Abstract
BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in older adults. While anti-vascular endothelial growth factor (anti-VEGF) therapies are available for neovascular AMD (nAMD), effective preventive strategies remain limited. Long-chain omega-3 polyunsaturated fatty acids (ω-3 PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have biological plausibility for retinal protection through structural roles in photoreceptor membranes and anti-inflammatory lipid mediator pathways. OBJECTIVES: This study aimed to synthesize contemporary evidence regarding omega-3 fatty acids in AMD prevention, with emphasis on subtype-specific associations, differences by omega-3 species, and contrasts between dietary intake and supplementation evidence. METHODS: This systematic review and meta-analysis was conducted in accordance with PRISMA 2020 guidance and registered the protocol in PROSPERO (CRD420251122413). PubMed, ScienceDirect, and the Cochrane Library were searched from inception to August 2, 2025. Eligible studies included observational studies of dietary ω-3 PUFA exposure in adults aged 50 years or older with AMD outcomes. Random-effects models models were used to pool adjusted effect estimates comparing the highest versus lowest ω-3 exposure categories. Prespecified subgroup analyses were performed by AMD subtype (early AMD, advanced AMD, nAMD, and geographic atrophy [GA]) and ω-3 species (EPA, DHA, and alpha-linolenic acid [ALA]). Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). Publication bias was evaluated using funnel plots and Egger's regression test. RESULTS: Eighteen studies were included. Higher ω-3 intake was associated with reduced odds of AMD overall (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.70-0.96; p = 0.01), with moderate heterogeneity (I² = 61%). Subtype analyses demonstrated stronger associations for nAMD (OR 0.57, 95% CI 0.40-0.81) and GA (OR 0.65, 95% CI 0.45-0.94), and a smaller association for early AMD (OR 0.83, 95% CI 0.72-0.97), whereas advanced AMD was not significantly different between high and low intake groups (OR 0.81, 95% CI 0.49-1.33; p = 0.41). In ω-3 species analyses, higher EPA intake was associated with lower AMD odds (OR 0.61, 95% CI 0.38-0.97; p = 0.04), while DHA showed a borderline association (OR 0.73, 95% CI 0.53-1.01; p = 0.05); ALA was not associated with benefit (OR 1.00, 95% CI 0.84-1.20; p = 0.96). Time-to-event pooling showed no significant long-term risk reduction (hazard ratio [HR] 0.98, 95% CI 0.84-1.15; p = 0.83). Funnel plot asymmetry was observed, and Egger's test suggested small-study effects (p = 0.04). CONCLUSIONS: Higher dietary intake of marine-derived ω-3 PUFAs is associated with reduced odds of AMD. However, long-term risk reduction was not demonstrated in time-to-event analyses, and small-study effects were suggested. These findings support the possibility that dietary patterns emphasizing ω-3-rich seafood may contribute to AMD risk reduction, whereas the effectiveness of isolated ω-3 PUFA supplementation for AMD prevention remains uncertain and warrants confirmation in future prospective studies and larger randomized controlled trials with long-term follow-up.