Age-related macular degeneration (AMD) is the common causes of low vision and blindness among the elderly (1). Its current global prevalence is approximately 8.69% among individuals aged 45–85 years, and the number of affected individuals is expected to rise to 288 million by 2040 (2). Consequently, the study and prevention of AMD risk factors have become a significant focus in clinical research. This disease arises from a complex interplay of aging, genetic predispositions, and environmental influences, including dietary habits (3–5). Late AMD presents in two forms: geographic atrophy (GA) and neovascular AMD. Neovascular AMD necessitates repeated intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs, whereas there are currently no clinical treatments available that can either slow progression or restore vision in cases of GA (2). Therefore, effective prevention and detection methods are crucial for mitigating AMD-induced blindness in the elderly population. Oral administration of a specific combination of antioxidants and mineral supplements has been shown to slow the progression from intermediate to late AMD, particularly in cases of neovascular AMD (6, 7). However, some observational studies have indicated that high intakes of specific dietary nutrients are associated with either a reduced or increased risk of early or late AMD (8, 9), although the findings remain inconsistent. Over the past few decades, research has predominantly centered on common factors influencing the development of AMD, such as age, gender, smoking, alcohol consumption, hypertension, diabetes, genetic factors, and environmental influences (10, 11). Recently, dietary factors have attracted increasing attention. Some studies have suggested that oral supplements containing certain nutrients can prevent the onset of AMD or delay its progression to intermediate or late stages, particularly in neovascular cases (7, 9). A growing body of observational studies has reported that higher intake of certain dietary components (such as vitamins A, B6, B12, C, and E) correlates with decreased or increased risks of early or late AMD (12–14). In addition, some studies have found that eating a healthy diet rich in folic acid (leafy vegetables, fruits, whole grains) may help to reduce vision loss due to advanced forms of AMD (15). Although the association between vitamins and AMD has been extensively investigated, the results remain inconclusive (4, 16–20). This study used a cross-sectional design to examine the association between dietary vitamin intake and AMD. Data were drawn from the National Health and Nutrition Examination Survey (NHANES), conducted by the National Center for Health Statistics (NCHS) under the U.S. Centers for Disease Control and Prevention (CDC). The analysis focused on the association between vitamin intake and AMD in a nationally representative U.S. population sample.

The objective of this study was to determine an independent association between vitamin intake and AMD. By utilizing two cycles of the NHANES data from 2005–2006 and 2007–2008 and controlling for several potential confounding variables, we found that individuals in the United States with high vitamin intakes B (1, 2, 6, and 12), E and folic acid were less likely to be diagnosed with AMD. The preventive effects of vitamin B2 and folic acid were especially notable.

According to clinical presentation, the Age-Related Eye Disease Study team classifies AMD into four stages: AMD-free, early, middle, and advanced. In the advanced stages, two distinct manifestations emerge (24). The first is the development of confluent areas of atrophy affecting photoreceptors and the retinal pigment epithelium, known as geographic atrophy (atrophic AMD). The second is the proliferation of abnormal blood vessels in the macular region, referred to as neovascular AMD (exudative AMD) (24). Neovascular AMD necessitates repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) drugs, whereas there is currently no clinical treatment available that can slow progression or restore vision in cases of geographic atrophy (24). Thus, effective prevention and early detection methods are essential for mitigating AMD-related blindness in the elderly population.

Oxidative stress is a significant factor contributing to the development of AMD (25). The retina is a tissue with a high oxygen demand, even exceeding that of the brain by weight. The local oxygen metabolic environment in the retina is critical for maintaining a balance between oxygen supply and demand. Retinal phototransduction is an ongoing process that converts light into vision, resulting in low energy consumption and the production of reactive oxygen species (ROS) as metabolic byproducts. Under normal circumstances, ROS facilitate regular cell metabolism; however, oxidative stress occurs when the levels of ROS exceed the capacity of the antioxidant system (26). Retinal tissue, particularly the retinal pigment epithelium (RPE) cell layer in the macula, is likely to generate excessive exogenous ROS in a high-oxygen environment. Elevated ROS levels can lead to oxidative damage to proteins, lipids, and mitochondrial DNA (27). During mitochondrial damage, certain proteins are released into the cytoplasm due to the permeabilization of the mitochondrial outer membrane, triggering cell death (28). Increasing research efforts are directed at understanding the processes that lead to RPE cell death under oxidative stress conditions (29, 30). Advanced AMD, especially geographic atrophy, is characterized by the loss of RPE cells and subsequent dysfunction of photoreceptors (24). In summary, oxidative stress is a critical factor in the pathogenesis of AMD.

This study found that the intake of vitamins B and E was negatively correlated with the prevalence of AMD. As an antioxidant, vitamin E slows the progression of AMD by inhibiting oxidative stress (31), which may explain the observed results. The potential of B vitamins to delay the onset of AMD may be attributed to several factors: B vitamins are crucial for DNA methylation, synthesis, repair, and replication (32) and they are involved in one-carbon metabolism. A deficiency in B vitamins could impair DNA methylation, leading to one-carbon metabolism disorders that may increase the risk of age-related neurodegenerative diseases (32, 33). Additionally, B vitamins help regulate plasma homocysteine levels in the body. Without B vitamin cofactors, homocysteine can build up, affecting amino acid and nucleotide metabolism (9). Elevated homocysteine is linked to an increased risk of neurodegenerative and cardiovascular diseases and is also associated with AMD (34). This association is complex and may be influenced by different states of the three B vitamin cofactors, other B vitamins, or common variants of methylenetetrahydrofolate reductase, a key enzyme in converting homocysteine to methionine (35). Furthermore, vitamin B1 acts as an antioxidant, similar to vitamin E, and may slow AMD progression by mitigating oxidative stress (36).

An overlap of confidence intervals was observed in the results. Based on previous research (35), the reason for this phenomenon may be that the amount of vitamin intake required at each age. This study categorized B vitamins and vitamin E into quartiles and conducted a logistic regression analysis. The findings indicated that the Q4 group of vitamin B1 was negatively correlated with AMD in model 1 and statistically differed from the Q1 group, suggesting that the Q4 group experienced a lower incidence of AMD. Similarly, the Q3 and Q4 groups of vitamin B2 exhibited a negative correlation with AMD across models 1, 2, and 3, and were statistically different from the Q1 group, again indicating a lower incidence of AMD in the Q4 group. The Q2 group of folic acid also showed a negative correlation with AMD in these models and was statistically different from the Q1 group, indicating a lower incidence of AMD in the Q2 group. These results suggest that after categorizing B vitamins and vitamin E into quartiles and conducted a logistic regression analysis, the effects of vitamins remain significant. The findings align with previous studies affirming the importance of B vitamin intake in the development of AMD (36).

Some differences were also observed in the subgroup analysis, which may be related to intestinal microbial changes and dietary habits (37). The adult intestines host a complex microbial ecosystem comprising an estimated 100 trillion organisms (Host–Bacterial Mutualism in the Human Intestine) (38). Numerous beneficial effects of gut commensals have been reported, including facilitating nutrient metabolism, maintaining the intestinal barrier, and preventing pathologic bacterial colonies from establishing themselves (38). The gut microbiota plays a crucial role in digestion, vitamin production, and the synthesis of short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate (39). A research study indicated that individuals with advanced AMD exhibited signs of intestinal dysbiosis, characterized by a distinct composition of gut bacteria compared to healthy older adults. Specifically, the bacterial genera Anaerotruncus and Oscillibacter, along with the species Ruminococcus torques and Eubacterium ventriosum, were found to be differentially abundant (39). Conversely, AMD subjects exhibited reduced levels of Oscillospira, Blautia, and Dorea compared to their healthy counterparts (40). In the pathogenesis of AMD, regulated immune activation involving the recruitment of microglia and macrophages to the subretinal and choroidal regions, mast cell activation, and immune responses from the retinal pigment epithelium (RPE) are considered key factors (41). The gut microbiota may potentially modulate inflammation and microglial function during the development and progression of AMD (39). Vitamin B1 is absorbed in the duodenum and converted, with magnesium as a cofactor, to its active form, thiamine pyrophosphate (TPP) (42). TPP acts as a cofactor at crucial steps in the citric acid cycle and the pentose phosphate pathway (42). TPP also plays a major role in the aerobic metabolism of glucose for energy production (42). Certain intestinal microbiota, including Bacteroides fragilis, Prevotella, Fusobacterium varium, Actinobacteria, and Clostridium, can produce vitamin B1 (43). About half of the enzymes present in these microbiotas are involved in the de novo synthesis of vitamin B1 (44). However, some gut microbiota lack the vitamin B1 synthesis pathway and require an external source for growth, such as Ruminococcaceae (44). This finding indicates that vitamin B1 intake can influence the composition of the gut microbiota. The active forms of vitamin B2 are essential for synthesizing niacin, folic acid, vitamin B6, and all heme proteins. Additionally, vitamin B2 is necessary for the metabolism of carbohydrates, proteins, and fats into glucose. Its antioxidant effects are crucial for cellular respiration and play a key role in immune system function (45). Vitamin B2 also influences the composition of the gut microbiome. Replenishment of vitamin B2 has been reported to alter the composition and diversity of gut microbiota in mice (46). In clinical interventions, vitamin B2 supplementation for two weeks increased the relative abundance of F. prausnitzii in healthy individuals (47). Moreover, treatment with vitamins B2 and C significantly notably the number of Proteobacteria while showing a trend toward an increase in Firmicutes and a decrease in Bacteroidetes (48). The active form of vitamin B6 is a coenzyme that supports numerous enzymes in performing various functions, including the maintenance of normal homocysteine levels, supporting immune function and brain health, and the breakdown of carbohydrates, proteins, and fats (49). Vitamin B6 also affects the growth of gut microbiota (50). Unfortunately, investigations about this topic are limited. Folic acid is crucial for nucleic acid synthesis and red blood cell production. It plays a role in converting homocysteine to methionine, which is essential for hematopoiesis and the prevention of megaloblastic anemia (51). Folic acid deficiency can impact bacterial diversity. In a study involving gnotobiotic mice, a folic acid-deficient diet increased microbial diversity after a 21-day treatment compared to a micronutrient-sufficient diet. However, a 14-day full diet treatment did not alter this trend (52). Another study assessed fecal microbiota composition based on human gut microbiota. The fecal microbiota community shows lower diversity in healthy volunteers on a diet low in folic acid. Additionally, the fecal microbiota has a higher potential to produce folic acid in in vitro experiments (53). This finding suggests that folic acid deficiency may decrease the richness of human gut microbiota. Vitamin B12 is required for red blood cell production, neurologic function, and myelin synthesis. This vitamin serves as a cofactor in DNA and RNA synthesis, as well as in the synthesis and metabolism of hormones, proteins, and lipids (49). In humans, vitamin B12 may increase the proportion of Proteobacteria and Verrucomicrobia (54) while reducing the abundance of Bacteroidetes (50). Vitamin E possesses strong antioxidant and anti-inflammatory properties (55). Research findings indicate that colon-targeted Vitamin E (−tocopherol, 100 mg/kg) supplementation increased the production of SCFAs and the relative abundance of beneficial microorganisms such as Akkermansia, Lactobacillus, Bifidobacterium, and Faeca libacterium (48). In addition to affecting the composition of the gut microbiota, the intake of B vitamins and vitamin E may influence SCFA metabolism by regulating gut microbiota. Subsequently, SCFAs impact neuroinflammation by altering glial cell morphology, continuously modulating microglia maturation, and regulating levels of neurotrophic factors, which enhances neurogenesis and improves neuronal homeostasis and function, further affecting AMD (56). Based on the above studies, we hypothesize that B vitamins and vitamin E may also affect AMD by regulating gut microbiome composition. However, differences in results may arise in subgroup analysis because the effects of each vitamin on the gut microbiome are not identical. Additionally, differences in race, age, and gender appear to influence the results of these analyses. Since the content of each vitamin varies across different dietary habits (37), and the amounts of vitamins required by individuals of different races and genders at various age stages are not the same, these factors may also contribute to the differences observed in subgroup analysis.

Some studies have reported a negative correlation between the intake of vitamins A, C, and D and the incidence of AMD (9, 30, 57, 58), which contrasts with the findings of the present study. The “Age-Related Eye Disease Study (AREDS)” was a significant multicenter prospective investigation of eye diseases, including AMD, conducted by the NIH in the United States (5, 15). The findings suggest that oral antioxidant supplements containing vitamin C, vitamin E, and provitamin A carotenoids may slow the progression of AMD. In a related multicenter, double-blind, randomized placebo-controlled trial, Li et al. (59) reported results that align with these findings. Additionally, Millen et al. (16) performed a prospective analysis involving a subset of participants (n = 1,225) from the Atherosclerosis Risk in Communities Study, indicating that high concentrations of 25(OH)D may be associated with lower odds of developing early AMD. The study by Kabatas et al. (60) found significantly reduced levels of 25(OH) vitamin D in individuals with advanced-stage AMD.

The discrepancies among these studies may arise from variations in sample size, ethnicity, and the confounding factors accounted for in each study. In the AREDS, 4,757 participants aged 55 to 80 years were recruited from 11 retinal specialty clinics across the United States between 1992 and 1998. In the AREDS2, 4,203 participants aged 50 to 85 years were enrolled from 82 retinal specialty clinics between 2006 and 2008 (61). The participants in Li’s study (59) were Chinese individuals diagnosed with AMD based on the classification system used in the Age-Related Eye Disease Study. The Atherosclerosis Risk in Communities Study (16) is a population-based, prospective investigation on atherosclerosis that has taken place since 1987–1989, involving participants aged 45 to 65 years at the initial visit and recruited from four centers: Forsyth County, North Carolina; Jackson, Mississippi; Minneapolis, Minnesota; and Washington County, Maryland. Participants in Kabatas’s study (60) were Turkish and were excluded if they had received immunomodulator treatment, had chronic renal, hepatic, or parathyroid diseases, had received intravitreal anti-VEGF injections within the previous month, or were undergoing antioxidant or vitamin D treatment. The NHANES consists of a series of cross-sectional interviews and examinations of the civilian, noninstitutionalized population of the United States, providing data on AMD only from 2005 to 2008. Moreover, the exclusion criteria applied in this study differed from those in prior research, contributing to the variations observed in the results.

This study has several limitations. First, as a cross-sectional study, it cannot establish a causal connection between vitamin consumption levels and AMD; instead, it can only suggest associations. Second, since our study focused exclusively on older Americans, the findings may not be generalizable to other populations. Further randomized clinical trials are needed to confirm these findings. However, our study also possesses notable strengths. Data were collected from a diverse and representative sample, enhancing the generalizability of the findings to the broader population of older Americans. Additionally, this research provides a comprehensive investigation into the association between vitamin intake and AMD within the U.S. population, contributing to its overall credibility.

This study found that higher vitamin intakes B and E were associated with a lower prevalence of AMD in the U.S. population. Eating a healthy diet rich in vitamins B and E, particularly B2 (eggs, green vegetables, meat, mushrooms, and almonds) may help to reduce vision loss due to AMD. However, since this is a cross-sectional study, causal associations between vitamin intake and AMD cannot be established. Further randomized clinical trials are needed to confirm these findings.