Risk Factors for Age-related Macular Degeneration
Introduction
Age-related macular degeneration is a disease involving typical lesions in the macula in older people, which cannot be attributed to infectious or inflammatory causes. The early stages of the disease are characterized by the development of drusen, which are yellow spots clinically observable on the retina, and pigmentary abnormalities with hyper- and hypo-pigmentation. Later stages of the disease comprise two types: geographic atrophy, and neovascular age-related macular degeneration. In geographic atrophy, the retinal pigment epithelium and overlying receptors degenerate. In cases of neovascular age-related macular degeneration, new vessels form under the retina, leading to the destruction of the retinal pigment epithelium. If the vessels leak, the resulting haemorrhage results in further scarring and visual loss.
Over the past 30 years there have been a number of epidemiological studies into the distribution and prevalence of eye disease, including age-related macular degeneration, in the population (Leibowitz et al., 1980; Klein and Klein, 1982; Gibson et al., 1985; Vinding, 1989; Bressler et al., 1989; Klein et al (1992), Klein et al (1995); Hirvela and Laatikainen, 1995; Pagliarini et al., 1997; Vingerling et al., 1995b; Mitchell et al., 1995; Friedman et al., 1999; Schachat et al., 1995). Details of these studies are set out in Table 1. One outcome of this work has been growing consensus as to how the disease should be classified in epidemiological studies. The International Age-Related Maculopathy Study Group brought together investigators from the large epidemiological studies and agreed a classification, which is set out in Table 2 (Bird et al., 1995). This is the terminology that is used in this paper. The Group propose an overall term “age-related maculopathy” encompassing early and late stages of the disease. Early age-related maculopathy refers to signs such as large, soft drusen and pigmentary abnormalities, that may, or may not develop into late stages of the disease. The term “age-related macular degeneration” describes geographic atrophy and neovascular age-related macular degeneration.
Age-related macular degeneration is the most important cause of visual loss in western industrialized countries. In the United Kingdom, approximately 30,000 people are registered blind or partially sighted every year, half of whom will have macular degeneration (Evans, 1995). This pattern in the registered population is reflected in Europe, North America and Australia (Bjornsson, 1981; Graf et al., 1999; Hansen, 1981; Krumpaszky and Klauss, 1992; Chan and Billson, 1991). Cataract is probably more frequent as an incident cause of visual loss but, as there is safe and effective surgery for cataract, it is less common as a prevalent cause of visual loss.
Age-related macular degeneration increased dramatically as a proportionate cause of registered visual loss in the 20th century (Evans and Wormald, 1996; Maruo et al., 1991). In 1933, just 6% of the registered population in England and Wales had “senile macular degeneration”, compared to nearly 50% in 1990 (Evans and Wormald, 1996). Most of this increase can be attributed to a combination of ageing population, declining importance of infectious causes of visual loss, and increasing effectiveness of ophthalmic surgery. However, examination of age-standardized population rates indicate an excess incidence of approximately 30%. This may reflect a real increase or simply indicate changes in the detection of this condition in parallel with its increasing importance.
Currently, there is no treatment that can restore vision in age-related macular degeneration. There are some treatments, for example, laser photocoagulation and photodynamic therapy, which can delay the progressive loss of visual function in a small proportion of people with neovascularisation (Fine et al., 2000). For that reason, there is considerable interest in possibilities for preventing the disease developing in the first place. Interest in the role of vascular factors has lead to investigations of cardiovascular disease risk factors in the development of age-related macular degeneration. It is also hypothesized that age-related macular degeneration occurs as a result of the inability of the retina to cope with the highly reactive oxygen species that are produced during visual processing. With developments in molecular biology and genetic methods, there is increasing potential for discovery of the genetic determinants that may underly the pathological mechanisms outlined above.
The aim of this paper is to investigate the epidemiological evidence behind the proposed hypotheses for the aetiology of age-related macular degeneration, namely, vascular factors, and oxidative processes. This will then be linked with what is known about the genetic determinants of the disease.
Table 3 sets out some of the epidemiological terms that will be used. Incidence refers to the number of new cases of disease arising in a cohort of people over a defined period of time. Prevalence is defined as the number of cases in a population at a given point in time. Exposure is used interchangeably with the term risk factor and refers to any agent or factor that is hypothesized or shown to have an adverse or beneficial risk on the development or progression of disease. Bias and confounding are important components of epidemiological studies that need to be addressed during their interpretation. Bias refers to any systematic error in the study design that means that the true estimate of effect is over or under-estimated. Confounding is said to occur when the observed association between exposure and disease can be attributed to another factor that is associated both with the exposure and the disease. Age is a common confounding factor.
Section snippets
Distribution of age-related macular degeneration within the population
The study of the distribution of disease in the population illuminates two areas: firstly, it gives us an idea of who is most affected by the disease — this can guide the delivery of health services; secondly, it can help us develop or confirm hypotheses on aetiology.
Vascular factors
In the next two sections, the evidence for the role of vascular factors and oxidative processes in the aetiology of age-related macular degeneration is examined. Much of the information used comes from the population-based studies set out in Table 1.
There are other types of epidemiological study that provide useful evidence. Firstly, case-control studies. In the case-control study, cases of disease are compared to controls with respect to the proportion of people “exposed” to a particular risk
Oxidative Processes
Photoreceptors in the retina are subject to oxidative stress throughout life due to combined exposures to light and oxygen (Young, 1988). The action of light on the photoreceptors generates free radicals. These are short-lived molecular fragments that have an unpaired electron in the outer orbital. This unstable structure is highly reactive and toxic. It attacks other molecules, particularly polyunsaturated fatty acids, which are an essential component of biological membranes.
It is thought that
Genetic factors
Work on the genetic determinants of age-related macular degeneration has been slow to develop for two reasons. Firstly, as age-related macular degeneration is a disease of old age, surviving parents and well-established family trees are rare. Secondly, it is likely to be a complex trait, that is, its inheritance is probably controlled by more than one gene. The study of complex traits has been a relatively recent development.
There is considerable evidence from the occurrence of age-related
Conclusions
The most important risk factor for developing age-related macular degeneration, apart from age itself, is underlying genetic risk. Over the next decade, many of the genes that contribute to the development of age-related macular degeneration will be uncovered. It is likely that “age-related macular degeneration” will, in genetic terms, turn out to be a heterogenous group of diseases.
There is accumulating evidence that smoking cigarettes results in increased risk of the disease. This is yet
Future directions
Further research on the interactions between genes and environment is likely to be the most productive way forward in elucidating the aetiology of age-related macular degeneration. Investigation of the role of the risk factors discussed in this paper in homogenous genetic subtypes of the disease will be very interesting. An understanding of the genes involved in the development of the disease will give more insight into the underlying biological mechanisms. This in turn will provide useful
References (102)
- et al.
Risk factors in age-related maculopathy complicated by choroidal neovascularization
Ophthalmology
(1986) - et al.
Visual disability and major causes of blindness in NSWa study of people aged 50 and over attending the Royal Blind Society 1984 to 1989 [see comments]
Aust. N. Z. J. Ophthalmol.
(1991) - et al.
Sun exposure and age-related macular degeneration. An Australian case-control study
Ophthalmology
(1997) - et al.
Racial differences in the prevalence of age-related macular degenerationthe Baltimore Eye Survey
Ophthalmology
(1999) - et al.
Risk factors of age-related maculopathy in a population 70 years of age or older
Ophthalmology
(1996) - et al.
Genetic association of apolipoprotein E with age-related macular degeneration
Am. J. Hum. Genet.
(1998) - et al.
The Wisconsin age-related maculopathy grading system
Ophthalmology
(1991) - et al.
The prevalence of age-related maculopathy by geographic region and ethnicity
Prog. Retin. Eye. Res.
(1999) - et al.
The relationship of cardiovascular disease and its risk factors to age-related maculopathy. The Beaver Dam Eye Study
Ophthalmology
(1993) - et al.
The relation of socioeconomic factors to age-related cataract, maculopathy, and impaired vision. The Beaver Dam Eye Study
Ophthalmology
(1994)
Prevalence of age-related maculopathy. The Beaver Dam Eye Study
Ophthalmology
Racial/ethnic differences in age-related maculopathy. Third National Health and Nutrition Examination Survey [published erratum appears in Ophthalmology 1995 Aug; 102(8):1126]
Ophthalmology
A twin study of age-related macular degeneration
Am. J. Ophthalmol.
Prevalence of age-related maculopathy in Australia
The Blue Mountains Eye Study. Ophthalmology
Iris color, skin sun sensitivity, and age-related maculopathy. The Blue Mountains Eye Study
Ophthalmology
Effect of light history on retinal antioxidants and light damage susceptibility in the rat
Exp. Eye. Res.
Essential fatty acids, plasma cholesterol, and fat-soluble vitamins in subjects with age-related maculopathy and matched control subjects
Am. J. Clin. Nutr.
Familial aggregation of age-related maculopathy (see comments)
Am. J. Ophthalmol.
The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration
Am. J. Ophthalmol.
The prevalence of age-related maculopathy in the Rotterdam Study
Ophthalmology
Relationship of senile macular degeneration to ocular pigmentation
Am. J. Ophthalmol.
Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration [see comments]
Science
Blindness in Iceland. A review of legally blind persons in Iceland 1. Dec. 1979
Acta. Ophthalmol.
The grading and prevalence of macular degeneration in Chesapeake Bay watermen
Arch. Ophthalmol.
Case-control study of the risk factors for age related macular degeneration. France-DMLA Study Group
Br. J. Ophthalmol.
A prospective study of cigarette smoking and risk of age-related macular degeneration in men [see comments]
JAMA
Sunlight and age-related macular degeneration. The Beaver Dam Eye Study
Arch. Ophthalmol.
Familial aggregation of age-related maculopathy [letter; comment]
Am. J. Ophthalmol.
Exclusion of TIMP3 as a candidate locus in age-related macular degeneration
Invest. Ophthalmol. Vis. Sci.
Smoking and age-related macular degeneration. The POLA Study Pathologies. Oculaires Liees a l’Age
Arch. Ophthalmol.
Monozygotic twin brothers with age-related macular degeneration
Ophthalmologica
Evaluation of the gene encoding the tissue inhibitor of metalloproteinases-3 in various maculopathies
Invest. Ophthalmol. Vis. Sci.
Drug therapyage-related macular degeneration (review)
N. Engl. J. Med.
A study of the prevalence of eye disease in the elderly in an English community
Trans. Ophthalmol. Soc. U. K.
Senile cataract and senile macular degenerationan investigation into possible risk factors
Trans. Ophthalmol. Soc. U. K.
Factors associated with age-related macular degeneration. An analysis of data from the first National Health and Nutrition Examination Survey
Am. J. Epidemiol.
Age related macular degeneration in monozygotic twins and their spouses in Iceland
Acta Ophthalmol. Scand.
Causes of blindness in Hessia
Klin. Monatsbl. Augenheilkd.
Twin study of age related macular degeneration
Invest. Ophthalmol. Vis. Sci.
Blindness in Norway, causes and prophylactic attempts
Tidsskr. nor. Laegeforen.
Cited by (293)
Epidemiological and clinical profile of age-related macular degeneration in Cameroon
2022, Journal Francais d'OphtalmologieAge-Related Macular Degeneration
2021, Age-Related Macular DegenerationProtection of human retinal pigment epithelial cells from oxidative damage using cysteine prodrugs
2020, Free Radical Biology and MedicineClassification, location, and intensity of granules in retinal pigment epithelium following sodium iodate injection in rat animal model
2024, Iranian Journal of Basic Medical Sciences