The Relationship of Dietary Lipid Intake and Age-Related Macular Degeneration in a Case-Control Study: AREDS Report No. 20

Objective  To evaluate the association of lipid intake with baseline severity of age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS).

Methods  Age-Related Eye Disease Study participants aged 60 to 80 years at enrollment (N = 4519) provided estimates of habitual nutrient intake through a self-administered semiquantitative food frequency questionnaire. Stereoscopic color fundus photographs were used to categorize participants into 4 AMD severity groups and a control group (participants with <15 small drusen).

Results  Dietary total ω-3 long-chain polyunsaturated fatty acid (LCPUFA) intake was inversely associated with neovascular (NV) AMD (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.41-0.90), as was docosahexaenoic acid, a retinal ω-3 LCPUFA (OR, 0.54; 95% CI, 0.36-0.80), comparing highest vs lowest quintile of intake, after adjustment for total energy intake and covariates. Higher fish consumption, both total and broiled/baked, was also inversely associated with NV AMD (OR, 0.61; 95% CI, 0.37-1.00 and OR, 0.65; 95% CI, 0.45-0.93, respectively). Dietary arachidonic acid was directly associated with NV AMD prevalence (OR, 1.54; 95% CI, 1.04-2.29). No statistically significant relationships existed for the other lipids or AMD groups.

Conclusion  Higher intake of ω-3 LCPUFAs and fish was associated with decreased likelihood of having NV AMD.

There is no known method to prevent the development of advanced age-related macular degeneration (AMD), the leading cause of irreversible vision loss in the United States among persons older than 65 years.^1-4 Identification of behaviorally modifiable risk factors is a promising approach with which to reduce the burden of AMD, a burden that will grow as the number of elderly persons in the population increases.^5-7 Nutrient-based preventive treatments for AMD development and progression were examined in a controlled randomized clinical trial in the Age-Related Eye Disease Study (AREDS).^8,9 The use of high doses of a combination of antioxidants (vitamin C, vitamin E, and beta carotene) and zinc reduced the risk of development of advanced AMD by about 25% in participants who had at least a moderate risk of developing AMD. The overall risk of moderate vision loss (>15 letters on the Early Treatment of Diabetic Retinopathy Study chart) was reduced by 19% at 5 years. In other analyses, AREDS baseline data were used to identify demographic, lifestyle, medical, and ocular factors associated with advanced AMD.

Bioactive molecules derived from diet may modify the risk of AMD onset and progression. Lipid-AMD relationships are plausible since certain lipids present in the retina have properties capable of modulating cellular damage that may be associated with advanced AMD.^10,11 We were particularly interested in the relationship of ω-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFAs) with AMD, since retinal concentrations of these compounds are dependent on and modifiable by diet.¹² Some studies have shown protective relationships of ω-3 LCPUFA^13,14 and ω-3 LCPUFA–rich food intake^5,13-16 with various stages of AMD. Although these relationships did not always persist after multivariable adjustments, measures of association remained in the direction of benefit. Monounsaturated fatty acid (MUFA)– and saturated fatty acid (SFA)–AMD relationships were also of interest as these nutrients are capable of modulating inflammation and signal transduction pathways associated with cell viability. Although not always attaining statistical significance, measures of association for MUFA-AMD relationships have been in the direction of harm for people reporting highest vs lowest intake.^5,13-15 This is also the case for total SFA^5,13-15,17 and cholesterol intake.^5,14,17

In this report, we evaluate the relationship of dietary lipid intake in the year prior to study enrollment with the baseline (enrollment) severity of AMD in AREDS. We examined these associations while considering the effect of nutrient- and nonnutrient-based predictors and correlates of drusen size and extent and pigment abnormalities associated with AMD, geographic atrophy, and neovascular (NV) AMD. An advantage of this case-control approach, compared with previous studies, was that it allowed us to efficiently recruit a large number of persons with advanced AMD.

Details of the AREDS design and methods appear in earlier publications.^8,9,18 In summary, 11 retinal specialty clinics enrolled 4757 participants from 1992 through 1998. Participants were 55 to 80 years of age at enrollment and had best-corrected visual acuity of 20/32 or better in at least 1 eye. At least 1 eye of each participant was free from advanced AMD (defined as NV AMD or geographic atrophy involving the center of the macula) and any eye disease that could complicate assessment of AMD or lens opacity progression, and that eye could not have had previous ocular surgery (except cataract surgery). Potential participants were excluded for illness or disorders that would make long-term follow-up or compliance with the study protocol unlikely or difficult. Persons aged 55 through 59 years were recruited only if they had intermediate AMD (AREDS Category 3) or unilateral advanced AMD (AREDS Category 4).^8,18 The present analysis of 4519 persons excludes all 110 persons in this age group, because there were no age-matched controls for these cases. This analysis also excludes the 128 persons with bilateral aphakia for whom presurgical refractive error was not available.

Persons were recruited for AREDS in 4 AMD categories determined by the size and extent of drusen in each eye, the presence of manifestations of advanced AMD, and visual acuity.⁸ Based on reading center grading of stereoscopic photographs taken at enrollment, participants in this study were divided into 5 groups. The groups analyzed in this report, numbered in order of increasing severity of drusen or type of AMD, were defined as follows.⁹ Subjects in group 1 (n = 1115) were free of drusen or had nonextensive small (<63 μm) drusen. Group 1 represented our referent controls. Subjects in group 2 (n = 1060) had at least 1 eye with 1 or more intermediate (63 μm-124 μm) drusen, extensive (cumulative area diameter of AREDS standard disc area) small drusen, or pigment abnormalities (hyperpigmentation or hypopigmentation) associated with AMD. Subjects in group 3 (n = 1568) had at least 1 eye with 1 or more large (≥125 μm) drusen or with extensive intermediate (65-124 μm) drusen. Subjects in group 4 (n = 118) had at least 1 eye with definite geographic atrophy anywhere within 3000 μm of the fovea. Subjects in group 5 (n = 658) had evidence of choroidal neovascularization or retinal pigment epithelial detachment in 1 eye (nondrusenoid retinal pigment epithelial detachment, serous sensory or hemorrhagic retinal detachment, subretinal hemorrhage, subretinal pigment epithelial hemorrhage, subretinal fibrosis) or scars of photocoagulation for AMD. The term neovascular was chosen as a simplified description of subjects in AMD group 5.

Participants were recruited through various sources: medical records of AREDS clinics; referring physicians; patient lists from hospitals and health maintenance organizations; screenings at malls, fairs, senior centers, and other gathering places; public advertisements (radio, television, newspapers, flyers); and friends and family of participants and of clinical center staff. The estimated percentage of participants by recruitment source for AMD groups 1 and 2 differed from groups 3, 4, and 5 mainly for medical records (17% vs 63%), public advertisements (53% vs 24%), and friends and family of participants (13% vs 7%).¹⁸

Before study initiation, the protocol was approved by a data and safety monitoring committee and by the institutional review board for each clinical center. Informed consent was obtained from all participants prior to enrollment. Detailed questionnaires were administered to obtain demographic information, history of smoking and sunlight exposure, medical history, history of specific prescription drug and nonprescription medication use, and history of vitamin and mineral use. General physical and ophthalmic examinations included measurement of height, weight, blood pressure, manifest refraction, best-corrected visual acuity, intraocular pressure, slitlamp biomicroscopy, and ophthalmoscopy. Stereoscopic fundus photographs of the macula were taken in each clinical center and graded at a photograph reading center.¹⁹

At enrollment, subjects completed a self-administered, 90-item, semiquantitative, food frequency questionnaire (AREDS FFQ) containing a food list with commonly consumed sources of zinc and vitamins A, C, and E. The food list also contained items rich in a variety of other nutrients that have putative associations with AMD, such as lipids, macular xanthophylls (lutein/zeaxanthin), pro–vitamin A carotenoids, and vitamins and minerals with antioxidant properties. Subjects were asked how often, on average, they had consumed each food or beverage item during the past year. Average frequency of consumption was recorded across 9 levels that ranged from “never or less than once per month” to “2 or more per day.” Average serving size was recorded as “small,” “medium,” or “large,” with respect to standard examples.

The AREDS FFQ was based on the validated 1987 National Cancer Institute Health Habits and History Questionnaire version 2.1, which was modified for use in AREDS with data obtained from 2-day food records sampled from 78 study-eligible persons selected from the 11 AREDS clinics. The instrument was validated using a telephone-administered 24-hour dietary recall at 3- and 6-month postenrollment in 197 randomly selected participants.²⁰ Correlations of 24-hour recall data with the AREDS FFQ were corrected for attenuation with the method of Rosner and Willett.²¹ Values for correlation coefficients are 0.64 for total SFA, 0.54 for MUFA, 0.45 for cholesterol, 0.36 for linoleic acid (LA), 0.27 for arachidonic acid (AA), 0.28 for α-linolenic acid, 0.35 for eicosapentaenoic acid (EPA), and 0.32 for docosahexaenoic acid (DHA).

Dietary intake data were processed with DIETSys software (version 3.0; National Cancer Institute, Information Management Services, Inc, Bethesda, Md, and Block Dietary Data Systems, Berkeley, Calif) at the Nutrition Coordinating Center, School of Public Health, University of Minnesota. The DIETSys system produced daily nutrient intake estimates for each subject by first multiplying the average age- and sex-adjusted portion size (derived from National Health and Nutrition Examination Survey II data) by the subject's reported serving size. The Nutrition Coordinating Center Food Composition Database (version 31, November 2000) was used with the estimated quantity of intake to derive individual nutrient values for each questionnaire item. Cumulative estimates for each nutrient were computed by summation of nutrient values across all foods and items.

Each of our 4 AMD groups (groups 2-5) was compared with the referent control group (group 1). Details of statistical modeling and analysis of nonnutritional risk factors appear in AREDS Report 3.¹⁸ Briefly, demographic factors, medical history, treatment history, and ocular factors associated with AREDS AMD categories were identified through polychotomous logistic regression analyses. Factors significant at P<.15 in any group were retained for multivariate modeling. This involved model simplification with the χ² test of change in deviance and goodness-of-fit diagnostics with the likelihood ratio criterion. Final models from AREDS Report 3 were the starting point for the multivariate analyses described in this report. Habitual dietary intake of DHA, EPA, total ω-3 LCPUFAs, AA, MUFA, SFA, and cholesterol across the year prior to enrollment are the primary independent variables in these analyses.

We applied a staged modeling technique in which energy-adjusted lipid values were first evaluated with age- and sex-adjusted logistic models and then with the final logistic models from AREDS Report 3. Single-nutrient and multinutrient models were constructed. We adjusted nutrient intake values for total energy intake by computing nutrient densities (nutrient intake/total energy intake). We classified nutrient density values into quintiles with the lowest-intake quintile as the referent exposure category and included a term for total energy intake in all models. When nutrient density scores are modeled as such, the nutrient density coefficient represents the relation of nutrient composition with AMD status, independent of energy intake. To explore relationships between single dietary nutrients and AMD, we used models with each nutrient and all AREDS AMD group–specific factors identified in AREDS Report 3 (each AMD group had a unique set; these are listed in the footnote to Table 1). Single nutrients associated with AMD at P values ≤.05 in AREDS Report 3 final models were included in multinutrient models. We added alcohol intake to final multinutrient models because alcohol may alter lipid metabolism, transport, and bioavailability.^22,23 We also added lutein/zeaxanthin intake on conceptual,^24-26 historical,^27-29 and statistical grounds, as these dietary xanthophylls compose macular pigment, are associated with decreased likelihood of AMD among people reporting lowest dietary intakes, and persist herein in multivariable models. In cases where we observed differences in odds between highest- and lowest-nutrient quintiles, we conducted trend tests with quintile medians modeled as a continuous variable. To examine the relationship of ω-3 LCPUFA–rich food with AMD, total and types of fish intake were added to these same models in place of ω-3 LCPUFA nutrient values.

Table 1 gives odds ratios (ORs) for sex-, age-, and calorie-adjusted and multivariable analyses of single nutrients with each AREDS AMD group. Values for AMD outcomes represent comparisons of the persons within the highest-intake quintile vs persons within the lowest-intake quintile. For multivariable models, protective relationships with NV AMD were observed for DHA (OR, 0.60; 95% confidence interval [CI], 0.42-0.85) and total ω-3 LCPUFAs (OR, 0.63; 95% CI, 0.45-0.89). Odds of NV AMD were increased in the highest-intake group for MUFA (OR, 1.80; 95% CI, 1.27-2.56) and SFAs (OR, 1.56; 95% CI, 1.09-2.23). The relationship of supplement years with AMD was negligible (data not shown) for all vitamins and minerals and was therefore not considered in subsequent models. Because the only multivariable lipid-AMD relationship observed outside of the NV AMD group was an increased likelihood of group 3 with increased cholesterol intake (OR, 1.34; 95% CI, 1.04-1.72), the remaining sections of this report will present multinutrient models for the NV AMD group only.

Table 2 gives ORs for NV AMD by quintiles of lipid intake; models contain terms for all nutritional factors that were statistically associated both with NV AMD and factors from AREDS Report 3. Nutritional factors included total energy intake, DHA, AA, lutein/zeaxanthin, and alcohol. Factors from AREDS Report 3 included age, race, sex, education, body mass index, refractive error, smoking history, hypertension, and lens opacity. Docosahexaenoic acid (OR, 0.54; 95% CI, 0.36-0.80; P trend = .004) and total ω-3 LCPUFA (OR, 0.61; 95% CI, 0.41-0.90; P trend = .01) intake persisted as independent factors in these models. Magnitude and precision of the ORs for DHA and total ω-3 LCPUFAs were not altered appreciably compared with multivariable single-nutrient models. Odds of NV AMD were significantly increased among participants classified in the highest quintile of AA intake (OR, 1.54; 95% CI, 1.04-2.29; P trend = .03). In these multinutrient models, neither ORs nor trends for NV AMD attained statistical significance for intake of MUFA, total SFAs, or cholesterol. As such, final models did not include terms for these factors (P>.10 for all comparisons).

Table 3 gives ORs for multivariable relationships of NV AMD with reported intake of ω-3 LCPUFA–rich foods. Based on results from the FFQ, intake of fish and shellfish contributed 93% of EPA and 71% of DHA intake. Odds ratios are relative to participants who reported consumption of a medium-size portion of the particular type of fish or shellfish less than 1 time per month in the year prior to AREDS enrollment. After controlling for caloric intake and covariates discussed in the preceding section, total fish intake of more than 2 medium servings per week was associated with lower odds of NV AMD (OR, 0.61; 95% CI, 0.37-1.00). Participants who consumed 4 oz of broiled/baked fish more than 1 time per week were also less likely to have a diagnosis of NV AMD (OR, 0.65; 95% CI, 0.45-0.93). Results were similar for tuna intake, although they did not attain statistical significance. The magnitude of ORs for these relationships was similar to that observed for ω-3 LCPUFAs.

Table 4 contains results of our final models for EPA and DHA run within upper (quintiles 4 and 5) and lower strata (quintiles 1 and 2) of AA. Arachidonic acid (C20:4ω-6) is a major LCPUFA of the ω-6 family. Major sources of AA in the diets of AREDS participants were beef and pork (32%), turkey and chicken (25%), eggs (20%), and fish (11%). Among participants reporting lower levels of AA intake, there was a significant trend for increased risk of NV AMD with decreasing DHA.

This report extends the findings of AREDS Report 3 to include lipid- and ω-3 LCPUFA–rich food-based factors. Higher levels of total ω-3 LCPUFA and ω-3 LCPUFA–rich food intake were associated with a lower likelihood of NV AMD after statistical control for nutrient- and nonnutrient-based predictors and correlates. Participants with reported ω-3 LCPUFA intake in the highest quintile were 40% less likely to be in the NV AMD group than participants with reported intake in the lowest quintile. Of ω-3 LCPUFAs, the strongest effects were observed for DHA intake. Trends of decreasing odds with increasing nutrient intake existed for EPA, DHA, and total ω-3 LCPUFAs. Relative to participants consuming less than 1 medium serving of broiled or baked fish per month, the magnitude and precision of the OR for ω-3 LCPUFA–rich food intake of 1 or more 4-oz servings of this food per week were similar to those for total ω-3 LCPUFA. Participants with reported intake in the highest quintile for AA, an ω-6 LCPUFA, were 1.5 times more likely to be in the NV AMD group than participants with intake in the lowest quintile. We found no associations of other lipid intake with NV AMD when essential fatty acids (α-linolenic acid and LA) and MUFA, SFA, and cholesterol intake were modeled as primary independent variables and adjusted for DHA, AA, alcohol, lutein/zeaxanthin, and the set of AMD group-specific covariates from AREDS Report 3.

Our study results are concordant with those in the extant literature for sight-threatening forms of AMD; ORs for comparisons of high vs low ω-3 LCPUFA and fish intake have been in the direction of benefit. The magnitude of effect for ω-3 LCPUFA–NV AMD ORs that we observed is also in the range of those reported previously. The Dietary Ancillary Study of the Eye Disease Case Control Study researchers describe a trend for decreasing odds of advanced (exudative) AMD among subjects reporting highest ω-3 LCPUFA and fish intake.¹³ We did not observe a relationship of DHA intake with geographic atrophy. In the Progression of Age-Related Macular Degeneration Study, the only published prospective study to our knowledge examining the relationship of lipid intake with progression to advanced AMD (defined as NV AMD or geographic atrophy), people reporting fish intake at frequencies of 2 or more times per week had a lower likelihood of progression to advanced AMD (P<.05) if they also reported lower levels of LA intake.¹⁵ The likelihood of having any AMD (with visual loss of 20/30 or worse in at least 1 eye) was reduced among people reporting highest DHA, tuna, and total fish intake within a prospective sample from the Nurses' Health Study and the Health Professionals Follow-up Study.¹⁴ When modeled simultaneously with intake of other dietary lipids, ω-3 LCPUFA–AMD relationships did not remain statistically significant, although they were in the direction of benefit (risk ratios for highest vs lowest of DHA and EPA intake were 0.8; 95% CI 0.5-1.1).¹⁴

Three population-based studies examined the relationship of fish intake with “late” (NV or atrophic) AMD as classified by the Wisconsin Age-Related Maculopathy Grading System.^30,31 Each of these studies had fewer than 55 cases of late AMD; however, although not statistically significant, ORs were in the direction of benefit. Our results were also within the range of those from other studies for MUFA^5,6,13-15 and SFA^5,6,13-15,17 intake.

Docosahexaenoic acid, EPA, and AA are major dietary LCPUFAs; DHA and AA are major structural LCPUFAs of retinal photoreceptor outer segments and vascular tissue.^32-34 The amount of DHA in retinal tissue^35,36 and plasma³⁷ is modifiable by and dependent on dietary intake. Long-chain polyunsaturated fatty acids may be obtained through diet or biosynthesized from essential fatty acids. α-Linoleic acid (18:3ω-3) is the essential fatty acid precursor to the ω-3 LCPUFAs and LA (18:2ω-6) is the precursor to ω-6 LCPUFAs. Intake levels of neither precursor attained statistical significance when modeled as the single nutrient in the final calorie-adjusted multivariable model for NV AMD.

While our models simultaneously controlling for ω-3 and ω-6 LCPUFAs yielded significant results, it is important to consider the potential for effect modification within levels of these nutritional variables, as they act as substrates in the same biochemical pathways for production of potent lipid mediators. Two studies suggest an effect modification of fish/ω-3 LCPUFA intake with LA intake in advanced AMD; both reported that the ORs for these factors were in the direction of benefit among subjects reporting lowest levels of LA intake.^13,15 In our analyses, a direction of benefit was seen for DHA with NV AMD among AREDS subjects in the highest levels (fourth and fifth quintiles) of LA (OR, 0.31; 95% CI, 0.11-0.97). However, evaluation of effect modification by another ω-6 fatty acid, AA, did yield a trend for a benefit among subjects in the lower level of AA intake (Table 4).

Long-chain polyunsaturated fatty acids are effected by and influence processes implicated in the pathogenesis of vascular and neural retinal diseases.¹⁰ Docosahexaenoic acid and EPA may serve as protective agents in the retina because of their influence on gene expression,^38-41 retinal cell differentiation,^42-44 and survival.^42-46 Free LCPUFAs, liberated when phospholipase A2 hydrolyzes DHA and AA from their primary storage forms in retinal tissue, are the precursors and substrates to families of bioactive molecules (eicosanoids,^47-51 endocannabinoids,^52,53 and LCPUFA-based autocoids^11,54) that act as potent regulators of retinal vascular function, cell survival, inflammation, and energy balance. Long-chain polyunsaturated fatty acids also affect factors and processes driving key events in the angiogenic cascade.^10,13 Docosahexaenoic acid may also be involved in rhodopsin regeneration⁵⁵ and work in signaling cascades to enhance activation of membrane-bound retinal proteins.^12,56-58

There are inherent limitations in the nature of this case-control sampling design. However, we believe a number of factors increase the strength of our inferences. The AREDS sample contains a large number of participants with NV AMD and dietary intake data. All data were collected with a standardized protocol by centrally trained staff. Trained graders at a reading center ascertained the AMD phenotype based on fundus photographs using a standardized grading system.

The potential for erroneous selection of nonnutrient-based variables is discussed in AREDS Report 3.¹⁸ Because all nonnutritional factors associated with NV AMD have been reported in previously published studies, we applied the simplifying assumption that we were unlikely to model factors identified through spurious relationships. However, the possibility of a consistent bias across studies cannot be excluded.

The sampling scheme for our clinic-based case-control design may have increased the probability of exposure misclassification among subjects. The Eye Disease Case Control Study¹³ researchers restricted their analysis exclusively to newly diagnosed AMD cases and found results similar to our own. Exposure misclassification may have occurred if (1) the accuracy of dietary recall varied between participants with eye disease and those in the comparison group (groups were defined on the basis of eye disease and this may have influenced classification of exposure) or (2) some participants with severe eye disease altered their diets in the years immediately prior to enrollment to conform to “healthy diet” recommendations. We would expect these conditions to modify our results toward no association.

The possible effect of selection bias also needs to be considered. Participants in AREDS classified with no AMD or lower severity of AMD (groups 1 and 2) were more likely than members of groups 3, 4, and 5 to volunteer in response to public advertisements. These people were also more likely to be enrolled in the study through familial association with participants in groups 3 and 4. As such, there were baseline group differences in the distributions of some demographic, behavioral, and medical factors previously associated with AMD. Our multivariable models included many of these potential confounders, but if this sampling scheme yielded imbalances in unknown and therefore unmeasured (behavioral and lifestyle) factors associated with diet and AMD, our findings could have been biased.

Nutrient intake values may partially reflect a more general lifestyle or socioeconomic-demographic construct associated with NV AMD. As such, we performed a number of analyses to evaluate the potential for effect modification. The strongest and most consistent factors associated with sight-threatening AMD (age and smoking) were not associated with ω-3 LCPUFA intake. Participants with a college education were almost twice as likely to be in a higher quintile of DHA intake than people with 12 or fewer years of education after adjusting for AREDS Report 3 factors (OR, 1.8; 95% CI, 1.6-2.1). While sample-restricted analyses compromised power of the statistical test, we observed no changes in the direction of previously observed lipid-AMD relationships when data were analyzed within each stratum. Observations were similar for other factors (eg, strata of race and body mass index).

Adding LCPUFAs, lutein/zeaxanthin, and alcohol to the model for NV AMD had a negligible effect on the magnitude and precision of ORs for factors from AREDS Report 3 that were associated with NV AMD (age, education, refractive error, race, smoking, and hypertension). Body mass index and lens opacity did not persist as statistically significant risk factors, although point estimates were changed only minimally. To evaluate the potential confounding impact of nutrient-nutrient relationships, we obtained partial correlation coefficients from linear regressions of log-transformed nutrient scores for all nutrients on each nutrient. The partial correlation coefficient allowed us to quantify the magnitude of relationships and also to determine the potential for colinearity. After controlling for all measured nutrients that varied independently with ω-3 LCPUFA intake, only EPA and DHA contributed more than 5% to variance in ω-3 LCPUFAs; these results indicate that the estimate of ω-3 LCPUFA intake is likely to reflect actual ω-3 LCPUFA intake. We believe that it is unlikely that EPA and DHA are markers for other nutrients.

This AREDS report provides evidence that people reporting highest levels of ω-3 LCPUFA intake have a decreased likelihood of having NV AMD relative to people reporting lowest levels of intake. Because increased intake of AA is also associated with an increased likelihood of having NV AMD, it is important to consider the balance and composition of dietary LCPUFAs from the ω-3 and ω-6 families. These results and those from other observational analytic investigations¹³ suggest that modifying diet to include more foods rich in ω-3 LCPUFAs could result in a reduction in the risk of having NV AMD. In addition to carefully designed observational analytic designs, clinical trials would provide unique information on whether dietary intervention or supplementation with ω-3 LCPUFAs may help prevent the development of advanced AMD.

Correspondence: AREDS Coordinating Center, The EMMES Corporation, 401 N Washington St, Suite 700, Rockville, MD 20850-1707 (aredspub@emmes.com).

Submitted for Publication: May 12, 2006; final revision received September 14, 2006; accepted September 14, 2006.

Financial Disclosure: None reported.

Funding/Support: This report was supported by contracts from the National Eye Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Md.