Background information

Update on Epidemiology of Age-related Maculopathy.
Caroline Klaver [Erasmus University | Rotterdam | The Netherlands] ARM Fundus

In the past decade, many researchers have studied the rise in frequency of early and late features of Age-related Maculopathy (ARM) with age, and investigated possible determinants. A total of 18 population-based studies around the world have provided significant data on prevalence of early changes as drusen and pigmentary irregularities, and late changes as atrophic and neovascular macular degeneration. All studies show a strong rise of early and late features with age, however, the variation in estimates is more pronounced for early age-related maculopathy. This variation may be genuine to some extent, but differences in classification of drusen size and type will be accountable to some extent. A reasonable overall prevalence for early age-related maculopathy among whites in the age-group 65-74 years is 15%, in 75-84 years 25%, and in 85 years-and-over 30%. The overall prevalence for late ARM among whites in the age-group 65-74 years is 1%, in 75-84 years 5%, and in 85 years-and-over 13%. Sex differences vary among studies, but, overall, women appear to be at a slightly increased risk of ARM. Race is a much more important determinant than sex. Studies among blacks show some variation in frequency of early ARM with prevalence estimates ranging from 5 to 25%, but all studies show that late stages of ARM are virtually non-existent in black populations.

The phenotypic variation of the disease is quite extensive, but from follow-up studies a natural course with predictors of disease progression can be detected. In general, the onset of ARM is determined by development of small hard drusen, then soft drusen with distinct bounderies emerge, which later become indistinct. The development of pigment changes at this stage further increases the risk of geographic or neovascular AMD. Incidence studies have shown that total area of drusen and presence of pigmentary changes are the most important predictors of disease progression, far more important than drusen size or number. Whether there are differences in natural course and etiology of atrophic or neovascular AMD is as yet unsettled. The two end stages most frequently occur as isolated phenotypes, but mixed forms are not uncommon and show a frequency rise with age. Genetic as well as environmental factors have been associated with ARM. From twin studies and familial aggregation studies it can be concluded that genetic factors play a major role in the occurrence of disease, with an overall contribution around 23%. Heritability scores have been estimated to identify the most hereditary fundus features, but results vary among study populations and families. It appears that relatives of affected probands are susceptible of developing the entire phenotypic range of ARM, but develop these features at an earlier age than a general population. The search for genes for ARM has only just begun, and a major gene has not been found to date. Nevertheless, the Stargardt ABCR (ABCA4) gene, and the APOE gene have been significantly associated in genetic association studies, and appear to play a role in at least a minority of cases. In addition, there has been a first report of a significant association with the genes for microsomal epoxide hydrolase and manganese superoxide dismutase.

The consistent environmental factor among epidemiologic studies is smoking. It has been associated with early ARM as well as with both late forms of ARM, and the relative risk estimated in incidence studies is 2. Age does not play a role in this association, for even smoking subjects older than 85 years are at an increased risk of disease progression. Other factors with less consistency among studies are cardiovascular factors, diet and anioxidants, sunlight, and cataractextraction. In conclusion, the most important and certain determinant of age-related maculopathy is age. Age determines the onset of early symptoms, and the rapid deterioration thereafter. To date, the only other undoubted factors implicated in the etiology are genetic factors, race, and smoking. Although this may seem a rather poor result after so many efforts, the upcoming genetic-epidemiologic era will definitely provide more conclusive risk factors, will more profoundly enable the study of genetic and environmental interactions, and will contribute many more insights in the disease etiology.