. This photography technique is well-established and accepted for documenting fundus changes and evaluating progression by capturing high-resolution retinal images.3
FAF is the gold standard for identifying and measuring GA, as regions of hypoautofluorescence associated with RPE loss are bordered by high-contrast hyperfluorescent regions. It creates high-contrast retinal images by detecting the natural fluorescence emitted from the breakdown products of photoreceptor outer segments, which accumulate as lipofuscin in the RPE.3
Angiography
Fluorescein angiography (FA) involves intravenous injection of a fluorescein dye, followed by repeated imaging of the retina over 10 minutes using short-wavelength excitation light and barrier filters. Until the recent advent of OCT, FA was the gold standard for diagnosing macular neovascularization (MNV).3
ICGA offers improved visualization of choroidal vessels compared to FA, as the dye has a high affinity for plasma proteins, leading to minimal leakage from the choriocapillaris. Additionally, the infrared wavelength (795 to 805nm) of indocyanine green allows for better visualization through overlying pigment, fluid, lipids, and hemorrhage than fluorescein.3
Learn more about the use cases and properties of vital dyes in eyecare in the article True Colors: What Dyes Reveal in Ocular Disease with Cheat Sheet!
OCT
Spectral-domain OCT (SD-OCT) has become the standard for diagnosing and managing nAMD. This imaging technique uses low-coherence laser light to create high-resolution, 3D images of the retina with an axial resolution of 3 to 6 micrometers. It effectively visualizes the retina's fluid compartments, which are crucial for planning and assessing anti-VEGF treatment.3
OCT angiography (OCT-A) is a non-invasive method that visualizes retinal and choroidal microvasculature by detecting blood flow through motion contrast, providing clear images of neovascular membranes and their anatomy.3
Visual field
Visual field testing, such as Amsler grid home monitoring and Humphrey 10-2 tests, is used to assess vision. A common pattern of visual field defects includes central scotomata surrounding the fixation point. Patients with nAMD may experience metamorphopsia along with large central blind spots.4
In cases of GA, patients may develop central or paracentral scotomas that expand as the condition advances. Perimetry may be less sensitive than structural imaging in early or dry disease forms, where OCT or fundus autofluorescence better detects subtle changes.4
Monitoring strategies
Higher-risk patients, such as those with a history of early AMD, family AMD, and smoking, should be monitored with Amsler grids at home to monitor progression. Additional home monitoring devices, such as ForseeHome, can be used, but obtaining insurance coverage can be challenging for some patients.3
Treatment strategies by AMD stage
AMD management is highly stage-dependent, requiring clinicians to tailor interventions—from lifestyle modifications in early disease to pharmacologic and procedural therapies in advanced stages.
Early AMD
Current management of early AMD focuses on slowing disease progression and includes lifestyle changes, such as quitting smoking, increasing physical activity, and following a Mediterranean diet.3
Emerging therapies like photobiomodulation are undergoing clinical trials. In a meta-analysis by Rassi et al. (2024), although VA and drusen volumes improved significantly, GA incidence did not decrease. Larger studies are needed to determine the clinical importance of the benefits.5
Julie Poteet, OD, MS, CNS, FOWNS, explained,“You want to intervene before you see structural changes, and that's where you get kind of the biggest bang for your buck and the more disease trajectory you can influence.”
Intermediate AMD
The AREDS1 and AREDS2 trials showed that patients with intermediate AMD may benefit from a combination of antioxidants and vitamins, reducing the risk of VA loss by 19% and the development of advanced AMD by 25% after 5 years.
Smokers and former smokers should use AREDS2 supplements, which do not contain β-carotene, due to the increased risk of lung cancer associated with higher doses of β-carotene found in AREDS1. Additionally, while high-dose statin therapy may promote drusen regression, further research is needed.3
Advanced AMD
Geographic atrophy
Nutritional supplementation and lifestyle changes are still paramount in patients with GA. There are two FDA-approved intravitreal complement inhibitors in the United States for the treatment of GA.
Pegcetacoplan is a complement 3 inhibitor administered either monthly or every other month. It has been shown to reduce the GA growth rate by 20 to 29%. Avacincaptad pegol, an anti-C5 aptamer, reduces GA growth by 27.3 to 27.8%. However, neither drug prevented a decline in visual function compared with the sham group over 2 years.3
nAMD
Vascular endothelial growth factor (VEGF) plays a pivotal role in MNV development, so inhibiting its actions has become the primary treatment for eyes with nAMD. Anti-VEGF drugs are injected into the vitreous via quick, in-office procedures with low associated risks, few adverse effects, and a quick recovery. These include pegaptanib sodium, bevacizumab, ranibizumab, aflibercept, and brolucizumab.3
nAMD patients should be treated with a personalized treatment approach. Patients are started with monthly intravitreal anti-VEGF injections until the eye stabilizes (dry macula and improved VA). A treat-and-extend regimen can then be implemented, adjusting every 2 to 4 weeks until the maximum 12- or 16-week increment is reached while maintaining disease control.
This approach reduces the number of injections and clinic visits while achieving VA improvements comparable to those in phase 3 trials. Patients are closely monitored for disease recurrence using optical coherence tomography to guide therapy changes as needed.3
Unfortunately for some patients, drug tolerance/tachyphylaxis may occur; these patients may benefit from switching medications. For some patients, thermal laser ablation and photodynamic therapy may be beneficial, especially for those with polypoidal vasculopathy.3
Low vision
For patients with advanced AMD, many will experience profound vision loss. While this irreversible vision loss may limit daily activities, vision rehabilitation with low-vision aids and occupational training can help improve patients' functional independence.
Low vision aids include magnifiers, high-power reading glasses, telescope-mounted glasses, and closed-circuit television systems. Additionally, optimizing their work and home environments to accommodate their functional limitations can enhance their quality of life.
Nutritional supplementation as part of AMD management
A healthy diet, maintaining an adequate body weight, and an active lifestyle are essential for overall health and to prevent age-related degeneration. The Mediterranean diet, rich in fruits, vegetables, olive oil, and omega-3 fatty acids from fatty fish, has been widely studied. Research indicates that high adherence to this diet is linked to a lower prevalence of early AMD. Additionally, a diet high in fruits, vegetables, nuts, and chicken has also been associated with reduced AMD prevalence.6
Supplements are a risk-reduction strategy for AMD progression. AREDS supplementation can reduce the risk of progression. In a study by Seddon et al. (2024), researchers found positive associations between dietary intake of green leafy vegetables, fish, lecithin, zeaxanthin, and omega-3 fatty acids and progression from early or intermediate AMD to more severe stages.
Furthermore, moderate consumption of each of these nutritional components was independently associated with a 15 to 25% lower risk of progressing to higher AMD severity than in individuals with no or low consumption.7
Beyond AREDS: Emerging science in ocular nutrition
Many patients struggle to obtain essential nutrients solely through diet, especially as nutrient absorption decreases with age. As a result, targeted supplementation has become an effective approach to support eye health and reduce the risk of AMD progression.8 There is extensive research on AMD supplementation, and it’s crucial to communicate this to patients.
AREDS1 and 2
The Age-Related Eye Disease Study (AREDS) found that a combination of oral supplements, including 500mg vitamins C, 400 IU vitamin E, 15mg β-carotene, 80mg zinc, and 2mg copper, reduced the five-year risk of developing advanced AMD in individuals with intermediate AMD.9
After the Age-Related Eye Disease Study 2 (AREDS2), the β-carotene component was replaced with carotenoids (lutein and zeaxanthin) in the updated AREDS supplement.10
The proposed mechanisms by which carotenoids protect the macula in AREDS2 include neutralizing free radicals to reduce oxidative stress and inflammation, as well as protecting against blue light-induced damage by increasing macular pigment.8
The results from a 10-year follow-up study indicated that the risk of developing lung cancer nearly doubled in former smokers who were assigned to the beta carotene group; however, this increase was not observed in those assigned to lutein and zeaxanthin. Furthermore, lutein and zeaxanthin were associated with a lower risk of progression to late AMD than beta carotene.10
Vitamin B
Low levels of B vitamins may be linked to a higher risk of AMD, potentially due to elevated homocysteine levels that can damage retinal tissue through oxidative stress, mitochondrial dysfunction, and inflammation. Emerging evidence suggests that B vitamins, particularly B6, B9, and B12, may help reduce the risk of developing AMD and slow its progression.8
A new supplement containing an updated formula of the B vitamin complex, including B1, B2, B3, B5, B6, B7, B9, and B12, is currently being developed in collaboration with the National Eye Institute for testing in the AREDS3 clinical trial.8 Kaleb Abbott, OD, FAAO, noted, "The nice thing about the launch of PreserVision AREDS3 is that we may be able to now reach some of those early AMD patients, as there's evidence that B complex can be helpful at preventing the onset of AMD and maybe help with some of those early AMD cases.”
Carotenoids
Carotenoids are natural pigments and lipid-soluble molecules that accumulate in lipid-rich compartments, such as lipoproteins, cell membranes, and intracellular membranes.11 Ocular carotenoids that have demonstrated functionality in reducing AMD include lutein, zeaxanthin, and beta-carotene.
In particular, lutein and zeaxanthin are concentrated in the macula and fovea, and supplementation protects against photochemical injury, neutralizes reactive oxygen species, reduces UV-induced peroxidation, and reduces lipofuscin formation.12
Omega-3 fatty acids
The retina is among the most lipid-rich tissues, with polyunsaturated fatty acids (PUFAs) making up 45% of its total phospholipids. As adults age, PUFAS decrease in the retina, retinal pigment epithelium (RPE), and choroid, while saturated fatty acids tend to accumulate.
Maintaining a healthy balance between unsaturated and saturated fatty acids is crucial. Research indicates that omega-3 PUFAs, particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may offer protective effects against AMD. Nonetheless, further research is necessary to understand these relationships.13
Mitochondria-targeted antioxidants
Mitochondrial dysfunction is a central pathogenic mechanism in AMD, particularly in the RPE, which is critical for retinal homeostasis. New compounds such as MitoQ and SKQ1 (Visomitin) target mitochondria to neutralize reactive oxygen species at their source. They are attached to lipophilic cations and cross lipid bilayers to reach high concentrations in mitochondria.14
Early trials suggest topical SKQ1 may improve retinal health, and 2024 preclinical studies show it halts AMD-like retinopathy in animals by inhibiting p38MAPK and ERK1/2 pathways, key to mitochondrial stress responses. Unfortunately, many mitochondrial antioxidants face translational challenges.14
Clinicians are responsible for staying informed about emerging data and providing recommendations, all while ensuring evidence-based care.
Evaluating supplement formulations
Not all supplements are created equal. When determining which supplement to recommend to a patient, it’s important to assess the quality, formulation, and clinical relevance. Clinicians should be able to assess the manufacturing standards and product consistency, and there should be transparency of formulations and clinical evidence supporting specific ingredients.
Nutrient delivery is as important as nutrient selection. Due to the variability in carotenoid bioavailability, influenced by individual genetic predispositions, bioactivity, and dietary patterns, strategies to enhance their bioavailability have become increasingly significant.
Factors that affect bioactivity and bioavailability include the molecular structure of carotenoids and the preparation of the supplement. For example, synthetic carotenoids are cheaper to produce but generate toxic waste and are dangerous at higher concentrations than naturally extracted carotenoids.15
Several factors influence the absorption of carotenoids from the diet. During digestion, these compounds are released, increasing their bioavailability. Cooking food helps break down cell walls, facilitating the release of carotenoids. The presence of fats is crucial, as carotenoids are transported in chylomicrons into the bloodstream. Additionally, factors like digestive health and gut microbiome composition affect absorption, while high fiber intake can limit fat and carotenoid absorption.16
Nanotechnology enhances the absorption and stability of carotenoids, improving their health benefits. Supramolecular transporters use noncovalent interactions to increase the solubility, stability, bioavailability, and cellular uptake of carotenoids in humans. These advanced systems protect carotenoids from degradation, aid absorption by intestinal cells, and ensure controlled release for effective utilization in the body.15
Special considerations in AMD management
When managing patients with AMD, several important considerations should be kept in mind.
Systemic and medication factors
Hydroxychloroquine is a well-established cause of retinal toxicity. Advanced AMD can appear to look like bull’s eye maculopathy, the characteristic sign of hydroxycholoquine toxicity. It’s important to take time to evaluate these differential diagnoses to ensure the patient undergoes the appropriate treatment.17
Early indicators of progression
Drusen and RPE abnormalities are linked to AMD progression, and studies show that drusen-related RPE disruption or elevation can signal a higher risk of advancing disease.18
A recent study by Csincsik et al. (2024) examined specific characteristics identified by SD-OCT, including irregular elevation of the RPE (IE), the double-layer sign (DLS), and shallow irregular retinal pigment epithelium elevation (SIRE). 19 The goal was to determine whether these features could serve as predictive biomarkers of progression to exudative macular neovascularization (eMNV) in the contralateral eye of patients with high-risk intermediate AMD.19
When all three SD-OCT biomarkers are present, the risk of progression to eMNV increases. However, DLS is associated with a higher and faster rate of progression than eyes that exhibit only IE and SIRE signs. Although SIRE is related to DLS, it does not appear to reduce the risk of progression.19
Managing co-morbidities
Peer-reviewed literature supports the relevance of coexisting ocular diseases such as cataract, glaucoma, and dry eye in patients with retinal disease, and dry eye is particularly common in glaucoma populations.
AMD and glaucoma are two leading causes of vision loss, particularly affecting elderly patients. Patients who have both AMD and glaucoma experience severe vision impairment that impacts their entire visual field. These patients often face greater limitations in vision-related activities, including challenges with walking safely.
Additionally, research has shown that among those affected by both conditions, there is a higher prevalence of co-morbidities such as heart failure and dementia. We believe that having these two different diseases simultaneously may serve as a pseudo-surrogate marker for increased susceptibility to other health issues.20
Both AMD and dry eye disease can cause a range of visual symptoms, including blurriness, difficulties with night driving, and decreased reading speed and comprehension. Research indicates that effectively managing dry eye disease in patients with AMD can lead to significant improvements in their overall QOL. Therefore, addressing any coexisting ocular surface conditions is essential for enhancing patient outcomes.21
For patients with cataracts and AMD, several factors should be considered before proceeding with cataract surgery, including:
- Assessing the quality of life benefits for patients with visually significant cataracts
- Avoiding cataract surgery within 6 months of starting treatment for nAMD
- Avoiding recommendations for multifocal intraocular lenses
- Considering intravitreal anti-VEGF therapy for nAMD during the month of cataract surgery
Additionally, it's important to note that patients who have received anti-VEGF injections are at an increased risk of developing acute or delayed endophthalmitis after surgery.22
Counseling patients on ocular supplements
Patients are increasingly proactive about eye health and nutrition, and clinicians play an important role in guiding expectations. Before sending a patient home with a supplement, explain its purpose and set realistic expectations for outcomes, stressing the importance of adherence to the treatment plan.
Some patients may assume that taking supplements like AREDS2 and changing their lifestyle may be the magical solution. However, it’s important to address the misconception that while supplements like AREDS can’t stop progression, they can lower risk and slow it down.
Key takeaways for clinical practice
Nutritional supplementation can significantly contribute to the management of AMD. While AREDS remains a foundational resource, ongoing research in ocular nutrition continues to advance our understanding. It's crucial to evaluate the quality and bioavailability of various formulations to ensure their effectiveness.
Moreover, clinician guidance plays a vital role in educating patients and promoting adherence to nutritional recommendations. To successfully integrate nutrition into AMD care, it is essential to base decisions on robust evidence.
