We found no overall association between lutein/zeaxanthin intake and early AMD risk, and the association did not differ by smoking status, vitamin C and E intakes, and BMI. There was some suggestion of a nonlinear inverse association between lutein/zeaxanthin intake and neovascular AMD risk, which tended to be clearer among nonsmokers.
Although there have been several epidemiologic studies of dietary or serum concentrations of lutein/zeaxanthin and AMD risk, the results have been inconclusive. A significant inverse association was found for dietary and serum lutein/zeaxanthin in a case-control study of neovascular AMD (356 cases) (17
). Subsequent epidemiologic studies of lutein/zeaxanthin have been mixed. Some (19
) but not others (25
), found an inverse association. Most of the studies, even those that found inverse associations, were small, used case-control or cross-sectional designs, where recall and selection biases are of concern, and included few neovascular AMD cases. A cross-sectional study of the participants in the third National Health and Nutrition Examination Survey found that a higher lutein/zeaxanthin intake was related to lower pigmentary abnormalities (n
= 51) and late AMD (n
= 16) in some age groups (19
). A case-control study of neovascular AMD (n
= 72) found that lutein/zeaxanthin intake was associated with lower risk (20
). A cross-sectional study with 64 early and 14 late AMD cases found an inverse association between plasma zeaxanthin but not lutein and AMD risk (21
). Another cross-sectional study with prediagnostic blood samples and 34 early and 7 late AMD found an inverse association with plasma lutein and zeaxanthin (23
). Three cohort studies with early AMD cases only or with mostly early AMD cases found no inverse association (27
). Therefore, the evidence of inverse association is more consistent for neovascular AMD. There is an ongoing randomized clinical trial of supplementation of lutein/zeaxanthin and n−3 fatty acids and AMD (Age-Related Eye Disease Study II), although the results may not be available in the near future. Previously in our 2 cohorts, we examined lutein/zeaxanthin intake as well as other antioxidant vitamins and carotenoids in relation to AMD risk and found no associations (33
). However, after adding more cases and, more importantly, after using recently updated nutrient data to our lutein/zeaxanthin score, we observed some inverse association, although it did not have a clear dose-response relation.
Smoking is a major oxidative stress and may lower the bioavailability of lutein/zeaxanthin. Smokers have lower serum lutein and zeaxanthin concentrations than do nonsmokers, independent of dietary lutein/zeaxanthin intake (54
). Therefore, a high intake of lutein/zeaxanthin may be more important for AMD risk among smokers. However, we found that dietary lutein/zeaxanthin intake was inversely associated with neovascular AMD only among nonsmokers. A modest antioxidant effect of lutein/zeaxanthin may be overwhelmed in the face of the strong oxidative stress due to smoking.
A recent experimental study suggests that zeaxanthin in combination with ascorbic acid or α
-tocopherol may protect the retina against oxidative damage (34
). Another study found an interaction between lutein and ascorbic acid in reducing oxidative stress (36
). When we examined lutein/zeaxanthin intake by intakes of vitamins C and E, there were suggestive inverse associations between intakes of lutein/zeaxanthin and neovascular AMD among those with high intakes of these vitamins.
Adipose tissue is a major storage organ for carotenoids, and a higher adipose tissue content may trap lutein/zeaxanthin and make it less available to other organs, including the macula (37
). If this is true, we hypothesized that we would find a stronger inverse association among those who are not overweight. In contrast with our hypothesis, however, the association between lutein/zeaxanthin intake and neovascular AMD, if anything, was stronger in those who were overweight or obese.
Our study had several strengths. To our knowledge, this is the largest study of lutein/zeaxanthin intake and AMD, with >400 neovascular AMD cases and one of the few prospective studies of diet and AMD risk. However, we did have limited statistical power in interaction analyses and were not able to evaluate the associations among current smokers and among the obese because of the limited number of cases in these categories. Also, vitamin C intake in our populations was relatively high and we were not able to evaluate the association among those consuming less than Recommended Dietary Allowance of 90 mg for women and 75 mg for men.
We had repeated measures of diet and were able to examine dietary intake incorporating these measures, which can minimize measurement error because of a one-time dietary assessment and thus best reflect long-term dietary intake, which may be most relevant to chronic diseases such as AMD with long duration of development (56
). However, the validation correlations for lutein/zeaxanthin calculated from the intake measured by FFQ and serum concentrations were not high compared with other nutrients in our cohort, probably because of variable bioavailabilities, although the values were higher than those from other studies (54
). Also, plasma concentrations of lutein/zeaxanthin are more strongly related to macular pigment density (reflecting lutein/zeaxanthin status in the eye) than to dietary intake (57
). Thus, more direct assessments of lutein/zeaxanthin status, such as serum concentrations of lutein/zeaxanthin or macular pigment density, may provide a clearer picture of the relation.
We used a more advanced definition of AMD than that of most other epidemiologic studies by restricting cases to those with visual acuity loss of at least 20/30 or worse. This is because we rely on self-report of AMD and because most early AMD cases do not have any symptoms; we might otherwise have misclassified these cases. Using a more advanced definition of AMD, we would have excluded some persons who might have been grouped as “cases” in other studies. As far as being cases in our studies are not related to lutein/zeaxanthin intake, our results would not be biased (58
). Persons who are more health conscious may seek medical attention and may have a diagnosis of AMD. However, this may be more of a concern for asymptomatic cases with no visual loss. Furthermore, we restricted participants in our analysis to those who received an eye examination during follow-up. Finally, if the association was biased, it may be more likely true for the less severe form (eg, early AMD cases). However, we found associations for neovascular AMD. Because we did not have a centralized review system for AMD diagnosis and relied on outside review, some diagnoses might have been misclassified, especially in determining the AMD subgroup. This type of misclassification may tend to attenuate the associations with neovascular AMD, if some early cases were included in this group.
It is possible that lutein and zeaxanthin each have a different impact on AMD (23
). Even if both carotenoids compose macular pigment, the distribution of the carotenoids in the macula is quite different; zeaxanthin predominates in the central part of the macula and lutein in the periphery (16
). A recent study found that zeaxanthin cannot convert to lutein, but, in the retina, lutein can convert to meso-zeaxanthin, which is a form of zeaxanthin that does not exist in the diet (16
). Thus, evaluation of either dietary or serum concentrations of lutein and zeaxanthin separately may be necessary to further clarify the role of these carotenoids. Currently, a nutrient database with separate values for the 2 carotenoids is not available. Studies using plasma concentrations may separate lutein and zeaxanthin values and focus on neovascular forms.
In conclusion, we found no association between lutein/zeaxanthin intake and early AMD risk in 2 large prospective cohorts of women and men. No inverse association was found across the cohorts, subtypes of AMD, and smoking status, intakes of vitamins C and E, and BMI. The suggestion of inverse associations related to risk of neovascular AMD needs to be examined further. Separate evaluation of lutein and zeaxanthin values either from diet or plasma may provide further insight on the roles of these carotenoids in relation to the development of neovascular AMD.