Epidemiology of AMD
Cécile Delcourt, MD, PhD
Inserm, U897, Bordeaux, France Université Bordeaux 2, Bordeaux, France
The epidemiological studies conducted in the past 25 years have helped identifying major modifiable risk factors for AMD. In particular, smoking and nutrition appear ever more important in determining the occurrence of AMD, and may, in the future, lead to prevention strategies.
Smoking is the best characterized risk factor for AMD(1). The initial observations performed in Caucasian populations from Western countries(2), are now being confirmed in other ethnic groups, such as African-Americans(3), Latino-American(4), or Asian populations(5-7). In most studies, the risk for late AMD was multiplied by 2.5 to 4.5 in current smokers. In addition, the dose-response relationship was explored in some studies(6,8-12). Most of these studies found that the risk for AMD increased with increasing number of cigarettes smoked per day, and, even more, with number of pack-years smoked, which is an indicator of cumulative smoking over the lifetime (mean number of packs smoked/day x duration of smoking (years). Moreover, the risk for AMD appeared to decrease with time from cessation of smoking. Former smokers generally demonstrated a lower risk for AMD than current smokers. Several studies have shown that the risk for AMD in subjects having ceased smoking for more than 20 years was similar to the risk in never smokers(8-10,13). One study suggested that passive smoking is also associated with an increased risk for AMD(9), while this association did not reach statistical significance in another study(14). Finally, smoking appeared to be related to similar risks for both types of late AMD (geographic atrophy and neovascular AMD)(9,13,15-16). By contrast, associations with early AMD were weaker in the vast majority of published studies, and often not statistically significant(8-9,13,15,17-18).
Overall, the strength of the association (about 3-fold increased risk in current smokers), its consistency across different populations, the observation of a clear dose-response relationship in most studies, and the decrease of the risk with stopping smoking are all strong arguments in favour of a causal role of tobacco smoking in the aetiology of late AMD.
The exact mechanisms by which smoking increases the risk for AMD are unclear, and probably multiple, including oxidative stress, inflammation and decreased macular pigment. Finally, recent studies gave important insights on the joint effects of smoking and genetic polymorphisms, showing that the risk for AMD is particularly high in smokers bearing at-risk polymorphisms in the CFH or LOC387715 genes(19-21).
Other vascular risk factors, such as systemic hypertension, obesity, diabetes, plasma lipids or alcohol drinking may be associated with an increased risk of AMD, but epidemiological studies have been inconsistent in this field(22). At the time being, they remain putative, but not clearly identified risk factors for AMD.
3. Nutritional factors
More recently, epidemiological studies have focused on the potential association of AMD with nutritional factors. Mainly three types of nutritional factors have been investigated for their potential protection against eye ageing: antioxidants (mainly vitamins C and E, zinc), the carotenoids lutein and zeaxanthin and omega 3 polyunsaturated fatty acids (PUFA).
The retina is particularly susceptible to oxidative stress because of the high level of in-site reactive oxygen species production, due in particular to light exposure and high metabolic activity(23).
Epidemiological studies are mostly in favour of a protective role of antioxidants for AMD(24).
Moreover, the Age-Related Eye Diseases Study (AREDS), a randomized clinical trial performed in the United States and including on almost 5000 subjects supplemented for five years, showed a significant 25% reduction of the incidence of late AMD with supplementation in antioxidants and zinc, by comparison with placebo(25). In this field, data from the United States should be extrapolated to European populations with caution. Indeed, vitamin supplements are widely used in the American population, while this is rarely the case in Europe. For instance, two thirds of the AREDS participants used vitamin supplements, in addition to the supplementation tested in the study(25). Plasma vitamin C concentration at baseline in the AREDS (before the initiation of the study supplementation) was 62 micromol/l(25), whereas it was 31.6 micromol/l in men and 40.5 micromol/l in women of the Pathologies Oculaires Liées à l’Age (POLA) Study, performed in the South of France(26). Similarly, in the EUREYE Study, plasma vitamin C concentrations ranged from 35.5 micromol/l to 48.4 micromol/l in seven European countries(27). Therefore, antioxidant intake is much lower in European populations than in the United States, with part of European populations being at risk of clinical deficiency in these vitamins. Two European studies suggested that the benefit to be expected from increased antioxidant intake may be more important in our populations with low antioxidant intake. Indeed, in the French POLA Study, we observed an 80% decreased risk for late AMD in the subjects with higher plasma vitamin E, by comparison to those with lower concentrations(28), a much stronger effect than the 25% reduction in risk observed in the AREDS Study. Moreover, we observed a 25% reduction in risk for early ARM, whereas the AREDS Study showed no benefit of antioxidant supplements for early ARM. Similarly, results from the Rotterdam Study showed a decreased risk for early ARM in subjects with high dietary intake of vitamin E or zinc, by comparison with those with low intake(29). A European supplementation study would be needed to better assess the benefit of antioxidant supplementation in European populations.
A more recent research domain evaluated the role of two carotenoids, lutein and zeaxanthin, in the protection of the retina and the lens. These carotenoids accumulate in the macula, where they are known as the macular pigment(30). Besides their antioxidant properties, they probably act as a filter against the phototoxic effects of blue light(30). To date, five epidemiological studies have assessed the associations of the risk of AMD with plasma concentration of lutein and zeaxanthin(31-35). As shown in Fig. 1, all five studies showed a decreased risk for AMD in subjects with high plasma concentrations of lutein and zeaxanthin, although the association was statistically significant only in 2 studies(32-35). With regard to dietary intake, four prospective population-based studies were published(29,36-38).
Figure 1. Association of the risk of AMD with plasma levels of lutein and zeaxanthin in cross-sectional and case-control studies (odds-ratios with 95% confidence interval)
OR below 1 suggest a protective role and OR greater than 1 suggest a deleterious role. References of the cited studies: Beaver Dam(31); EDCC(32); NHANES III(33); Gale et al(34); POLA(35)
These studies assessed the risk for developing AMD (in subjects initially free of AMD), according to their dietary intake of lutein and zeaxanthin. As shown in Fig. 2, the results for these dietary studies are less clear than for those on plasma measurements.
Figure 2. Associations of the risk for AMD with dietary lutein and zeaxanthin, in published epidemiological prospective studies. References of the cited studies: Beaver Dam(36); Health Professionals(37); Rotterdam(29); Blue Mountains(38).
Only one study found a significantly reduced risk for AMD in subjects with high dietary intake of lutein and zeaxanthin(38). However, dietary assessment methods rely on the subjects’ memory and perceptions and face the difficulties of the extreme day-to-day variability of human diet, the bias in reporting due to social standards and nutritional recommendations and the estimations of nutritional contents of food items. Biomarkers have the advantages of being objective, and of taking into account individual variations in bioavailability and metabolism. For instance, smoking and obesity are known to decrease the bioavailability of carotenoids(39-40). Despite normal dietary intake in lutein and zeaxanthin, subjects may be at higher risk for AMD because of decreased bioavailability, associated with lower plasma concentrations of these components. However, currently available studies including plasma measurements are cross-sect