Dr Ray O’Connor takes a look at macular degeneration, and outlines how, while age is the most significant risk factor, genetic and environmental factors also play a role
Age-related macular degeneration (AMD), the leading cause of blindness in developed countries, is a complex condition that affects central vision and is influenced by various factors. Dry AMD accounts for about 85–90 per cent of all AMD cases. Wet (neovascular or exudative) macular degeneration accounts for only 10–15 per cent of AMD, but causes most cases of severe vision loss.
While age is the most significant risk factor, genetic and environmental factors also play a role. It’s pathogenesis is poorly understood. Proteomics is the large-scale study of proteins—the molecules that perform most of the functions inside cells. While genomics tells us what could happen (the genes an organism has), proteomics tells us what is actually happening by examining the proteins that are being produced, modified, and used.
Dr Ray O’Connor
Proteomics can identify significantly altered proteins in AMD patients, aiding in understanding the disease’s pathophysiology and potentially improving diagnosis or treatment strategies. This study1 was a systematic review of proteomic studies in AMD.
Proteins significantly altered in dry and wet AMD and those tested as biomarkers were presented according to sample type (aqueous humor, plasma, urine, vitreous, retinal pigment epithelium/choroid, and tear film) and type of assay (mass spectrometry or aptamers) used in the individual studies. Proteins that exhibited at least a two-fold change (FC) were further analysed through functional enrichment analysis and protein-protein interaction networks (STRING database).
Twenty-two studies (case-control and cohorts) with a total of 6,932 participants were included. The included studies showed significant heterogeneity, and most of them lacked sufficient power. Results suggested that various proteins and pathways are implicated in AMD, and there were differences when comparing results from the individual studies. Although many proteins differed significantly between AMD and control groups, most exhibited less than a 2-FC.
Functional analysis of proteins with greater than 2-FCs (identified by unbiased proteomics in multiple biofluids) highlighted lipid metabolism and protease regulation pathways as central to both dry and wet AMD. Complement and coagulation cascades, chaperones, and glycolysis pathways were significant in wet AMD, whereas matrix remodelling pathways were enriched mostly in dry AMD.
The authors concluded that combining proteomics from various studies could reveal new protein-protein interaction networks and associated functional pathways that may suggest novel potential therapeutic targets for AMD. However, there is a scarcity of data available for early AMD from ocular biofluids, and it should be the aim of future proteomics studies.
OCT (Optical Coherence Tomography) biomarkers are specific, quantifiable microscopic features on eye scans that indicate the presence, severity, or progression of diseases like macular degeneration. The objective of this meta-analysis2 was to determine the effect estimates and certainty of evidence for baseline OCT biomarkers predicting visual acuity (VA) and changes in VA from baseline at six, 12, and 24 months after anti—vascular endothelial growth factor (anti-VEGF) therapy for neovascular AMD. Twenty-nine reports (8,863 eyes) evaluating 80 biomarkers were included.
This was a complex analysis. The authors concluded that, with low-certainty evidence, the baseline presence of an intact external limiting membrane and ellipsoid zone predicted better VA at 12 months, and the presence of intra-retinal fluid (IRF), IRF in the foveal centre point, and subretinal hyperreflective material predicted worse VA at 12 months.
The authors recommend that improved standardization in biomarker classification and control of confounding variables is needed.
Photobiomodulation (PBM) delivers light wave-lengths in the 500 to 1,000 nm range from a laser or light-emitting diode (LED) applied directly to target tissues for cellular effect. The primary proposed resulting in energy production, stabilization of metabolic function, and cytoprotection. Retinal tissue has one of the highest energy demands in the body. Mitochondrial dysfunction is known to play a role in degenerative eye disease. From a mechanistic standpoint, PBM therapy is a treatment strategy for degenerative ocular disorders.
LIGHTSITE III used a double-masked, randomized, sham-controlled, parallel-group, prospective study design.3 The purpose of the study was to evaluate the safety and efficacy of multiwavelength PBM in dry AMD. Subjects were enrolled with a diagnosis of dry AMD and treated with multiwavelength PBM or sham treatment. A treatment series included 9 PBM or sham treatments delivered 3x/week over three to five weeks every four months (M) for 24 M. A total of 148 eyes (100 subjects) with dry AMD were randomized into the study. LIGHTSITE III met the prespecified primary efficacy end point at M21 with a significant difference between treatment groups.
A favourable safety profile was observed with no signs of photo-toxicity. Disease progression to Geographic Atrophy (GA) showed a significant decrease in incidence (Sham, 24.0 per cent vs. PBM, 6.8 per cent) after PBM treatment at M24. Significant benefit in vision QoL was observed. It must however be pointed out that the LIGHTSITE III clinical trial was developed, sponsored, and commercialized by ‘LumiThera’, a U.S.-based medical device company specializing in PBM for retinal diseases.
This next study examines the long-term effectiveness of anti-VEGF therapy in managing neovascular age-related macular degeneration (nAMD). Despite the well-established short-term improvements of anti-VEGF therapy, there is limited data on its continued efficacy over extended periods. This meta-analysis4 synthesised real-world data to evaluate anti-VEGF therapy’s long-term outcomes systematically. The authors conducted a comprehensive literature review across PubMed, EMBASE and Cochrane databases, focusing on studies that reported outcomes of anti-VEGF treatment for nAMD over a decade.
The search produced 12 observational studies encompassing 7509 eyes, with 1,274 completing 10-years of follow-up. The most substantial improvement in VA was observed in the first year following the initiation of anti-VEGF therapy.
On average, there was a decline of 8.11 letters in VA after 10 years from baseline. In some cases, VA reverted to baseline levels after 10 years; in others, it declined significantly below baseline. Meta-regression showed that mean VA change was greater in those with a lower baseline VA and those treated with a higher number of injections over 10 years.
The authors’ conclusion was that the mean visual acuity of eyes treated for nAMD deteriorates progressively over the long-term from two years after starting treatment. Regular injections appear crucial for preserving maximum vision. The authors also caution that, while their analysis did not identify an increased incidence of serious ocular adverse events, the long-term impact of anti-VEGF therapy on geographic atrophy remains unclear and warrants further investigation. 
References:
Sideri O et al. Systematic Review of Proteomics in Age-Related Macular Degeneration and Pathway Analysis of Significant Protein Changes. Ophthalmology Science 2025;5:100793 https://doi.org/10.1016/j.xops.2025.100793.
Nanji K et al. Baseline OCT Biomarkers Predicting Visual Outcomes in Neovascular Age-Related Macular Degeneration. A Meta-Analysis. Ophthalmology 2025;132:1241-1252. https://doi.org/10.1016/j.ophtha.2025.06.018.
Jaffe GJ et al. Long-term efficacy and safety of photobiomodulation in dry age-related macular degeneration (LIGHTSITE III: 24-month analysis). Retina, the Journal of Retinal and Vitreous Diseases 2026; volume 46; number 5. doi: 10.1097/IAE.0000000000004822.
Spooner K et al. Real-World 10-Year Outcomes of Anti-VEGF Therapy for Neovascular Age-Related Macular Degeneration: A Meta-Analysis. Clinical & Experimental Ophthalmology, 2025; 53:773–790 https://doi.org/10.1111/ceo.14559.