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Risk Factors for Age-related Macular Degeneration

Published Online: January 24th 2012 European Ophthalmic Review, 2011;5(2):143-153 DOI: http://doi.org/10.17925/EOR.2011.05.02.143
Authors: Emma J Berrow, Hannah E Bartlett, Frank Eperjesi, Jonathan M Gibson
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Abstract:
Overview

Although the pathogenesis of age-related macular disease (ARMD) is still not fully understood, genetic and environmental factors are implicated. Epidemiological studies have found conflicting findings between ARMD development and many potential risk factors. This review provides an up-to-date account of modifiable and non-modifiable risk factors associated with ARMD development, with potential mechanisms between risk factors and ARMD development described. Age, smoking and genetic factors appear to be consistently associated with an increased risk of developing ARMD. However, ageing and genetic disposition cannot be currently modified, leading to increased interest as to how other modifiable factors may reduce the risk of ARMD.

Keywords

Macular degeneration, risk, nutritional supplements, age related, smoking, genetics

Article:

Age-related macular disease (ARMD) is a degenerative disease of the macula, most common over the age of 50 years.1 It is the leading cause of visual loss within western industrialised countries.2–4 The number of blind registrations attributable to the disease increased by 30–40 % between 1950 and 19903 and the number of cases each year is continuing to rise4–6 as these populations have an increasing longevity.

Definition of Age-related Macular Disease


Age-related macular disease (ARMD) is a degenerative disease of the macula, most common over the age of 50 years.1 It is the leading cause of visual loss within western industrialised countries.2–4 The number of blind registrations attributable to the disease increased by 30–40 % between 1950 and 19903 and the number of cases each year is continuing to rise4–6 as these populations have an increasing longevity.

Definition of Age-related Macular Disease

The international age-related maculopathy group has defined an international classification system for quantifying and defining the different subgroups of ARMD in an attempt to permit easier comparison of research findings between groups.1
Age-related maculopathy (ARM) is a disorder of the macular area most apparent after age 50 and is characterised by the following:

  • Areas of drusen which are external to the neuroretina and retinal pigment epithelium (RPE). They are soft and distinct or soft and indistinct. Hard drusen are not characteristic of ARM. Drusen are discrete white-yellow spots containing abnormal extracellular lipoprotein deposits that accumulate between the RPE basal lamina and the inner collagenous layer of Bruch’s membrane.7
  • Hyperpigmentation in the outer retina or choroid with drusen.
  • Hypopigmentation of the RPE with drusen.

This early stage of the condition may not affect vision, but can predispose patients to visual loss (see Figure 1).
Later stages of the condition are classified as ‘wet’ or ‘dry’ age-related macular degeneration (AMD). These forms of the disease can occur with or without the involvement of new blood vessel growth. If new vessels are not involved (dry AMD), clinical presentation is a sharply defined round or oval area of hypopigmentation where choroidal vessels are more visible than the surrounding area, with a diameter greater than 175 μm1 (see Figure 2). This is also known as geographic atrophy (GA).
The term ‘wet AMD’, also known as disciform AMD, exudative AMD or neovascular AMD refers to the development of choroidal neovascularisation (see Figure 3) and has numerous manifestations, including:

  • choroidal neovascularisation (CNV);
  • RPE detachment(s);
  • subretinal or sub-RPE neovascular membrane(s);
  • deposition of scarring, glial tissue or fibrin-like material within the epiretinal, intraretinal, subretinal or sub-RPE layers;
  • subretinal haemorrhages (without other retinal vascular cause); and
  • hard exudates (formed from lipid) associated with the above manifestations (without other retinal vascular cause).

This article uses the terms ARM, AMD and ARMD as per the international classification system described.

Physiology of Age-related Macular Disease

The RPE rests on Bruch’s membrane and separates the neural retina from the choriocapillaris. The RPE phagocytoses the outer segment discs of the photoreceptors and is a point of metabolite and waste exchange, which is considered crucial to retinal function.8 The initial signs of ARMD are variations within and below the RPE, seen as alterations in the pigmentation of the RPE, with or without the occurrence of drusen.9 Drusen are discrete white-yellow spots containing abnormal extracellular lipoprotein deposits that accumulate between the RPE basal lamina and the inner collagenous layer of Bruch’s membrane.7 Within the ageing eye a build up of lipofuscin granules can be seen in the RPE,10 possibly caused by a reduced ability of the RPE’s phagocytic-lysosomal system to efficiently digest photoreceptor outer segment membranes,11 leading to an accumulation of lipids from this material in Bruch’s membrane reducing membrane permeability. This in turn may interrupt the supply of nutrients from the choroid to the retina ultimately leading to photoreceptor atrophy.12 Oxidative stress causes injury and inflammation to the RPE and choriocapillaris which may lead to an altered extracellular matrix. This affects nutrient supply to the RPE and retina, possibly thus further damaging the RPE and retina, leading to the retinal atrophy seen in the later stages of ARMD.13

Aetiology of Age-related Macular Disease

Although the precise aetiology of ARMD is currently unknown, there are several hypotheses that have been postulated.

Oxidative Stress

Ageing is associated with cumulative oxidative damage.14 The retina is constantly under high oxygen tension and is thus susceptible to this damage. Reactive oxygen intermediates (ROIs), a term used to describe hydrogen peroxide, singlet oxygen and free radicals, are synthesised as byproducts of phototransduction and cell metabolism.15 Phagocytosis of photoreceptor outer segments by the RPE produces ROIs, increasing oxidative stress. Outer segments of photoreceptors contain polyunsaturated fatty acids and vitamin A. Under high oxygen tension and light irradiation the outer segments undergo lipid peroxidation, especially within the macular area.16 Light irradiation induces photoreceptor damage.17 It is suggested that lipid peroxidation may be involved in the cause of light induced retinal degeneration.18 A healthy RPE is required for the correct functioning of the retina19 but RPE changes occur with age as lipofuscin granules accumulate within RPE cells. Lipofuscin is composed of vitamin A metabolites and lipid peroxides, and is constantly exposed to visible light (400–700 nm) and high oxygen tension (~70 mmHg),20 which cause reactive oxygen species synthesis and possible RPE membrane damage. Lipofuscin accumulates in the human RPE from approximately 20 years of age and continues throughout life.21 Lipofuscin is a photosensitiser that may increase the risk of retinal photodamage and contribute to the development of ARMD.22 There are differing thoughts as to whether RPE melanosomes provide a protective effect to the RPE by scavenging reactive free radicals.23 Therefore their decline within the RPE with increasing age24 may reduce free radical scavenging by these cells. However, an increase in phototoxic melanin–lipofuscin complexes (melanolipofuscin) also occur with increasing age and may have a detrimental effect to the RPE as their accumulation more closely reflects the onset of AMD than lipofuscin accumulation alone. 25

Genetics

Although knowledge about the role of genetic variants in ARMD is currently rudimentary, many genes have been identified as providing either deleterious or protective effects against the disease.26,27 Several genes have been associated with an increased risk of developing ARMD and have been verified in further studies.28 The LOC387715 variant29 and complement factor H gene polymorphisms (Y402H) predispose people to an increased risk of developing ARMD.30 Protective genes have also been identified such as the complement factor B and complement component 2 gene, although current knowledge is limited and continued genetic research may yield further information.31 Although the extent of heritability and the number of genes involved in ARMD is presently unknown32 there has been evidence to suggest increased risk of disease development with a positive family history of the disease.33–36 Many studies have assessed familial predisposition to ARMD by looking at monozygotic and dizygotic twins,34,37–41 with monozygotic twins showing a stronger concordance than dizygotic twins. The higher prevalence of ARMD in first-degree relatives of those with the disease than those without the disease further strengthens the case that genetic factors may play a part in ARMD pathogenesis.42–44 More may be learnt over time as genetic marker testing becomes increasingly sophisticated, identifying greater numbers of genes associated with ARMD. It appears likely that a combination of exposure to environmental stimuli and genetic predisposition to ARMD are implicated in the pathogenesis of the disease.3,45

Deterioration of Ruysch’s Complex

Ruysch’s complex consists of the RPE, Bruch’s membrane and choriocapillaris. The hydraulic conductivity of Bruch’s membrane reduces with increasing age.9,46,47 Bruch’s membrane collagen solubility decreases with increasing age particularly at the posterior pole and is thought to interfere with the function of the RPE48 whose cell attachment rates are decreased on an aged Bruch’s membrane.49 Cross-linking of collagen fibres within Bruch’s membrane increases with increasing age and a rise in ultraviolet absorbance and fluorescence also occurs within the membrane.50
In ARMD, deposition of long-space collagen and basement membrane proteins can be observed between the RPE plasma membrane and RPE basement membrane.51 These deposits are termed basal laminar deposits (BlamD). Basal linear deposits (BlinD) are found between the basement membrane of RPE cells and Bruch’s membrane (soft drusen) mostly comprising membranous debris.52 Histopathologically, ARMD is characterised by occurrence of both deposits.52,53 The presence of BlamD is strongly associated with the presence of AMD,54 which compromises photoreceptor cell function,55 and BlinD are also specific for AMD.52 Histopathological studies have correlated BlamD with CNV56,57 and a severely compromised RPE.51
With increasing age Bruch’s membrane progressively accumulates lipid content58,59 and fluid diffusion is slowed.46 It is thought that the debris within Bruch’s membrane is derived from RPE metabolic activity58 and this rise in lipid and protein quantity within Bruch’s membrane reduces permeability, thus impeding flow of macromolecules between the RPE and choroid.60 This may lead to slowed regeneration of photopigment due to retinoid deficiency, ultimately causing photoreceptor loss.61 Bruch’s membrane thickens with increasing age,62 which is associated with a decline in phagocytosis of photoreceptor outer segments by RPE cells63 and increases the distance for oxygen transport between the choriocapillaris and outer retina, reducing the oxygen to the outer retina.64 In the normally functioning RPE, angiogenic growth factors such as vascular endothelial growth factor (VEGF) and anti-angiogenic factors like pigment-epithelium derived factor are optimally balanced within the RPE. Oxidative stress and the accumulation of deposits within the RPE and Bruch’s membrane may disrupt this balance65,66 upregulating VEGF, which increases vascular permeability and angiogenesis, contributing to the development of CNV.67–69
There is evidence that choroidal circulation attenuation may be responsible for development of ARMD. Ninety per cent of the oxygen requirement of the photoreceptors is provided by the choroidal circulation70 and reduced choroidal blood flow has been associated with ARMD.71,72 Choriocapillaris density and lumen diameter reduce with age,73 which may decrease oxygen to the RPE and photoreceptors and reduce clearance of waste products from Bruch’s membrane, leading to its thickening with age.13 Retinal hypoxia increases the release of VEGF within Ruysch’s complex leading to CNV.74 Vascular deficits are further advanced in AMD75 with a linear relationship between reduced choroidal blood flow and increased risk for development of CNV.76 Retinal hypoxia drives the synthesis of VEGF, which gives rise to the angiogenesis seen in CNV.77

Factors Associated with an Increased Risk of Age-related Macular Disease Development

There are many modifiable and non-modifiable risk factors that have been linked with an increased risk of developing ARMD. When reporting risk, many studies use either the odds ratio (OR) or the relative risk (RR). The OR is the ratio of the odds of a disease occurring in people exposed to a risk factor to the odds of it occurring in people not exposed to a risk factor. The RR is a ratio of the probability of a disease occurring in a risk factor exposed group versus a non-exposed group. The hazard ratio (HR) is a ratio of the chance of events occurring in people exposed to a risk factor compared with people not exposed to a risk factor. Estimates of OR, RR or HR greater than 1.0 are statistically significant and suggest a positive association or increased risk of developing a disease. If described in the literature, statistically significant OR, RR and HR are reported in this article.

Modifiable Risk Factors
Smoking

Smoking is the one modifiable risk factor that has been largely consistently associated with an increased risk of developing ARMD.78–86 The Rotterdam study found that the higher the pack-years smoked, the higher the risk of developing neovascular AMD, with a 6.6-fold increase in risk for developing neovascular AMD compared with non-smokers.87 The Pathologies Oculaires Liees a l’Age (POLA) study found an increased risk of neovascular AMD and GA in people who smoked for more than 20 years (OR 3.0 for 20–39 pack-years and 5.2 for 40 pack-years). The risk remained elevated until 20 years after smoking cessation.88 Smoking was not associated with risk for ARM development in this study. Increase of ARMD development risk with increase in smoking was also demonstrated in a study by Seddon et al.89 in a 12-year prospective study of 31,843 women with a RR of 2.4 for developing AMD compared with women who never smoked. This was echoed in a 12-year prospective study of 21,157 males by Christen et al.,90 showing a RR of 2.46. The Rotterdam study results are echoed in a study on Japanese men with an OR of 2.97 in smokers compared with non-smokers of developing neovascular AMD.91 All of these studies show that even previous smokers who had ceased smoking still had an elevated risk of ARMD development compared with non-smokers, but not as elevated as current smokers. A study undertaking pooled and separate analysis of 14,752 participants from the Beaver Dam eye study, the Rotterdam study and the Blue Mountains eye study showed that apart from age, smoking was the only consistent risk factor associated with any form of ARMD (OR 3.12).92 This pooled study was taken from three different continents (North America, Europe and Australia). Another study based on 3,271 Australians also highlighted this consistent association for AMD and smoking (OR 2.39).93 A review of the literature in conjunction with New Zealand morbidity and smoking prevalence data estimated that 26.8 % of all AMD cases were attributable to current and past smoking in New Zealand.94 In the UK, a two-fold risk of ARMD has been associated with smoking when compared with non-smoking in 28,000 individuals (OR 2.15).95 Cigar smoking in India has also been linked with a higher risk for developing AMD (OR 3.29).96 A study of Latino subjects also demonstrated an association between smoking and AMD in the Hispanic population (OR 2.4).97 The effects of passive smoking on AMD risk have been examined in a UK study comparing 435 people with end-stage AMD with 280 healthy controls. The results showed an OR of 1.87 in passive smoking exposure in non-smokers.98 This prolific evidence across continents and differing ethnicities suggests that smoking is highly toxic to the retina, although the pathogenic mechanisms between smoking and retinal toxicity still remain unclear.
There are approximately 4,000 toxic components in cigarette smoke, one of which is nicotine. A study assessing the effects of nicotine on the vascular smooth muscle cells confirmed that nicotine increases CNV size and severity in laser-induced CNV in the mouse eye model.99 Nicotine attaches to nicotinic acetylcholine receptors on photoreceptors, bipolar, horizontal and ganglion cells.100 Tar within cigarette smoke contains hydroquinone – an oxidant that in the mouse eye has been shown to encourage sub-RPE deposits and thickening of Bruch’s membrane.101 Cadmium is another toxic oxidant found in cigarette smoke; higher urinary levels in smokers have been linked with an increased risk of AMD.102 It accumulates at levels 2.5 times higher in the choroid–RPE complex of smokers compared with non-smokers103 and increases reactive oxygen species, alters RPE cell morphology and decreases cell survival.104 Studies on mice eyes have demonstrated that chronic exposure to smoke causes changes to the RPE similar to those observed in AMD, with RPE apoptosis, increased oxidative damage,105 DNA damage to the RPE and increased inflammatory activity.106
The effects of the combination of smoking and genetics of ARMD have been analysed in many studies. An additive effect of smoking for increased risk of developing ARMD has been shown when there is a genetic disposition for the disease.107–111

Alcohol Intake

Studies assessing the association between ARMD risk and alcohol intake have shown inconsistent findings.85,112,113 A relationship between beer consumption and risk for CNV has been identified in the Beaver Dam eye study (OR 1.41), although no such relationship was seen with wine or spirit consumption.114 This was echoed in subjects from the Latino community with beer consumption (OR 2.9) and high alcohol intake (OR 5.8) being linked with a greater risk of developing the disease.97 Conversely, no association between any type of alcohol and ARMD risk has been shown in other studies.97,115–117 Interestingly, moderate wine consumption has been associated with a decreased risk of developing AMD (OR 0.86)118 and in the Reykjavik eye study alcohol consumption decreased the risk for drusen formation (OR 0.34),119 suggesting a protective effect of alcohol against ARMD. Chronic, heavy alcohol consumption is linked with an increased accumulation of ethyl esters and an increase in laser-induced CNV of 28 % within the rat choroid models.120 Ethanol is the key component of alcohol. When photoreceptor outer segments of zebrafish are exposed to ethanol this leads to inhibited photoreceptor outer segment growth, leading to poor photoreceptor function as demonstrated by reduced a- and b-wave amplitudes of the electroretinogram (ERG).121 Red wine has a high level of phenolic compounds that increase antioxidant activity, which may reduce oxidative stress and abnormal proliferation of the RPE.122

Socioeconomic Factors

Socioeconomic factors have been inconsistently associated with an increased risk of developing ARMD. A Canadian study looking at socioeconomic status and CNV found that the severity of CNV appeared to be associated with lower socioeconomic status, although ORs or RRs were not provided in this study.123 However, in another Brazilian study assessing AMD in two differing socioeconomic populations no association between AMD and socioeconomic background was seen (p=0.113).124 No association was demonstrated between ARMD and socioeconomic factors in a case–control study by Hyman et al.35 or in the Framingham eye study,125 the Beaver Dam eye study126 and the third National Health and Nutrition Examination Survey (NHANES) study.127 Although the underlying reasons for increased risk of ARMD development with lower socioeconomic status have not been determined, possible mechanisms include the underuse of eye care services, poor nutrition and exposure to adverse work and home environments.

Education

The Age-related eye disease study (AREDS) report number three found that people with higher education had a lower risk for developing drusen (OR 0.73), GA (OR 0.45) and CNV (OR 0.44).128 The Eye Disease Case–Control Study Group (EDCCS) found a similar trend for education and neovascular AMD risk (OR 0.7 when 12 years of education or greater was completed compared with those who completed less than 12 years of education), although no statistical significance was demonstrated in their final multiple regression model.78 The first NHANES study also demonstrated this association (OR 0.64) but statistical significance was lost on logistic regression modelling.129 The mechanisms associating risk for ARMD development and educational level are not clear. People with lower educational level are more likely to be unemployed or in lower incomes jobs, leading to poorer socioeconomic status. Lower education may limit the ability to read and comprehend the importance of health literature.

Nutrition

Nutrition as an associated risk factor for developing ARMD has also been subject to conflicting findings in the literature. The first NHANES study found high levels of dietary vitamin A provides a protective effect against AMD (OR 0.74) with no beneficial effect shown with vitamin C.129 The Beaver Dam eye study found no association between vitamins A, C and E and reduced risk of developing ARM.130 Another study of serum lycopene in the Beaver Dam eye study showed an increased risk of ARMD with reduced lycopene levels (OR 2.2).131 However, lower levels of lutein, zeaxanthin and vitamin E were not related to an increased risk for ARMD development in this study. Conversely, higher serum alpha tocopherol was found to be conducive to lower ARMD risk in the Baltimore longitudinal study (OR 0.43).132 The Physicians Health study and the Blue Mountains eye study did not find a protective effect for vitamin C, E and multivitamins133 and vitamin E and beta carotene134 against ARMD, respectively. The EDCCS found a 70 % reduced risk of AMD with high (>0.67 μmol/l) compared with low (0.25 μmol/l) levels of serum carotenoids.135 A further study from the EDCCS reported that spinach and collards, high in the carotenoids lutein and zeaxanthin, were most strongly associated with a reduced risk for AMD (p<0.001).136 Collard greens are various loose-leafed vegetables of Brassica oleracea, the same species that produces cabbage and broccoli. They are genetically similar to kale and spring greens. Eyes with intermediate drusen, large drusen and non-central GA of people taking high-dose vitamins C, E, beta carotene and zinc were found to have a lower risk (OR 0.72) of developing advanced AMD in a large trial undertaken by the AREDS group.137 Improvements in visual function in eyes with ARM or non-exudative AMD were reported in several studies involving carotenoids.138–141
High levels of omega-3 fatty acid consumption (≥64.0 mg/day versus <26.0 mg/day) have been shown to provide a protective effect against progression to AMD (HR 0.73).142 Lowering the dietary glycaemic index with higher omega-3 intake also showed a reduction in AMD progression in this study (p<0.001). The benefits of a low glycaemic diet in reducing ARM risk have been identified in other studies.142–144 The Blue Mountains eye study found a lower risk of developing ARM when consuming omega-3 fatty acids in the form of one serving of fish per week (RR 0.69).145 Consumption of linoleic acid in the form of one to two servings of nuts per week was also associated with reduced ARM risk in this study (RR 0.65). The AREDS studies found a reduction in risk of progression from drusen to GA in people with the highest dietary intake of omega-3 fatty acid (OR 0.45)146 and reduced risk of developing neovascular AMD (OR 0.61147 and 0.68148) and GA (OR 0.65).148 It is thought that omega-3 provides a protective role in the retina by inhibiting oxidative stress and reducing inflammation in the retina.149
An association between higher trans-unsaturated fat intake and increased prevalence of AMD was reported in a large study of 6,734 people (OR 1.76).150 Omega-3 fatty acids and olive oil were associated with a reduced prevalence of ARM and AMD in this study (OR 0.85 and 0.48, respectively). However, the third NHANES results showed no association between dietary fat intake and ARM risk in 7,883 people151 and this was echoed in 3,654 people taking part in the Blue Mountains eye study.152 Studies of mouse retinae have shown an increase in the accumulation of basal laminar deposits when consuming a high fat and cholesterol diet.153 Some studies have shown that diets higher in fats have a propensity to be lower in essential nutrients and antioxidants.130,154

Body Mass Index

A high body mass index (BMI) has been inconsistently linked with risk for developing ARMD. The Blue Mountains eye study found an OR of 1.78 for risk of early ARM in people with obesity compared with those with a normal BMI.155 The AREDS group reported that a higher BMI was associated with a risk for developing neovascular AMD156 and GA (OR 1.93).157 A 2.29-fold risk of AMD and a 1.54-fold risk of pigmentary abnormalities were demonstrated in the POLA study in people with obesity.158 The RR was 2.35 for a BMI of 30 or more and 2.32 for a BMI of 25–29 for developing AMD in another study.159 Larger waist circumference (RR 2.04) and a larger waist–hip ratio (RR 1.84) also increased the risk of progression to AMD.159 An inverse relationship between BMI and retinal levels of L and Z (often referred to as macular pigment optical density) was reported.160 The authors also assessed dietary L and Z intake and found that people with the highest BMI consumed lower amounts of L and Z. They concluded that lower dietary intake of L and Z, and/or competition between adipose tissue and retina for L and Z uptake were likely to affect retinal levels of L and Z.160 Conversely, associations between lean men and dry AMD have been found.161 A pooled study of 14,752 people from the Beaver Dam eye study, the Rotterdam study and the Blue Mountains eye study did not report any consistent association between BMI and risk for any forms of ARMD92 and this was echoed in other studies.86,162

Cardiovascular Disease

Cardiovascular disease (CVD) has been associated with risk for developing ARMD in several studies and discounted in others. The Beaver Dam eye study showed no association between CVD and neovascular AMD or GA.163 Arterial stiffness – an indicator for CVD, has been shown to be associated with the presence of AMD.164 The Blue Mountains eye study did show associations between CVD (RR 1.57) for early incident ARM.165 C-Reactive protein is an inflammatory marker for CVD. Some studies have shown increased levels of C-reactive protein in ARMD,166–168 suggesting an inflammatory role in the development of ARMD. Conversely, better cardiovascular health was associated with an increased risk of ARMD in the Cardiovascular Health and Age-Related Maculopathy (CHARM) study (OR 2.54).169 The POLA study showed a reduced risk (OR 0.72) for developing drusen and no association between AMD and a history of cardiovascular disease.158 No association between CVD and ARMD risk was reported in the AREDS studies,128,157 the EDCCS study78 or Smith et al.’s pooled analysis from the Rotterdam, Blue Mountains and Beaver Dam eye studies.92 Hyman et al. found a link between ARMD and CVD (OR 1.7)35 in an earlier study but not in a later study.170
Hyman et al. also found an association between moderate to severe hypertension (diastolic >95 mmHg) and risk for developing neovascular AMD (OR 4.4), especially in people receiving antihypertensive medication.170 The same association was not found for GA and hypertension, leading the authors to suggest that comparable disease processes may occur in neovascular AMD and hypertension.170 Reduced choroidal blood flow in people with hypertension with neovascular AMD may account for this relationship.171 The Framingham eye study125 and the first NHANES study (OR 1.5 for systolic blood pressure≥170 mmHg)129 reported links between ARMD development risk and hypertension. The AREDS group found increased risk for developing neovascular AMD (OR 1.45) and large drusen (OR 1.19) in people with hypertension and those taking hypertensive treatment,128 although no association with incident neovascular AMD was seen in a further AREDS study.157 Hypertensive disease severity has been linked with neovascular AMD, with doubled odds in the severest of hypertension (OR 3.21).172 The Beaver Dam eye study,173,174 the Blue Mountains eye study165, the EDCCS78 and others175,176 found no evidence to suggest that ARMD development risk and hypertension are linked.

Cholesterol Levels and Treatment

Links between cholesterol levels, cholesterol-lowering treatments and risk of ARMD development have been conflicting. A possible protective effect of statins and lipid-lowering treatments against ARMD has been found in a number of studies (OR 0.14–0.79).177–181 Some studies have suggested statins protect the vascular endothelium from oxidative damage182 and reduce basal linear deposit accumulation in Bruch’s membrane by reducing cholesterol.183 Conversely, an article assessing pooled data on the use of statins and lipid-lowering treatments did not show a reduced risk of developing ARMD when using statins.184 Pooled data analysis of the Beaver Dam, Rotterdam and Blue Mountains eye studies did not report the effects of statins on ARMD risk.92 Other studies have found no association between statin use and reduced risk for developing ARMD.158,185–187 Furthermore, an observational study reported an increased risk of ARMD development in people taking statins (OR 1.19).188 In the EDCCS higher levels of cholesterol were associated with an increased risk of neovascular AMD (≥6.7 mm/l=OR 4.1),78 but no information about statins was presented in this study. The AREDS study also did not provide data about statin use or cholesterol levels.128 The benefits of statins for reducing heart disease and lowering cholesterol were not largely reported and routinely used until 1994189 and this is the likely reason for the lack of data before this period. The first NHANES study found no association between cholesterol levels and risk for ARMD development, but again statins were not assessed here as the study results were published in 1988.129 Higher HDL cholesterol levels were protective for late AMD (RR per standard deviation increase 0.74), and a high total/HDL cholesterol ratio was linked to an increased risk of late AMD (RR per standard deviation increase 1.35) and GA (RR per standard deviation increase 1.63) in the Blue Mountains eye study.165 Statins (HR 0.51) and aspirin (HR 0.63) were found to be associated with reduced rates of CNV in a retrospective study of 326 patients as possible mechanisms for increasing AMD risk after cataract extraction.226 Other studies, such as the AREDS group report 25, found no risk of ARMD progression after cataract surgery.227,228 It has been postulated that the cataract itself increases the risk of developing ARMD. In pooled findings from three studies severe cataract was associated with a higher prevalence of AMD, although this was not statistically significant.229 Studies assessing the risk of ARMD development associated with the use of newer intraocular lenses with short-wavelength blue light filtering properties may provide more information in the coming years.

Cognitive Impairment

Evidence from the AREDS group showed a trend between reduced cognitive impairment and increased risk of AMD development (p<0.01 for a mental state examination and 0.048 for a logical memory test).230 This was resonated in people with ARM in the Cardiovascular Health Study (OR 1.38),231 a weak association in another study (OR 1.6 for ARM)232 and in people with AMD in an Australian population (OR 2.2).233 The Rotterdam study demonstrated that tobacco and atherosclerosis may play a role in the pathogenesis of both ARMD and Alzheimer’s disease.234 Amyloid beta peptide is found in the neuritic plaques in Alzheimer’s disease and also in drusen. It contributes to inflammatory processes in both of these diseases235 and in many neurodegenerative diseases of ageing such as Parkinson’s disease, arthritis, atherosclerosis and myocardial infarction.236 Many people with ARMD reduce their physical and mental activity levels, which is associated with cognitive decline.237 Conversely, no significant relationship was established between Alzheimer’s disease and ARMD238 in 33 people with Alzheimer’s disease compared with 24 controls. The authors believe that a small sample size and age differences between the groups may have accounted for the lack of any relationship. They did not specify between ARM or AMD for their study.

Gender

Female gender has been associated with increased risk for development of ARMD, although no consensus seems to prevail. A Croatian study of 6,617 patients found that ARMD incidence was slightly increased in women compared with men (56 versus 46 %).5 This was echoed by the AREDS group, with ARM being more apparent in women (OR 1.22)128 and in other work (no OR, RR or HR reported).216 However this was not replicated in a pooled analysis from the Beaver Dam, Rotterdam and Blue Mountains Eye studies.92,239 Men were more likely to undergo photodynamic therapy than women for neovascular AMD in an Israeli study (0.21 versus 0.16 %, p=0.03)240 and were more likely to have AMD than women in two Japanese studies (statistical significance was not reached in one of the studies, but the other having an OR of 2.97).241,242 The authors suggest that this may be due to the significantly higher proportion of Japanese men who smoke. A recent study of the Beaver Dam offspring study also showed that being male was associated with ARM (OR 1.65).86

Arthritis

An association between arthritis and increased likelihood of ARM was reported in one AREDS study (OR 1.26),128 whereas another AREDS study suggested a protective effect of anti-inflammatory medications against AMD development (OR 0.22).157 One study found people with rheumatoid arthritis had less prevalence of AMD and suggested anti-inflammatory agents, commonly used to manage the symptoms of rheumatoid arthritis, provide a protective effect against development of ARMD,243 since there is some evidence that inflammation may play a role in the development of ARMD.244 However, environmental and genetic factors may also be relevant as rheumatoid arthritis is commonly a disease of the young and ARMD is more apparent over 50 years of age.245

Ethnicity

Higher prevalence of ARMD has been shown in white people compared with black people, although genetics, culture and diet may play a role in these differences. Darker iris pigmentation may also confer some protective effect in the black population.246 The AREDS group found a higher risk of developing large drusen (OR 1.88) and CNV (OR 4.22) in white people.128 A further AREDS study echoed these results for incident CNV (OR 6.77).157 However, no such association was found in a Brazilian study of 107 people with ARMD.124 In the Salisbury Eye Evaluation project the risk of developing large drusen (OR 2.10) and RPE pigmentation (OR 2.22) was higher in white people than in black people but the risk of developing GA or CNV was no different for white and black people.247 A south Indian study found a prevalence of AMD in its population similar to other developed countries.96 A Japanese population study reported similar prevalence of ARM to the white population of the Blue Mountains eye study. This similarity also held true for AMD in Japanese men, but AMD prevalence was lower in Japanese women compared with the Blue Mountains Eye Study population. This disparity was assumed to occur because of a high proportion of Japanese male smokers according to the authors.241 Another Japanese study compared the incidence of ARMD in the Japanese population with the Beaver Dam eye study, the Blue Mountains eye study (both with a predominantly white population) and the Barbados eye study (a predominantly black population).242 The authors concluded that the nine-year incidence of ARMD was lower among the Japanese population than among white people, but AMD was higher in the Japanese population than among black people. The prevalence of ARM in South Koreans was also found to be similar to other studies but the prevalence of AMD was lower.221 Exudative AMD was found to be higher in Chinese people (OR 4.3) compared with white people in a study assessing four different ethnic groups, even when smoking age, gender, pupil size, BMI, alcohol intake, diabetes and hypertension were adjusted for.248 A putative mechanism for reduced risk of ARMD in black people compared with white people is the protective effect of the darker pigmentation of the iris246 and higher concentrations of melanin within the choroid of black people compared with white people.249 Melanin acts as an antioxidant, scavenging free radicals and reducing oxidative stress.24

Iris Pigmentation

Iris pigmentation has been inconsistently associated with an increased risk for ARMD with the EDCCS demonstrating no association between iris colour and neovascular AMD,78,250 incident ARMD251 or GA.250 Conversely light irises were associated with increased risk for ARMD in other studies (OR 1.22–5.0).218,252,253 Blue iris colour was linked with increased risk of both ARM and AMD in the Blue Mountains eye study (OR 1.69).254 However, five years later, longitudinal data did not support this association. A study of 1,000 Danes also showed no difference between light iris and dark iris colour for AMD.255

Hypermetropia

Hypermetropia and its associated shorter axial length have been linked with increased ARMD development risk35,256–260 (in these studies, either p<0.05 or OR 1.54–2.4, depending on the statistics used). An association with ARMD.178 Aspirin was not found to be related to an increased risk of ARM or AMD development in the AREDS study,128 but was positively correlated in a later AREDS study (OR 1.88).157 It was not linked in other studies190–192 or its effects were not reported.35,78,129

Medication

Conflicting associations between the use of other medication and risk for developing ARMD have been reported. Those with GA were more likely to take antacids (OR 2.13) and those with large drusen or extensive intermediate drusen were more likely to take hydrochlorothiazide diuretics (OR 1.51) in one AREDS report.128 Antacid use was associated with a reduced risk of developing GA (OR 0.29) in another AREDS group study.157 This report also highlighted an association between anti-inflammatory medication and reduced incidence of GA (OR 0.22). In a further study assessing the use of antacids and thiazide diuretics in ARMD no relationship was found for increased risk of the disease and either medication.193 Van Leeuwen et al. found an increased risk for ARM development in people taking antihypertensive treatment (OR 1.3) and a decreased risk in women taking tricyclic antidepressants (OR 0.4).194

Hormones

The use of differing hormones has been associated with risk for developing ARMD. Thyroid hormones were associated with an increased risk of GA in the AREDS study (OR 1.99), although the use of oestrogen and progesterone in women was not associated with any form of ARMD in this study.128 Thyroid and antithyroid hormones were not associated with ARMD in another study.193 There was also no association between the use of hormone replacement therapy (HRT), hysterectomy or oopherectomy in women and ARMD risk in the POLA study.195 However, a protective effect of HRT was found in another study, with a 48 % lower risk of developing CNV compared with women who had never used HRT, although no protective effect was found for ARM.196 A reduced risk of developing ARM was seen in another study in women taking HRT (OR 0.6).194 A lack of oestrogen was shown to be associated with an increase in basal laminar deposits and thickened Bruch’s membranes in mice retinae.197 The authors postulated that oestrogen downregulated matrix metalloproteinase-2, which is responsible for breaking down Bruch’s membrane and RPE basement membranes. Another study demonstrated that a lack of oestrogen upregulates a glycoprotein called YKL-40, leading to CNV. The function of YKL-40 in the retina is unknown.198

Type II Diabetes

Inconsistent links between type II diabetes and ARMD risk have been described. The Blue Mountains eye study also found a relationship between type II diabetes and development of GA after 10 years with a RR of 3.89, but no relationship for neovascular AMD.165 Type II diabetes was associated with an increased risk for developing ARMD compared with type I diabetes (p<0.001) and controls (p<0.005).199 The European Eye study (EUREYE) and AREDS group demonstrated a relationship between type II diabetes and risk of neovascular AMD development (OR 1.81 and 1.88, respectively) but not for GA and type II diabetes.157,200 Conversely, a study assessing the 10-year follow-up of 133 people with newly diagnosed type II diabetes and 144 controls found no significant difference between groups in risk for ARMD development over the 10 years.201 No relationship between type II diabetes and ARMD was seen in the POLA study,158 a further Blue Mountains eye study155 or reported by others.78,92 The mechanisms for any association between diabetes and ARMD are unknown. Hyperglycaemia in diabetes has been associated with reduced choroidal circulation within the foveal area.202,203 This may reduce the exchange of oxygen, nutrients and waste products within the outer retina, which may increase susceptibility to ARMD.

Sunlight Exposure

There are contradictory findings in the literature about the relationship between exposure to sunlight and risk for ARMD development. No statistically significant associations were reported in a Brazilian study,124 an Italian study204 or studies from other global locations.78,128,205,206 Intriguingly, two studies demonstrated a protective effect of light against ARMD (OR 0.73 in one study and annual sun exposure of controls at 940 versus 770 hours in those with ARMD, p=0.0002).207,208 However, other studies have shown a detrimental effect of sunlight with increased risk of ARMD development. Blue light exposure was associated with an increased risk of developing GA in a study of 838 watermen (OR 1.36).209 The Beaver Dam eye study found a relationship between high sunlight exposure and a higher 10-year incidence of ARM (RR 2.20),210 with sunglasses and headwear providing protection against drusen development (RR 0.55) and RPE depigmentation (RR 0.51). The Blue Mountains eye study found that high (OR 2.54) and low (OR 2.18) skin sensitivity to sunlight was associated with AMD but not ARM.211 Retinal photochemical injury occurs cumulatively over a long period to tolerable light levels. Sunlight damages the RPE-photoreceptor complex, causing the formation of free radicals that peroxidise the fatty acids within the photoreceptor outer segments, leading to RPE and photoreceptor dysfunction and death.212 Free radicals also increase the production of lipofuscin in RPE cells. A2E, a major fluorophore of lipofuscin, generates free radicals in response to light, which leads to RPE apoptosis.213

Miscellaneous

Other, less reported modifiable risk factors inconsistently associated with ARMD include parity greater than zero. Increased risk of neovascular AMD has been seen with parity greater than zero in the EDCCS study (OR 1.8)78 but this relationship is not apparent in another study.214 Conversely, parous women were found to have a 26 % lower risk of developing ARM196 in a more recent study. Although not clear, hormonal mechanisms such as the effects of oestrogen mentioned previously may play a role.

Non-modifiable Risk Factors

It is well reported that increasing age is strongly linked with a higher risk of developing ARMD92,96,128,204,215–221 and certain genes have been recognised for their association with disease development, but there are other non-modifiable risk factors for developing the disease that are inconsistent in the literature.

Cataracts and Intraocular Lenses

Cataracts are known to protect the retina by reducing the amount of ultraviolet and blue light entering the eye. Thus, after cataract extraction, the retina is subjected to increased light levels and increased photochemical damage. The Blue Mountains eye study and the Beaver Dam eye study found an increased risk for developing ARMD in eyes that had undergone cataract surgery (OR 1.3–5.7 in these studies).222–224 This was evident in other work, showing an increased risk of AMD in eyes after cataract extraction, with neovascular AMD developing in 19.1 % of post-cataract surgery eyes compared with 4.3 % of non-operated fellow eyes.225 Intra-operative photic damage and surgical inflammation have also been discussed between ARM risk and hypermetropia was found in the Blue Mountains eye study (OR 2.0)261 and the Rotterdam study (OR 1.20 for advanced hyperopia compared with emmetropia).262 In a further Blue Mountains eye study no association was found between hypermetropia and the five-year incidence of ARM.263 Large drusen (OR 1.28) and CNV (OR 2.31) were associated with hypermetropia in the AREDS study.128 Other studies have reported no effect of hypermetropia on risk for developing ARMD.124,264 A biological mechanism for increased risk of ARMD with hypermetropia has not yet been elucidated. One study suggests shorter, thicker eyes with increased scleral rigidity decreases choroidal blood flow and thus retinal nutrient and waste exchange, leading to increased oxidative stress.262

Miscellaneous

Other, less reported non-modifiable risk factors inconsistently associated with ARMD include hand-grip strength, optic disc appearance and birth weight. A couple of studies have linked decreased hand grip strength to increased risk for AMD (no OR, RR or HR given).35,125 Unusual optic disc appearance has been associated with ARMD risk (no risk statistics reported)265 but repealed in other studies.266,267 Babies with increased birth weight were found to have a higher possibility of developing AMD than those with lower birth weight in one study (OR 1.5)268 and this was echoed in another study, but only in white people for ARM (OR 1.2), although AMD risk was not assessed in this study.269

Summary

There are many risk factors associated with ARMD development, with varying degrees of consistency. Age, smoking and genetics appear to be congruously linked with increased risk for developing the disease. With the costly management of neovascular AMD and limited treatment for dry AMD, the potential for modification of environmental factors in reducing the risk of ARMD development is an important research area. The oxidative stress theory for the aetiology of ARMD provokes interest in how antioxidants may play a role in reducing the risk of disease development and progression. ■

Article Information:
Disclosure

The authors have no conflicts of interest to declare.

Correspondence

Emma J Berrow, Ophthalmic Research Group, School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK. E: berrowej@aston.ac.uk

Received

2011-07-08T00:00:00

References

  1. Bird AC, Bressler NM, Bressler SB, et al., An international classification and grading system for age-related maculopathy and age-related macular degeneration, Surv Ophthalmol, 1995;39:367–74.
  2. Klein R, Klein BEK, Tomany SC, et al., Ten-year incidence and progression of age-related maculopathy, Ophthalmology, 2002;109:1767–79.
  3. Evans J, Wormald R, Is the incidence of registrable age-related macular degeneration increasing?, Br J Ophthalmol, 1996;80:9–14.
  4. Yong VK, Morgan WH, Cooper RL, et al., Trends in registered blindness and its causes over 19 years in Western Australia, Ophthalmic Epidemiol, 2006;13:35–42.
  5. Njiric S, Misljenovic T, Mikulicic M, Pavicevic L, Incidence of age-related macular degeneration in correlation with age, sex and occupation, Coll Antropol 2007;31:107–10.
  6. Korobelnik JF, Moore N, Blin P, et al., Estimating the yearly number of eyes with treatable neovascular age-related macular degeneration using a direct standardization method and a markov model, Invest Ophthalmol Vis Sci, 2006;47:4270–6.
  7. Bonnel S, Mohand-Said S, Sahel J-A, The aging of the retina, Exp Gerontol, 2003;38:825–31.
  8. Kaur C, Foulds WS, Ling EA, Blood–retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management, Prog Retin Eye Res, 2008;27:622–47.
  9. Moore DJ, Age-related variation in the hydraulic conductivity of Bruch’s membrane, Invest Ophthalmol Vis Sci, 1995;36:1290–7.
  10. Wing GL, The topography and age relationship of lipofuscin concentration in the retinal pigment epithelium, Invest Ophthalmol Vis Sci, 1978;17:601–7.
  11. Katz ML, Drea CM, Eldred GE, et al., Influence of early photoreceptor degeneration on lipofuscin in the retinal pigment epithelium, Exp Eye Res, 1986;43:561–73.
  12. Bird A, Marshall J, Retinal pigment epithelium detachments in the elderly, Trans Ophthalmol Soc UK, 1986;105:674–82.
  13. Zarbin M, Current concepts in the pathogenesis of age-related macular degeneration, Arch Ophthalmol, 2004;122:598–614.
  14. Wallace DC, Brown MD, Melov S, Graham B, Lott M. Mitochondrial biology, degenerative diseases and aging. Biofactors 1998;7:187–190.
  15. Dargel R, Lipid peroxidation – a common pathogenetic mechanism?, Exp Toxicol Pathol, 1992;44:169–81.
  16. Delapaz M, Anderson RE, Region and age-dependent variation in susceptibility of the human retina to lipid-peroxidation, Invest Ophthalmol Vis Sci, 1992;33:3497–9.
  17. Organisciak DT, Vaughan DK, Retinal light damage: mechanisms and protection, Prog Retin Eye Res, 2009;29:113–34.
  18. Wiegand RD, Giusto NM, Rapp LM, Anderson RE, Evidence for rod outer segment lipid-peroxidation following constant illumination of the rat retina, Invest Ophthalmol Vis Sci, 1983;24:1433–5.
  19. Kasahara E, Lin LR, Ho YS, Reddy VN, SOD2 protects against oxidation-induced apoptosis in mouse retinal pigment epithelium: implications for age-related macular degeneration, Invest Ophthalmol Vis Sci, 2005;46:3426–34.
  20. Wassell J, Davies S, Bardsley W, Boulton M, The photoreactivity of the retinal age, pigment lipofuscin, J Biol Chem, 1999;274:23828–32.
  21. Delori FC, Goger DG, Dorey CK, Age-related accumulation and spatial distribution of lipofuscin in RPE of normal subjects, Invest Ophthalmol Vis Sci, 2001;42:1855–66.
  22. Rozanowska M, Wessels J, Boulton M, et al. Blue light-induced singlet oxygen generation by retinal lipofuscin in non-polar media, Free Radic Biol Med, 1998;24:1107–12.
  23. Rozanowski B, Burke JM, Boulton ME, et al., Human RPE melanosomes protect from photosensitized and iron-mediated oxidation but become pro-oxidant in the presence of iron upon photodegradation, Investi Ophthalmol Vis Sci, 2008;49:2838–47.
  24. Sarna T, Burke JM, Korytowski W, et al., Loss of melanin from human RPE with aging: possible role of melanin photooxidation, Exp Eye Res, 2003;76:89–98.
  25. Warburton S, Davis WE, Southwick K, et al., Proteomic and phototoxic characterization of melanolipofuscin: correlation to disease and model for its origin, Mol Vis, 2007;13:318–29.
  26. Yoshimura N, Age-related macular degeneration and genetics, Clin Exp Ophthalmol, 2010;38:1.
  27. Katta S, Kaur I, Chakrabarti S, The molecular genetic basis of age-related macular degeneration: an overview, J Genet, 2009;88:425–49.
  28. Baird PN, Hageman GS, Guymer RH, New era for personalized medicine: the diagnosis and management of age-related macular degeneration, Clin Exp Ophthalmol, 2009;37:814–21.
  29. Shuler RK, Schmidt S, Gallins P, et al., Phenotype analysis of patients with the risk variant LOC387715 (A69S) in age-related macular degeneration, Am J Ophthalmol, 2008;145:303–7.
  30. Seddon JM, Francis PJ, George S, et al., Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA, 2007;297:1793–800.
  31. Patel N, Adewoyin T, Chong NV, Age-related macular degeneration: a perspective on genetic studies, Eye, 2008;22:768–76.
  32. Gorin MB, Breitner JC, De Jong PT, et al., The genetics of age-related macular degeneration, Mol Vis, 1999;5:29.
  33. Smith W, Mitchell P, Family history and age-related maculopathy: the Blue Mountains eye study, Arch Ophthalmol, 1998;26:203–6.
  34. Klein M, Mauldin W, Stoumbos V, Heredity and age-related macular degeneration. Observations in monozygotic twins, Arch Ophthalmol, 1994;112:932–7.
  35. Hyman LG, Lilienfeld AM, Ferris FL, Fine SL, Senile macular degeneration – a case–control study, Am J Epidemiol, 1983;118:213–27.
  36. Ting AYC, Lee TKM, MacDonald IM, Genetics of age-related macular degeneration, Curr Opin Ophthalmol, 2009;20:369–76.
  37. Meyers S, Zachary A, Monozygotic twins with age-related macular degeneration, Arch Opthalmol, 1988;106:651–3.
  38. Meyers S, A twin study on age-related macular degeneration, Trans Am Ophthalmol Soc, 1994;92:775–844.
  39. Meyers S, Greene T, Gutman F, A twin study of age-related macular degeneration, Am J Ophthalmol, 1995;120:757–66.
  40. Melrose M, Magargal L, Lucier A, Identical twins with subretinal neovascularization complicating senile macular degeneration, Ophthalic Surg, 1985;16:648–51.
  41. Grizzard W, Beck R, Twin study of age-related macular degeneration, Invest Ophthalmol Vis Sci, 1994;35:1504.
  42. Seddon JM, Ajani UA, Mitchell BD, Familial aggregation of age-related maculopathy, Am J Ophthalmol, 1997;123:199–206.
  43. Klaver C, Wolfs R, Assink J, Genetic risk of age-related maculopathy. Population-based familial aggregation study, Arch Ophthalmol, 1998;116:1646–51.
  44. Silvestri G, Johnston P, Hughes A, Is genetic predisposition an important risk factor in age-related macular degeneration?, Eye, 1994;8:564–8.
  45. Silvestri G, Age-related macular degeneration: genetics and implications for detection and treatment, Mol Med Today, 1997;3:84–91.
  46. Starita C, Hussain AA, Pagliarini S, Marshall J, Hydrodynamics of ageing Bruch’s membrane: implications for macular disease, Exp Eye Res, 1996;62:565–71.
  47. Feeneyburns L, Ellersieck MR, Age-related changes in the ultrastructure of Bruch’s membrane, Am J Ophthalmol, 1985;100:686–97.
  48. Karwatowski WSS, Jeffries TE, Duance VC, et al., Preparation of Bruch’s membrane and analysis of the age-related changes in the structural collagens, Br J Ophthalmol, 1995;79:944–52.
  49. Ho TC, DelPriore LV, Reattachment of cultured human retinal pigment epithelium to extracellular matrix and human Bruch’s membrane, Invest Ophthalmol Vis Sci, 1997;38:1110–18.
  50. Booij JC, Baas DC, Beisekeeva J, et al., The dynamic nature of Bruch’s membrane, Prog Retin Eye Res, 29:1–18.
  51. Sarks S, Cherepanoff S, Killingsworth M, Sarks J, Relationship of basal laminar deposit and membranous debris to the clinical presentation of early age-related macular degeneration, Invest Ophthalmol Vis Sci, 2007;48:968–77.
  52. Curcio C, Millican C, Basal linear deposit and large drusen are specific for early age-related maculopathy, Arch Ophthalmol, 1999;117:329–39.
  53. Green WR, Enger C, Age-related macular degeneration histopathologic studies – the 1992 Lorenz E. Zimmerman lecture, Ophthalmology, 1993;100:1519–35.
  54. Spraul CW, Lang GE, Grossniklaus HE, Lang GK, Characteristics of drusen and Bruch’s membrane in post-mortem eye with age-related macular degeneration, Ophthalmologe, 1998;95:73–9.
  55. Johnson PT, Lewis GP, Talaga KC, et al., Drusen-associated degeneration in the retina, Invest Ophthalmol Vis Sci, 2003;44:4481–8.
  56. Reale E, Groos S, Eckardt U, et al., New components of ‘basal laminar deposits’ in age-related macular degeneration, Cells Tissues Organs, 2009;190:170–81.
  57. Lommatzsch A, Hermans P, Weber B, Pauleikhoff D, Complement factor H variant Y402H and basal laminar deposits in exudative age-related macular degeneration, Graefes Arch Clin Exp Ophthalmol, 2007;245:1713–16.
  58. Guymer R, Luthert P, Bird A, Changes in Bruch’s membrane and related structures with age, Prog Retin Eye Res, 1999;18:59–90.
  59. Pauleikhoff D, Harper C, Marshall J, Bird A, Ageing changes in Bruch’s membrane. A histochemical and morphological study, Ophthalmology, 1990;97:171–8.
  60. Moore DJ, Clover GM, The effect of age on the macromolecular permeability of human Bruch’s membrane, Invest Ophthalmol Vis Sci, 2001;42:2970–5.
  61. Curcio CA, Owsley C, Jackson GR, Spare the rods, save the cones in aging and age-related maculopathy, Invest Ophthalmol Vis Sci, 2000;41:2015–18.
  62. Sarks S, Ageing and degeneration in the macular region: a clinico-pathological study, Br J Ophthalmol, 1976;60:324–41.
  63. Sun K, Cai H, Tezel TH, et al., Bruch’s membrane aging decreases phagocytosis of outer segments by retinal pigment epithelium, Mol Vis, 2007;13:2310–19.
  64. Linsenmeier RA, Padnick-Silver L, Metabolic dependence of photoreceptors on the choroid in the normal and detached retina, Invest Ophthalmol Vis Sci, 2000;41:3117–23.
  65. Ohno-Matsui K, Morita I, Tombran-Tink J, et al., Novel mechanism for age-related macular degeneration: an equilibrium shift between the angiogenesis factors VEGF and PEDF, J Cell Physiol, 2001;189:323–33.
  66. Schlingemann RO, Role of growth factors and the wound healing response in age-related macular degeneration, Graefes Arch Clin Exp Ophthalmol, 2004;242:91–101.
  67. Holekamp NM, Bouck N, Volpert O, Pigment epitheliumderived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration, Am J Ophthalmol, 2002;134:220–7.
  68. Bhutto IA, McLeod DS, Hasegawa T, et al., Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in aged human choroid and eyes with age-related macular degeneration, Exp Eye Res, 2006;82:99–110.
  69. Tong JP, Yao YF, Contribution of VEGF and PEDF to choroidal angiogenesis: a need for balanced expressions, Clin Biochem, 2006;39:267–76.
  70. Ahmed J, Braun RD, Dunn R, Linsenmeier RA, Oxygen distribution in the macaque retina, Invest Ophthalmol Vis Sci, 1993;34:516–21.
  71. Friedman E, Krupsky S, Lane AM, et al., Ocular blood flow velocity in age-related macular degeneration, Ophthalmology, 1995;102:640–6.
  72. Ciulla TA, Harris A, Chung HS, et al., Color Doppler imaging discloses reduced ocular blood flow velocities in nonexudative age-related macular degeneration, Am J Ophthalmol, 1999;128:75–80.
  73. Ramrattan RS, Vanderschaft TL, Mooy CM, et al., Morphometric analysis of Bruch’s membrane, the choriocapillaris, and the choroid in aging, Invest Ophthalmol Vis Sci, 1994;35:2857–64.
  74. D’amore PA, Mechanisms of retinal and choroidal neovascularization, Invest Ophthalmol Vis Sci, 1994;35:3974–9.
  75. Grunwald JE, Hariprasad SM, DuPont J, et al., Foveolar choroidal blood flow in age-related macular degeneration, Invest Ophthalmol Vis Sci, 1998;39:385–90.
  76. Grunwald JE, Metelitsina TI, DuPont JC, et al., Reduced foveolar choroidal blood flow in eyes with increasing AMD severity, Invest Ophthalmol Vis Sci, 2005;46:1033–8.
  77. Ambati J, Ambati BK, Yoo SH, et al., Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies, Surv Ophthalmol, 2003;48:257–93.
  78. EDCCS Group, Risk factors for neovascular age-related macular degeneration. The Eye Disease Case Control Study Group, Arch Ophthalmol, 1992;110:1701–8.
  79. Smith W, Mitchell P, Leeder S, Smoking and age-related maculopathy. The Blue Mountains eye study, Arch Ophthalmol, 1996;114:1518–23.
  80. Hawkins BS, Bird A, Klein R, West SK, Epidemiology of age-related macular degeneration, Mol Vis, 1999;5:U7–10.
  81. Chakravarthy U, Augood C, Bentham GC, et al., Cigarette smoking and age-related macular degeneration in the EUREYE study, Ophthalmology, 2007;114:1157–63.
  82. Tan JSL, Mitchell P, Kifley A, et al., Smoking and the long-term incidence of age-related macular degeneration – the Blue Mountains eye study, Arch Ophthalmol, 2007;125:1089–95.
  83. Klein R, Knudtson MD, Cruickshanks KJ, Klein BEK, Further observations on the association between smoking and the long-term incidence and progression of age-related macular degeneration, Arch Ophthalmol, 2008;126:115–21.
  84. Neuner B, Komm A, Wellmann J, et al., Smoking history and the incidence of age-related macular degeneration – results from the Muenster Aging and Retina Study (MARS) cohort and systematic review and meta-analysis of observational longitudinal studies, Addict Behav, 2009;34:938–47.
  85. Coleman AL, Seitzman RL, Cummings SR, et al., The association of smoking and alcohol use with age-related macular degeneration in the oldest old: the study of osteoporotic fractures, Am J Ophthalmol, 2010;149:160–9.
  86. Klein R, Cruickshanks KJ, Nash SD, et al., The prevalence of age-related macular degeneration and associated risk factors, Arch Ophthalmol, 2010;128:750–8.
  87. Vingerling JR, Hofman A, Grobbee DE, deJong P, Age-related macular degeneration and smoking – the Rotterdam study, Arch Ophthalmol, 1996;114:1193–6.
  88. Delcourt C, Diaz J, Ponton-Sanchez A, Smoking and age-related macular degeneration, Arch Ophthalmol, 1998;116:1031–5.
  89. Seddon JM, Willett WC, Speizer FE, et al., A prospective study of cigarette smoking and age-related macular degeneration in women, JAMA, 1996;276(14):1141–6.
  90. Christen WG, Glynn RJ, Manson JE, et al., A prospective study of cigarette smoking and risk of age-related macular degeneration in men, JAMA, 1996;276(14):1147–51.
  91. Tamakoshi A, Yuzawa M, Matsui M, et al., Smoking and neovascular form of age-related macular degeneration in late middle aged males: findings from a case–control study in Japan, Br J Ophthalmol, 1997;81:901–4.
  92. Smith W, Assink J, Klein R, et al., Risk factors for age related macular degeneration – Pooled findings from three continents, Ophthalmology, 2001;108:697–704.
  93. McCarty CA, Mukesh BN, Fu CL, et al., Risk factors for age-related maculopathy – the Visual Impairment Project, Arch Ophthalmol, 2001;119:1455–62.
  94. Wilson GA, Field AP, Wilson N, Smoke gets in your eyes: smoking and visual impairment in New Zealand, N Z Med J, 2001;114:471–4.
  95. Evans JR, Fletcher AE, Wormald RPL, 28,000 Cases of age related macular degeneration causing visual loss in people aged 75 years and above in the United Kingdom may be attributable to smoking, Br J Ophthalmol, 2005;89:550–3.
  96. Krishnaiah S, Das T, Nirmalan PK, et al., Risk factors for age-related macular degeneration: findings from the Andhra Pradesh Eye Disease Study in South India, Invest Ophthalmol Vis Sci, 2005;46:4442–9.
  97. Fraser-Bell S, Wu J, Klein R, et al., Smoking, alcohol intake, estrogen use, and age-related macular degeneration in latinos: the Los Angeles Latino eye study, Am J Ophthalmol, 2006;141:79–87.
  98. Khan JC, Thurlby DA, Shahid H, et al., Smoking and age related macular degeneration: the number of pack years of cigarette smoking is a major determinant of risk for both geographic atrophy and choroidal neovascularisation, Br J Ophthalmol, 2006;90:75–80.
  99. Suner IJ, Espinosa-Heidmann DG, Marin-Castano ME, et al., Nicotine increases size and severity of experimental choroidal neovascularization, Invest Ophthalmol Vis Sci, 2004;45:311–17.
  100. Blute TA, Strang C, Keyser KT, Eldred WD, Activation of the cGMP/nitric oxide signal transduction system by nicotine in the retina, Vis Neurosci, 2003;20:165–76.
  101. Espinosa-Heidmann DG, Suner IJ, Catanuto P, et al., Cigarette smoke-related oxidants and the development of sub-RPE deposits in an experimental animal model of dry AMD, Invest Ophthalmol Vis Sci, 2006;47:729–37.
  102. Erie JC, Good JA, Butz JA, et al., Urinary cadmium and age-related macular degeneration, Am J Ophthalmol, 2007;144:414–18.
  103. Erie JC, Butz JA, Good JA, et al., Heavy metal concentrations in human eyes, Am J Ophthalmol, 2005;139:888–93.
  104. Wills NK, Ramanujam VMS, Chang J, et al., Cadmium accumulation in the human retina: effects of age, gender, and cellular toxicity, Exp Eye Res, 2008;86:41–51.
  105. Fujihara M, Nagai N, Sussan TE, et al., Chronic cigarette smoke causes oxidative damage and apoptosis to retinal pigmented epithelial cells in mice, Plos One, 2008;3:e3119.
  106. Wang AL, Lukas TJ, Yuan M, et al., Changes in retinal pigment epithelium related to cigarette smoke: possible relevance to smoking as a risk factor for age-related macular degeneration, Plos One, 2009;4:e5304.
  107. Hughes AE, Orr N, Patterson C, et al., Neovascular age-related macular degeneration risk based on CFH, LOC387715/HTRA1, and smoking, Plos Med, 2007;4:1993–2000.
  108. Tuo J, Ross RJ, Reed GF, et al., The HtrA1 promoter polymorphism, smoking, and age-related macular degeneration in multiple case-control samples, Ophthalmology, 2008;115:1891–8.
  109. Chu J, Zhou CC, Lu N, et al., Genetic variants in three genes and smoking show strong associations with susceptibility to exudative age-related macular degeneration in a Chinese population, Chin Med J (Engl) , 2008;121:2525–33.
  110. Lee AY, Brantley MA, CFH and LOC3877151ARMS2 genotypes and antioxidants and zinc therapy for age-related macular degeneration, Pharmacogenomics, 2008;9:1547–50.
  111. Ayala-Haedo JA, Gallins PJ, Whitehead PL, et al., Analysis of single nucleotide polymorphisms in the NOS2A gene and interaction with smoking in age-related macular degeneration, Ann Hum Genet, 2010;74:195–201.
  112. Chong EWT, Kreis AJ, Wong TY, et al., Alcohol consumption and the risk of age-related macular degeneration: a systematic review and meta-analysis, Am J Ophthalmol, 2008;145:707–15.
  113. Boekhoorn SS, Vingerling JR, Hofman A, de Jong P, Alcohol consumption and risk of aging macula disorder in a general population – the Rotterdam Study, Arch Ophthalmol, 2008;126:834–9.
  114. Ritter LL, Klein R, Klein BE, et al., Alcohol use and age-related maculopathy in the Beaver Dam eye study, Am J Ophthalmol, 1995;120:190–6.
  115. Smith W, Mitchell P, Alcohol intake and age-related maculopathy, Am J Ophthalmol, 1996;122:743–5.
  116. Ajani UA, Christen WG, Manson JE, et al., A prospective study of alcohol consumption and the risk of age related macular degeneration, Ann Epidemiol, 1999;9:172–7.
  117. Knudtson MD, Klein R, Klein BEK, Alcohol consumption and the 15-year cumulative incidence of age-related macular degeneration, Am J Ophthalmol, 2007;143:1026–9.
  118. Obisesan TO, Hirsch R, Kosoko O, et al., Moderate wine consumption is associated with decreased odds of developing age-related macular degeneration in NHANES-1, J Am Geriatr Soc, 1998;46:1–7.
  119. Arnarsson A, Sverrisson T, Stefansson E, et al., Risk factors for five-year incident age-related macular degeneration: the Reykjavik eye study, Am J Ophthalmol, 2006;142:419–28.
  120. Bora PS, Kaliappan S, Xu Q, et al., Alcohol linked to enhanced angiogenesis in rat model of choroidal neovascularization, Febs J, 2006;273:1403–14.
  121. Matsui JI, Egana AL, Sponholtz TR, et al., Effects of ethanol on photoreceptors and visual function in developing zebrafish, Invest Ophthalmol Vis Sci, 2006;47:4589–97.
  122. King RE, Kent KD, Bomser JA, Resveratrol reduces oxidation and proliferation of human retinal pigment epithelial cells via extracellular signal-regulated kinase inhibition, Chem Biol Interact, 2005;151:143–9.
  123. Chew H, Maberley DAL, Ma P, et al., Socioeconomic status and clinical features of patients undergoing photodynamic therapy or transpupillary thermotherapy for subfoveal choroidal neovascularization due to age-related macular degeneration, Can J Ophthalmol, 2005;40:384–8.
  124. Santos LPF, Diniz JR, Leao AC, Sena MF, Age-related macular degeneration: analysis in two ophthalmological centers in Pernambuco-Brazil, Arq Bras Oftalmol, 2005;68:229–33.
  125. Kahn HA, Leibowitz HM, Ganley JP, et al., The Framingham eye study 2. Association of ophthalmic pathology with single variables previously measured in the Framingham heart study, Am J Epidemiol, 1977;106:33–41.
  126. Klein R, Klein BEK, Linton KLP, Prevalence of age-related maculopathy – the Beaver Dam eye study, Ophthalmology, 1992;99:933–43.
  127. Klein R, Klein BEK, Jensen SC, et al., Age-related maculopathy in a multiracial United States population – the National Health and Nutrition Examination Survey III, Ophthalmology, 1999;106:1056–65.
  128. The AREDS Research Group, Risk factors associated with age-related macular degeneration – a case–control study in the Age-Related Eye Disease Study: Age-related Eye Disease Study report number 3, Ophthalmology, 2000;107:2224–32.
  129. Goldberg J, Flowerdew G, Smith E, et al., Factors associated with age-related macular degeneration – an analysis of data from the 1st National-Health and Nutrition Examination Survey, Am J Epidemiol, 1988;128:700–10.
  130. MaresPerlman JA, Klein R, Klein BEK, et al., Association of zinc and antioxidant nutrients with age-related maculopathy, Arch Ophthalmol, 1996;114:991–7.
  131. Mares-Perlman JA, Brady WE, Klein R, et al., Serum antioxidants and age-related macular degeneration in a population-based case-controlled study, Arch Ophthalmol, 1995;113:1518–23.
  132. West S, Vitale S, Hallfrisch J, et al., Are antioxidants or supplements protective for age-related macular degeneration, Arch Ophthalmol, 1994;112:222–7.
  133. Christen WG, Ajani UA, Glynn RJ, et al., Prospective cohort study of antioxidant vitamin supplement use and the risk of age-related maculopathy, Am J Epidemiol, 1999;149:476–84.
  134. Smith W, Mitchell P, Rochester C, Serum beta carotene, alpha tocopherol, and age-related maculopathy: the Blue Mountains eye study, Am J Ophthalmol, 1997;124:838–40.
  135. Yannuzzi LA, Sorenson JA, Sobel RS, et al., Antioxidant status and neovascular age-related macular degeneration, Arch Ophthalmol, 1993;111:104–9.
  136. Seddon JM, Ajani UA, Sperduto RD, et al., Dietary carotenoids, vitamin A,C and E and advanced age-related macular degeneration, JAMA, 1994;272:1413–20.
  137. The AREDS Research Group, A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss – AREDS report no. 8, Arch Ophthalmol, 2001;119:1417–36.
  138. Cangemi FE, TOZAL study: an open case control study of an oral antioxidant and omega-3 supplement for dry AMD, BMC Ophthalmol, 2007;7:3.
  139. Richer S, Stiles W, Statkute L, et al., Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial), Optometry, 2004;75:216–30.
  140. Parisi V, Tedeschi M, Gallinaro G, et al., Carotenoids and antioxidants in age-related maculopathy italian study: multifocal electroretinogram modifications after 1 year, Ophthalmology, 2008;115:324–33 e322.
  141. Richer S, ARMD – pilot (case series) environmental intervention data, J Am Optom Assoc, 1999;70:24–36.
  142. Chiu CJ, Klein R, Milton RC, et al., Does eating particular diets alter the risk of age-related macular degeneration in users of the Age-Related Eye Disease Study supplements?, Br J Ophthalmol, 2009;93:1241–6.
  143. Chiu CJ, Milton RC, Gensler G, Taylor A, Association between dietary glycernic index and age-related macular degeneration in nondiabetic participants in the Age-Related Eye Disease Study, Am J Clin Nutr, 2007;86:180–8.
  144. Chiu CJ, Milton RC, Klein R, et al., Dietary carbohydrate and the progression of age-related macular degeneration: a prospective study from the age-related eye disease study, Am J Clin Nutr, 2007;86:1210–8.
  145. Tan JSL, Wang JJ, Flood V, Mitchell P, Dietary fatty acids and the 10-year incidence of age-related macular degeneration the Blue Mountains eye study, Arch Ophthalmol, 2009;127:656–65.
  146. SanGiovanni JP, Chew EY, Agron E, et al., The relationship of dietary {omega}-3 long-chain polyunsaturated fatty acid intake with incident age-related macular degeneration: AREDS report no. 23, Arch Ophthalmol, 2008;126:1274–9.
  147. SanGiovanni JP, Chew EY, Clemons TE, et al., The relationship of dietary lipid intake and age-related macular degeneration in a case–control study – AREDS report no. 20, Arch Ophthalmol, 2007;125:671–9.
  148. SanGiovanni JP, Agrón E, Meleth AD, et al., ω−33 Long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central geographic atrophy: AREDS report 30, a prospective cohort study from the Age-Related Eye Disease Study, Am J Clin Nutr, 2009;90:1601–7.
  149. SanGiovanni JP, Chew EY, The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina, Prog Retin Eye Res, 2005;24:87–138.
  150. Chong EWT, Robman LD, Simpson JA, et al., Fat consumption and its association with age-related macular degeneration, Arch Ophthalmol, 2009;127:674–80.
  151. Heuberger RA, Mares-Perlman JA, Klein R, et al., Relationship of dietary fat to age-related maculopathy in the Third National Health and Nutrition Examination Survey, Arch Ophthalmol, 2001;119:1833–8.
  152. Chua B, Flood V, Rochtchina E, et al., Dietary fatty acids and the 5-year incidence of age-related maculopathy, Arch Ophthalmol, 2006;124:981–6.
  153. Kliffen M, Lutgens E, Daemen M, et al., The APO*E3-Leiden mouse as an animal model for basal laminar deposit, Br J Ophthalmol, 2000;84:1415–19.
  154. VandenLangenberg GM, Mares-Perlman JA, Klein R, et al., Associations between antioxidant and zinc intake and the 5-year incidence of early age-related maculopathy in the Beaver Dam eye study, Am J Epidemiol, 1998;148:204–14.
  155. Smith W, Mitchell P, Leeder SR, Wang JJ, Plasma fibrinogen levels, other cardiovascular risk factors, and age-related maculopathy – the Blue Mountains eye study, Arch Ophthalmol, 1998;116:583–7.
  156. Anand R, Bressler SB, Davis MD, et al., Risk factors associated with age-related macular degeneration – a case–control study in the Age-Related Eye Disease Study: Age-Related Eye Disease Study report number 3, Ophthalmology, 2000;107:2224–32.
  157. Milton RC, Clemons TE, Kurinij N, Sperduto RD, Age Related Eye Dis Study Research Group, Risk factors for the incidence of advanced age-related macular degeneration in the Age-related Eye Disease Study (AREDS) – AREDS report no. 19, Ophthalmology, 2005;112:533–9.
  158. Delcourt C, Michel F, Colvez A, et al., Associations of cardiovascular disease and its risk factors with age-related macular degeneration: the POLA study, Ophthalmic Epidemiol, 2001;8:237–49.
  159. Seddon JM, Cote J, Davis N, Rosner B, Progression of age-related macular degeneration – association with body mass index, waist circumference, and waist–hip ratio, Arch Ophthalmol, 2003;121:785–92.
  160. Hammond BR, Ciulla TA, Snodderly DM, Macular pigment density is reduced in obese subjects, Invest Ophthalmol Vis Sci, 2002;43:47–50.
  161. Schaumberg DA, Christen WG, Hankinson SE, Glynn R, Body mass index and the incidence of visually significant age-related maculopathy in men, Arch Ophthalmol, 2001;119:1259–65.
  162. Moeini HA, Masoudpour H, Ghanbari H, A study of the relation between body mass index and the incidence of age related macular degeneration, Br J Ophthalmol, 2005;89:964–6.
  163. Klein R, Klein BEK, Franke T, The relationship of cardiovascular disease and its risk factors to age-related maculopathy – the Beaver Dam eye study, Ophthalmology, 1993;100:406–14.
  164. Sato E, Feke GT, Appelbaum EY, et al., Association between systemic arterial stiffness and age-related macular degeneration, Graefes Arch Clin Exp Ophthalmol, 2006;244:963–71.
  165. Tan JSL, Mitchell P, Smith W, Wang JJ, Cardiovascular risk factors and the long-term incidence of age-related macular degeneration – the Blue Mountains eye study, Ophthalmology, 2007;114:1143–50.
  166. Seddon JM, George S, Rosner B, Rifai N, Progression of age-related macular degeneration – prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers, Arch Ophthalmol, 2005;123:774–82.
  167. Seddon JM, Gensler G, Milton RC, et al., Association between C-reactive protein and age-related macular degeneration, JAMA, 2004;291:704–10.
  168. Seddon JM, Gensler G, Klein ML, Milton RC, C-Reactive protein and homocysteine are associated with dietary and behavioral risk factors for age-related macular degeneration, Nutrition, 2006;22:441–3.
  169. McCarty CA, Dowrick A, Cameron J, et al., Novel measures of cardiovascular health and its association with prevalence and progression of age-related macular degeneration: the CHARM Study, BMC Ophthalmol, 2008;8:25.
  170. Hyman L, Schachat A, He Q, Hypertension, cardiovascular disease,and age-related macular degeneration, Arch Ophthalmol, 2000;117:351–8.
  171. Metelitsina TI, Grunwald JE, DuPont JC, Ying G-S, Effect of systemic hypertension on foveolar choroidal blood flow in age related macular degeneration, Br J Ophthalmol, 2006;90:342–6.
  172. Hogg RE, Woodside JV, Gilchrist SECM, et al., Cardiovascular disease and hypertension are strong risk factors for choroidal neovascularization, Ophthalmology, 2008;115:1046–52.e1042.
  173. Klein R, Klein B, Franke T, The relationship of cardiovascular disease and its risk factors to age-related maculopathy: the Beaver Dam eye study, Ophthalmology, 1993;100:406–14.
  174. Klein R, Klein BEK, Jensen SC, The relation of cardiovascular disease and its risk factors to the 5-year incidence of age related maculopathy – the Beaver Dam eye study, Ophthalmology, 1997;104:1804–12.
  175. Klein R, Klein BEK, Marino EK, et al., Early age-related maculopathy in the cardiovascular health study, Ophthalmology, 2003;110:25–33.
  176. Wang S, Xu L, Jonas JB, et al., Major eye diseases and risk factors associated with systemic hypertension in an adult Chinese population: the Beijing eye study, Ophthalmology, 2009;116:2373–80.
  177. Hall NF, Gale CR, Syddall H, et al., Risk of macular degeneration in users of statins: cross sectional study, Br Med J, 2001;323:375–6.
  178. Wilson HL, Schwartz DM, Bhatt HRF, et al., Statin and aspirin therapy are associated with decreased rates of choroidal neovascularization among patients with age-related macular degeneration, Am J Ophthalmol, 2004;137:615–24.
  179. McGwin GJ, Owsley C, Curcio C, Crain R, The association between statin use and age-related maculopathy, Br J Ophthalmol, 2003;87:1121–5.
  180. McGwin JG, Xie A, Owsley C, The use of cholesterol-lowering medications and age-related macular degeneration, Ophthalmology, 2005;112:488–94.
  181. Tan JSL, Mitchell P, Rochtchina E, Wang JJ, Statins and the long-term risk of incident age-related macular degeneration: the Blue Mountains eye study, Am J Ophthalmol, 2007;143:685–7.
  182. Yilmaz MI, Baykal Y, Kilic M, et al., Effects of statins on oxidative stress, Biol Trace Elem Res, 2004;98:119–27.
  183. Dithmar S, Curcio CA, Le NA, et al., Ultrastructural changes in Bruch’s membrane of apolipoprotein E-deficient mice, Invest Ophthalmol Vis Sci, 2000;41:2035–42.
  184. Chuo JY, Wiens M, Etminan M, Maberley DA, Use of lipid-lowering agents for the prevention of age-related macular degeneration: a meta-analysis of observational studies, Ophthalmic Epidemiol, 2007;14:367–74.
  185. Kaiserman N, Vinker S, Kaiserman I, Statins do not decrease the risk for wet age-related macular degeneration, Curr Eye Res, 2009;34:304–10.
  186. Maguire MG, Ying G-S, McCannel CA, et al., Statin use and the incidence of advanced age-related macular degeneration in the Complications of Age-related Macular Degeneration Prevention Trial, Ophthalmology, 2009;116:2381–5.
  187. Smeeth L, Cook C, Chakravarthy U, et al., A case control study of age related macular degeneration and use of statins, Am J Ophthalmol, 2006;141:238.
  188. Etminan M, Brophy JM, Maberley D, Use of statins and angiotensin converting enzyme inhibitors (ACE-Is) and the risk of age-related macular degeneration: nested case–control study, Curr Drug Saf, 2008;3:24–6.
  189. Scandinavian Simvastatin Survival Study Group, Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), The Lancet, 1994;344:1383–9.
  190. Christen WG, Glynn RJ, Chew EY, Buring JE, Low-dose aspirin and medical record-confirmed age-related macular degeneration in a randomized trial of women, Ophthalmology, 2009;116:2386–92.
  191. Christen W, Age-related macular degeneration (AMD) in a randomized trial of low dose aspirin, Invest Ophthalmol Vis Sci, 1997;38:S472.
  192. Klein R, Klein B, Jensen S, et al., Medication use and the 5-year incidence of early age-related maculopathy, Arch Ophthalmol, 2001;119:1354–9.
  193. Douglas IJ, Cook C, Chakravarthy U, et al., A case–control study of drug risk factors for age-related macular degeneration, Ophthalmology, 2007;114:1164–9.
  194. van Leeuwen R, Tomany SC, Wang JJ, et al., Is medication use associated with the incidence of early age-related maculopathy? Pooled findings from 3 continents, Ophthalmology, 2004;111:1169–75.
  195. Defay R, Pinchinat S, Lumbroso S, et al., Sex steroids and age-related macular degeneration in older French women: the POLA study, Ann Epidemiol, 2004;14:202–8.
  196. Feskanich D, Cho E, Schaumberg DA, et al., Menopausal and reproductive factors and risk of age-related macular degeneration, Arch Ophthalmol, 2008;126:519–24.
  197. Cousins SW, Marin-Castano ME, Espinosa-Heidmann DG, et al., Female gender, estrogen loss, and Sub-RPE deposit formation in aged mice, Invest Ophthalmol Vis Sci, 2003;44:1221–9.
  198. Rakic JM, Lambert V, Deprez M, et al., Estrogens reduce the expression of YKL-40 in the retina: implications for eye and joint diseases, Invest Ophthalmol Vis Sci, 2003;44:1740–6.
  199. Giansanti R, Fumelli C, Boemi M, Fumelli P, Age-related macular disease in diabetes mellitus, Arch Gerontol Geriatr, 1996;22(Suppl. 1):473–6.
  200. Topouzis F, Anastasopoulos E, Augood C, et al., Association of diabetes with age-related macular degeneration in the EUREYE study, Br J Ophthalmol, 2009;93:1037–41.
  201. Voutilainen-Kaunisto RM, Terasvirta ME, Uusitupa MI, Niskanen LK, Age-related macular degeneration in newly diagnosed type 2 diabetic patients and control subjects: a 10-year follow-up on evolution, risk factors, and prognostic significance, Diabetes Care, 2000;23:1672–8.
  202. Nagaoka T, Kitaya N, Sugawara R, et al., Alteration of choroidal circulation in the foveal region in patients with type 2 diabetes, Br J Ophthalmol, 2004;88:1060–3.
  203. Schocket LS, Brucker AJ, Niknam RM, et al., Foveolar choroidal hemodynamics in proliferative diabetic retinopathy, Int Ophthalmol, 2004;25:89–94.
  204. Carresi C, Cruciani F, Paolucci F, et al., Montelparo study: risk factors for age-related macular degeneration in a little rural community in Italy, Clin Ter, 2009;160:e43–51.
  205. Khan JC, Shahid H, Thurlby DA, et al., Age related macular degeneration and sun exposure, iris colour, and skin sensitivity to sunlight, Br J Ophthalmol, 2006;90:29–32.
  206. West SK, Rosenthal FS, Bressler NM, et al., Exposure to sunlight and other risk-factors for age-related macular degeneration, Arch Ophthalmol, 1989;107:875–9.
  207. Delcourt C, Carriere I, Ponton-Sanchez A, Light exposure and the risk of age-related macular degeneration: the POLA study, Arch Ophthalmol, 2001;119:1463–8.
  208. Darzins P, Mitchell P, Heller RF, Sun exposure and age-related macular degeneration. An Australian case–control study, Ophthalmology, 1997;104:770–6.
  209. Taylor HR, West S, Munoz B, et al., The long-term effects of visible-light on the eye, Arch Ophthalmol, 1992;110:99–104.
  210. Tomany SC, Cruickshanks KJ, Klein R, et al., Sunlight and the 10-year incidence of age-related maculopathy: the Beaver Dam eye study, Arch Ophthalmol, 2004;122:750–7.
  211. Mitchell P, Smith W, Wang JJ, Iris color, skin sun sensitivity, and age-related maculopathy – the Blue Mountains eye study, Ophthalmology, 1998;105:1359–63.
  212. Wu J, Seregard S, Algvere PV, Photochemical damage of the retina, Surv Ophthalmol, 2006;51:461–81.
  213. Algvere PV, Marshall J, Seregard S, Age-related maculopathy and the impact of blue light hazard, Acta Ophthalmol Scand, 2006;84:4–15.
  214. Nirmalan PK, Katz J, Robin AL, et al., Female reproductive factors and eye disease in a rural South Indian population: the Aravind Comprehensive Eye Survey, Invest Ophthalmol Vis Sci, 2004;45:4273–6.
  215. Maltzman B, Mulvihill M, Greenbaum A, Senile macular degeneration and risk factors: a case–control study, Ann Ophthalmol, 1979;11:1197–201.
  216. Gibson J, Shaw D, Rosenthal A, Senile cataract and senile macular degeneration: an investigation into possible risk factors, Trans Ophthalmol Soc UK, 1986;105:463–8.
  217. Vinding T, Appleyard M, Nyboe J, Jensen G, Risk factor-analysis for atrophic and exudative age-related macular degeneration – an epidemiologic study of 1000 aged individuals, Acta Ophthalmol, 1992;70:66–72.
  218. Starzycka M, Slomska J, Gorniak-Bednarz A, Ortyl E, [Risk factors for age-related macular degeneration], Klin Oczna, 1997;99:249–51.
  219. Chen SJ, Cheng CY, Peng KL, et al., Prevalence and associated risk factors of age-related macular degeneration in an elderly Chinese population in Taiwan: the Shihpai Eye Study, Invest Ophthalmol Vis Sci, 2008;49:3126–33.
  220. CAPT, Risk factors for choroidal neovascularization and geographic atrophy in the Complications of Age-Related Macular Degeneration Prevention Trial, Ophthalmology, 2008;115:1474–9.e1476.
  221. Song SJ, Youm DJ, Chang Y, Yu HG, Age-related macular degeneration in a screened South Korean population: prevalence, risk factors, and subtypes, Ophthalmic Epidemiol, 2009;16:304–10.
  222. Cugati S, Mitchell P, Rochtchina E, et al., Cataract surgery and the 10-year incidence of age-related maculopathy: the Blue Mountains eye study, Ophthalmology, 2006;113:2020–5.
  223. Klein R, Klein BEK, Wong T, et al., The association of cataract and cataract surgery with the long-term incidence of age-related maculopathy, Arch Ophthalmol, 2002;120:1551–8.
  224. Wang JJ, Klein R, Smith W, et al., Cataract surgery and the 5-year incidence of late-stage age-related maculopathy: pooled findings from the Beaver Dam and Blue Mountains eye studies, Ophthalmology, 2003;110:1960–7.
  225. Pollack A, Marcovich A, Bukelman A, Oliver M, Age-related macular degeneration after extracapsular cataract extraction with intraocular lens implantation, Ophthalmology, 1996;103:1546–54.
  226. Libre P, Intraoperative light toxicity: a possible explanantion for the association between cataract surgery and age-related macular degeneration, Am J Ophthalmol, 2003;136:961.
  227. Armbrecht A, Findlay C, Aspinall P, et al., Cataract surgery in patients with age-related macular degeneration – one-year outcomes, J Cataract Refract Surg, 2003;29:686–93.
  228. Chew EY, Sperduto RD, Milton RC, et al., Risk of advanced age-related macular degeneration after cataract surgery in the Age-Related Eye Disease Study AREDS report 25, Ophthalmology, 2009;116:297–303.
  229. Freeman EE, Munoz B, West SK, et al., Is there an association between cataract surgery and age- related macular degeneration? Data from three population-based studies, Am J Ophthalmol, 2003;135:849–56.
  230. Clemons TE, Rankin MW, McBee WL, Cognitive impairment in the Age-Related Eye Disease Study: AREDS report no. 16, Arch Ophthalmol, 2006;124:537–43.
  231. Baker ML, Wang JJ, Rogers S, et al., Early age-related macular degeneration, cognitive function, and dementia: the Cardiovascular Health Study, Arch Ophthalmol, 2009;127:667–73.
  232. Wong TY, Klein R, Nieto FJ, et al., Is early age-related maculopathy related to cognitive function? The Atherosclerosis Risk in Communities Study, Am J Ophthalmol, 2002;134:828–35.
  233. Pham TQ, Kifley A, Mitchell P, Wang JJ, Relation of age-related macular degeneration and cognitive impairment in an older population, Gerontology, 2006;52:353–8.
  234. Klaver CCW, Ott A, Hofman A, et al., Is age-related maculopathy associated with alzheimer’s disease? The Rotterdam Study, Am J Epidemiol, 1999;150:963–8.
  235. Anderson DH, Talaga KC, Rivest AJ, et al., Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration, Exp Eye Res, 2004;78:243–56.
  236. McGeer PL, McGeer EG, Inflammation and the degenerative diseases of aging, Ann N Y Acad Sci, 2004;1035:104–16.
  237. Rovner BW, Casten RJ, Leiby BE, Tasman WS, Activity loss is associated with cognitive decline in age-related macular degeneration, Alzheimers Dement, 2009;5:12–17.
  238. Roca-Santiago HM, Lago-Bouza JR, Millan-Calenti JC, et al., [Alzheimer’s disease and age-related macular degeneration], Arch Soc Esp Oftalmol, 2006;81:73–8.
  239. Tomany SC, Wang JJ, Van Leeuwen R, et al., Risk factors for incident age-related macular degeneration: pooled findings from 3 continents, Ophthalmology, 2004;111:1280–7.
  240. Kaiserman I, Kaiserman N, Elhayany A, Vinker S, Risk factors for photodynamic therapy of predominantly classic choroidal neovascularization in age-related macular degeneration, Am J Ophthalmol, 2006;142:441–7.
  241. Kawasaki R, Wang JJ, Ji GJ, et al., Prevalence and risk factors for age-related macular degeneration in an adult Japanese population: the Funagata study, Ophthalmology, 2008;115:1376–81, 1381.e1–2.
  242. Yasuda M, Kiyohara Y, Hata Y, et al., Nine-year incidence and risk factors for age-related macular degeneration in a defined Japanese population the Hisayama study, Ophthalmology, 2009;116:2135–40.
  243. McGeer PL, Sibley J, Sparing of age-related macular degeneration in rheumatoid arthritis, Neurobiology of Aging, 2005;26:1199–203.
  244. Bhutto IA, Baba T, Merges C, et al., C-reactive protein and complement factor H in aged human eyes and eyes with age-related macular degeneration, Br J Ophthalmol, 2011;95(9):1323–30.
  245. Gaynes BI, Sparing of age-related macular degeneration in rheumatoid arthritis, Neurobiol Aging, 2006;27:1531–2.
  246. Frank RN, Puklin JE, Stock C, Canter LA, Race, iris color, and age-related macular degeneration, Trans Am Ophthalmol Soc, 2000;98:109–15; discussion 115–17.
  247. Chang MA, Bressler SB, Munoz B, West SK, Racial differences and other risk factors for incidence and progression of age-related macular degeneration: Salisbury Eye Evaluation (SEE) Project, Invest Ophthalmol Vis Sci, 2008;49:2395–402.
  248. Klein R, Klein BE, Knudtson MD, et al., Prevalence of age-related macular degeneration in 4 racial/ethnic groups in the multi-ethnic study of atherosclerosis, Ophthalmology, 2006;113:373–80.
  249. Weiter JJ, Delori FC, Wing GL, Fitch KA, Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes, Invest Ophthalmol Vis Sci, 1986;27:145–52.
  250. Drobek-Slowik M, Karczewicz D, Safrano K, [Eye’s risk factors in age-related macular degeneration (AMD). Part I], Klin Oczna, 2008;110:40–3.
  251. Clemons TE, Milton RC, Klein R, et al., Risk factors for the incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19, Ophthalmology, 2005;112(4):533–9.
  252. Chaine G, Hullo A, Sahel J, et al., Case–control study of the risk factors for age related macular degeneration, Br J Ophthalmol, 1998;82:996–1002.
  253. Fraser-Bell S, Choudhury F, Klein R, et al., Ocular risk factors for age-related macular degeneration: the Los Angeles Latino Eye Study, Am J Ophthalmol, 2010;149:735–40.
  254. Mitchell P, Smith W, Wang JJ, Iris color, skin sun sensitivity, and age-related maculopathy, the Blue Mountains eye study, Ophthalmology, 1998;105:1359–63.
  255. Vinding T, Pigmentation of the eye and hair in relation to age-related macular degeneration: an epidemiological study of 1000 aged individuals, Acta Ophthalmol Copenh, 1990;68:53–8.
  256. Delaney WV, Jr, Oates RP, Senile macular degeneration: a preliminary study, Ann Ophthalmol, 1982;14:21–4.
  257. Xu L, Li Y, Zheng Y, Jonas JB, Associated factors for age related maculopathy in the adult population in China: the Beijing eye study, Br J Ophthalmol, 2006;90:1087–90.
  258. Xu L, You QS, Jonas JB, Refractive error, ocular and general parameters and ophthalmic diseases. The Beijing eye study, Graefes Arch Clin Exp Ophthalmol, 2010;248:721–9.
  259. Sandberg M, Tolentino Z, Miller S, Hyperopia and neovascularization in age-related macular degeneration, Ophthalmology, 1993;100:1009–13.
  260. Lavanya R, Kawasaki R, Tay WT, et al., Hyperopic refractive error and shorter axial length are associated with age-related macular degeneration: the Singapore Malay eye study, Invest Ophthalmol Vis Sci, 2010;51:6247–52.
  261. Wang JJ, Mitchell P, Smith W, Refractive error and age-related maculopathy: the Blue Mountains eye study, Invest Ophthalmol Vis Sci, 1998;39:2167–71.
  262. Ikram MK, van Leeuwen R, Vingerling JR, et al., Relationship between refraction and prevalent as well as incident age-related maculopathy: the Rotterdam study, Invest Ophthalmol Vis Sci, 2003;44:3778–82.
  263. Wang JJ, Jakobsen KB, Smith W, Mitchell P, Refractive status and the 5-year incidence of age-related maculopathy: the Blue Mountains eye study, Clin Exp Ophthalmol, 2004;32:255–8.
  264. Wong TY, Klein R, Klein BE, Tomany SC, Refractive errors and 10-year incidence of age-related maculopathy, Invest Ophthalmol Vis Sci, 2002;43:2869–73.
  265. Gordon R, Chatfield RK, Pits in the optic disc associated with macular degeneration, Br J Ophthalmol, 1969;53:481–9.
  266. Budde W, TJonas J, Schonherr U, Age-related macular degeneration and optic disc morphology, Am J Ophthalmol, 1999;127:220–21.
  267. Hall ER, Klein BE, Knudtson MD, et al., Age-related macular degeneration and optic disk cupping: the Beaver Dam Eye Study, Am J Ophthalmol, 2006;141:494–7.
  268. Hall NF, Gale CR, Syddall H, et al., Relation between size at birth and risk of age-related macular degeneration, Invest Ophthalmol Vis Sci 2002;43:3641–5.
  269. Liew G, Wang JJ, Klein R, et al., The relationship between birthweight and early age-related maculopathy: the atherosclerosis risk in communities study, Ophthalmic Epidemiol, 2008;15:56–61.

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