Etiology of Late Age-Related Macular Disease

Etiology of Late Age-Related Macular Disease

Maximiliano Olivera


Age-related macular disease (AMD) is a chronic, progressive disease of the retina, specifically the macula. AMD is an important cause of vision loss in the United States and all over the world. AMD, in all of its forms, has an overall prevalence of 6.5%, but some demographics, such as non-Hispanic White people, have a higher incidence (7.3%). Non-Hispanic Black people have a lower incidence rate (2.4%). The incidence of AMD increases with age. The incidence in individuals over 60 years old is 13.4% compared to an incidence in the 40- to 59-year-old group of 2.8% (1).

Like many other chronic diseases, it is important to understand its complex pathophysiology in order to develop screening and treatment strategies. Although we do not have a complete understanding of the complex pathophysiology of AMD, several studies over the last 20 years have identified many environmental and genetic risk factors. Identification of risk factors allows for the development of screening strategies in order to make a diagnosis as early as possible, improving the chances of a better visual outcome. For example, the understanding of pathophysiologic mechanisms involved in the development and progression of neovascular AMD, such as the role of the vascular endothelial growth factor (VEGF), permitted the design and development of anti-VEGF therapy for AMD. This has resulted in a radical change in the expectations for patients and physicians (2).


AMD is not only about changes in the eye fundus examination. To diagnose AMD and determine what kind of AMD the patient has, it is important to consider the patient’s symptoms.

In addition, it is important to understand that the aging eye is associated with certain changes (3). Most of these changes are almost clinically undetectable, and patients have no visual symptoms at all. These changes include the following:

  • ▪ A decrease in density and distribution of photoreceptors

  • ▪ Loss of melanin granules, lipofuscin accumulation, and residual body accumulation in the retinal pigment epithelium (RPE)

  • ▪ Accumulation of basal lamellar deposits, formed by a lipidrich granular material and collagen fibers, between the lamina basalis (plasma membrane) of the RPE cells and inner face of the basal membrane of RPE

  • ▪ Changes in choriocapillaris

The characteristic physical sign of AMD is the presence of drusen. Drusen are small, rounded, yellowish lesions located beneath the RPE, inner to the Bruch’s membrane. Drusen are classified by size: small (diameter less than 64 µm), intermediate (diameter between 64 and 124 µm), and big (diameter 125 µm or above). They may
also be classified by the discreteness of their boundaries: hard (well defined), soft (not well defined), and confluent (contiguous limits between drusen).

In addition to drusen, other physical signs such as RPE hyper- and hypopigmentation, RPE atrophy, RPE detachments, choroidal neovascular membranes (CNVM), and hemorrhages give us information about the clinical status of the patient with AMD. Clinically, it is useful to classify AMD into early/late or dry/wet.

Early AMD

Early AMD is usually asymptomatic and clinically presents with drusen and RPE changes consisting of focal hyper- or hypopigmentation.

Late AMD

The main characteristic of late AMD is severe loss of vision.

The late stages of AMD have two different forms (dry and wet), although both forms may occur simultaneously in the same eye. Over time, dry AMD may develop to wet AMD.


Patients with dry AMD have poor visual acuity, hyperpigmented RPE spots (usually juxtafoveal), and an area with visible choroidal vessels. Choroidal vessels are visible because the RPE cells over them have become atrophic. As these areas become confluent, they take on an appearance referred to as geographic atrophy. No neovascularization is present.


Wet AMD is characterized by the presence of CNVM. Patients with wet AMD may experience a sudden onset of decreased visual acuity, metamorphopsia, and paracentral scotoma. Clinical findings include subretinal fluid, subretinal or sub-RPE hemorrhages, subretinal or intraretinal lipids, pigmentary subretinal ring, RPE irregularities and detachment, gray-white subretinal lesions, and cystoid macular edema (3).


Incidence of AMD

According to the 2005-2008 NHANES (National Health and Nutrition Examination Survey) (1), the most AMD-compatible lesions were found in persons aged 60 or older in all the three ethnic groups studied (non-Hispanic Black, non-Hispanic White, and Mexican American). The incidence of early AMD is similar for non-Hispanic White persons aged 40 to 59 years (3%) and Mexican American persons aged 40 to 59 years (2.7%). The incidence of early AMD is lowest in non-Hispanic Black persons. Late AMD was more prevalent in non-Hispanic White persons.

The estimated total prevalence of any AMD in the US population aged 40 or older was 6.5%. Of a total of 7.2 million persons having any kind of AMD, 0.89 million (95% CI, 552,000-1.2 million) were estimated to have late AMD (see Ref. (1) for more details).

Risk Factors for AMD

The most important risk factor for AMD is age, but over the years, many factors, including genetic, demographic, behavioral, dietary, and other factors, have been studied as risk or protective factors for AMD. The AREDS (Age-Related Eye Disease Study) was a clinical trial sponsored by the National Eye Institute, one of the National Institutes of Health in the United States. The trial was designed to investigate the natural history and risk factors for AMD and cataracts and to evaluate the effect of high doses of antioxidants and zinc on the progression in patients with AMD. This study describes the demographic, behavioral, medical, and nonretinal factors associated with progression to neovascular AMD and central geographic atrophy (CGA).

Of all the studied factors, only a few were statistically associated with AMD. Subjects with advanced AMD, relative to the early AMD group, tend to be older, have fewer years of formal education, smoke more, have higher body mass index (BMI), have higher blood pressure, be myopic, have a history of angina, be more likely to have a lens opacity, and be less likely with hormone replacement therapy. Neovascular AMD was associated with white race and smoking more than 10 pack-years. CGA was associated with fewer years of formal education, being obese (higher BMI), smoking more than 10 pack-years, and not using antiacids (4).

There were also some other weak associations, such as diabetes, use of nonsteroidal anti-inflammatory agents, and hormone replacement therapy, that were reported in other studies (5,6,7,8,9,10,11,12,13,14) but not fully demonstrated on AREDS. Of note, hormone replacement therapy was reported to be a protective factor in some patients with specific polymorphisms in ARMS2 (HtrA serine peptidase 1) (15).

In contrast to risk factors for progression to neovascular AMD and CGA, black race (16,17); increased intake of docosahexanoic acid (18), monounsaturated fatty acids (19), fish (20,21,22), and dark green leafy vegetables (23); and higher levels of serum carotenoids (24) were associated with a lower risk of progression.


Patients with a positive familiar history of AMD have a higher risk of development of this disease (8,25,26). Late AMD is a polygenic disease. No single-gene defect accounts for disease. There are variations and defects in
genes functionally related to complement and immune processes, high-density lipoprotein (HDL) cholesterol, and mechanisms involving collagen formation, extracellular matrix production, and angiogenesis considered to be associated with the onset, progression, and bilateral involvement of early, intermediate, and advanced states of AMD (see Table 4.1 and Refs. (27,28,29,30,31,32,33,34) for more details) (35). Several pharmacogenetic studies found that variants in some genes are related to different treatment outcomes (Table 4.2) (36).



ATP-binding cassette transporter; chr 1


Apolipoprotein E; chr 19


HtrA serine peptidase 1; chr 10


Complement factor 1; chr 4


Complement component 2; chr 6


Complement component 3; chr 19


Choleterylester transfer protein; chr 16


Complement factor B; chr 6


Complement factor H; chr 1


Collagen type 8 alpha 1 subunit; chr 3


Fyn-related kinase/alpha chain of type X collagen; chr 6


Hepatic lipase; chr 15


Tissue inhibitor of metalloproteinase 3; chr 22


Toll-like receptor 3; chr 4


Tumor necrosis factor receptor superfamily 10a; chr 8


Vascular endothelial growth factor A; chr 6

Adapted from Lim LS, Mitchell P, Seddon JM, et al. Age-related macular degeneration. Lancet. 2012;379:1728-1738.

Genetic variations in genes encoding the complement proteins and regulators have been identified as protective or risk factors for AMD. Many of them are single nucleotide polymorphisms (SNPs), causing a change of a single amino acid in the polypeptide chain that could affect the binding affinity of the complement protein to its substrates. This suggests that certain individuals with some of these variations may be genetically predisposed to AMD. Variations of the complement system likely interact with environmental risk factors to determine overall risk.

Complement Factor H

Complement factor H (CFH), an important regulator of the alternative pathway, was the first complement protein to be implicated in the pathogenesis of AMD. Physiologically, CFH binds C3b and accelerates the decay of the alternative C3 convertase (C3bBb) and acts as cofactor for the inactivation of C3b by complement factor I (CFI) (37). CFH is produced locally in the eye by the RPE cells (38) and accumulates in the drusen, sub-RPE space, RPE, interphotoreceptor matrix, and choroid (38,39). Environmental factors vary CFH production by the RPE cells. In vitro studies show an increase in RPE CFH production by interferon gamma (40) and reduction in conditions of oxidative stress (38).

The CFH gene is located at chromosome position 1q23. Mutations of this gene manifest as dominant mendelian disorders (41). In 2005, three groups simultaneously (27,42,43) reported a nonsynonymous SNP in the CFH gene (rs1061170), resulting in a substitution of tyrosine by histidine at position 402 of the polypeptide (Y402H), which was important in the development of AMD. This change alters the ligand binding site of CRP (C-reactive protein), heparin, M protein, and glycosaminoglycans, probably leading to a reduced binding to cell surfaces and therefore impaired regulation of the alternative C3 convertase (44). A meta-analysis (45) suggested that this variant (Y402H) is a contributing factor in over half of all cases of AMD. Other SNPs throughout the CFH gene, including the SNP 162 V (38), resulting in substitution of isoleucine with valine residue within the C3b binding site, have been associated with AMD (32,38,41,46,47,48,49,50) and AMD progression (51,52,53,54,55).

Variations in VEGF Gene

Some authors (56,57,58) proposed that the SNP A/A in the allele rs3024997 and G/G re2010963 in the VEGF gene are associated with a better response to antiangiogenic (bevacizumab) therapy with regard to visual acuity outcomes. In a more recent study (59), using a multivariate data analysis and a higher number of patients, this SNP was not found to be associated with a different response to antiangiogenic therapy.


In order to understand AMD, it is important to understand the physiologic aging of the eye. The age-related changes in the retina that predispose a person to AMD occur in the outer retina: the photoreceptors (PRs), the RPE, the Bruch’s membrane, and the choriocapillaris. Most of these changes are not clinically detectable until a late stage, when they start to affect the visual function of the patients.

The Photoreceptors

PR cells translate light into electric activity that can be understood by the brain and central nervous system.
Anatomically, PR cells have four different regions: the outer segment (OS), the inner segment, the cell body, and the synaptic terminal. The OS of the PR is composed of membranous disks, which have a high concentration of visual pigment. Rhodopsin, the visual pigment of rods, is a G protein-coupled receptor that when stimulated by a photon of light undergoes a conformational change initiating a series of biochemical steps leading to the onset of the electric activity (3). Numerous studies of the human and animal retina show that excessive light exposure leads to photochemical injury causing damage to the outer segment of the PR. Excessive light exposure is considered to be an environmental factor associated with AMD (60), but the magnitude of this risk is hard to evaluate and is controversial. Even under normal light conditions, the PR incurs significant oxidative stress, due to the great energy requirement for visual phototransduction (61). This stimulation increases the oxygen-reactive species, damaging DNA and other macromolecular complexes important for the PR survival (62,63). For a longterm survival of the PR cells, it is important to have a healthy RPE participating in the visual cycle, renewing the PR OSs and producing the interphotoreceptor cell matrix (3).






Photodynamic therapy



(Y402H) Controversial: Outcome for CC genotype lagged CT and TT; outcome for TT was poor; no genotype association


Rs10490924 (A69S)

No significant genotype association


Rs2808635, Rs2146323

Anatomic outcome was strongly associated with SNPs.


Rs2808635, Rs876538

Positive response was significantly associated with both variants.



No significant association



Better outcome associated in patients carrying both genetic variants





Better outcome associated with variants



Better outcome associated with variants

Intravitreal bevacizumab


Rs1061170 (Y402H)

CC genotype responded significantly better than TC and TT. CC genotype more likely to require reinjection


Rs10490924 (A69S)

No significant association

Antioxidants and zinc


Rs1061170 (Y402H)

TT genotype responds better than CC.


Rs10490924 (A69S)

No significant association

Adapted from Chen Y, Bedell M, Zhang K. Age-related macular degeneration: genetic and environmental factors of disease. Mol Interv. 2010;10(5):271-281.

The Retinal Pigment Epithelium

The RPE is a postmitotic, cuboidal monolayer of cells located between the neural retina and the Bruch’s membrane. Physiologically, it has a very high metabolic rate and performs several important functions for the retina. Of all the functions of the RPE, the most important for understanding AMD (64) are the following:

  • ▪ Regeneration of bleached visual pigments (opsins)

  • ▪ Formation and maintenance of the interphotoreceptor matrix and Bruch’s membrane

  • ▪ Transport of fluids and ions between PRs and choriocapillaris

  • ▪ Phagocytosis

The reconstitution of the visual pigment rhodopsin occurs mainly in the RPE cells, through many intermediate steps. This mechanism has a key role for normal function of both cones and rods, transforming the all-trans-retinyl esters into 11-cis-retinal (65). As a phagocytic system, the RPE is essential for the renewal of PRs (66). Each PR has hundreds of disks in its outer segment. These disks are formed by plasma membrane, containing transmembrane protein rhodopsin, which is positioned in combination with four phospholipids and docosahexanoic acid. The OS disks
of the PR cells are engulfed by the RPE. In the RPE, the disks fuse with lysosomes, forming phagolysosomes, where the contents are degraded. In young, healthy individuals, most of the disks are fully degraded, and lipofuscin accumulation is minimal, but over time, the self-limited phagocytic and degradative capacity of the RPE cells becomes more and more overloaded. This incompletely degraded membrane material accumulates in the form of lipofuscin in secondary lysosomes or residual bodies (67).

Lipofuscin is a yellow-brown, autofluorescent molecule that accumulates in all postmitotic cells, particularly the RPE (68,69,70,71). The presence of lipofuscin may act as a cellular aging indicator, and its quantity in tissues may be estimated by amounts of autofluorescence present. The autofluorescence from the eye fundus, mostly derived from lipofuscin, can be clinically and noninvasively quantified, allowing for an estimate of the aging degenerative process of the eye and a diagnostic and follow-up method for patients with AMD (72). Some factors increase (vitamin E deficiency) while others decrease (oxygen-free conditions and vitamin A deficiency) lipofuscin pigment formation.

The retinoid A2E is the major fluorophore of lipofuscin (73). Once it is synthesized, it cannot be eliminated by the RPE. Precursors of A2E, all-trans-retinal and ethanolamine, are formed within the PRs (74), but the fully synthesized A2E molecule arises from the phagolysosomal compartment of the RPE cells. When it reaches a critical concentration, the metabolism of phagocytized OS lipids by the RPE is impaired. Phagocytized and oxidized OS membranes are extruded by the RPE into the Bruch’s membrane, contributing to drusen formation and membrane thickening.

A2E is toxic for the RPE. It inhibits the proton pump of lysosomes (75), causing leakage of the contents of the lysosomes into the cytoplasm of RPE cells. It inhibits phagolysosomal degradation of PR phospholipids (76) and can also damage the DNA of RPE cells. A2E also accumulates in the mitochondrial membranes, decreasing mitochondrial activity and enabling the translocation of cytochrome C and AIF (apoptosis-inducing factor) to the cytosol and nucleus, respectively. Functionally, the release of cytochrome C from the inner mitochondrial membrane generates oxidative stress and decreased electron flow, leading to impaired ATP synthesis. Both mechanisms are highly relevant for apoptosis by causing leakiness of the inner mitochondrial membrane and release of the propapoptotic proteins, activating the caspase cascade. AIF is a pro-apoptotic protein, which is strictly located in the mitochondria. Its translocation to the nucleus induces apoptosis, functionally independent from caspases (77). A2E also inhibits the normal activity of the enzyme RPE65 isomerohydrolase, a key enzyme of the visual cycle, which is responsible for the isomerization of all-trans-retinyl ester to 11-cis-retinol, the precursor of 11-cis-retinal (78

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May 22, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on Etiology of Late Age-Related Macular Disease

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