Pathogenesis and Pathophysiology of Age-Related Macular Degeneration

Pathogenesis and Pathophysiology of Age-Related Macular Degeneration

Ana Machín Mahave

Ernesto Romera Redondo

John Barnwell Kerrison


Age-related macular degeneration (AMD) is the leading cause of severe visual acuity loss in the United States among people older than 60 years, representing 54% of legal blindness (1). In the general population, the number of people in this group is increasing. As a result, vision loss from macular degeneration is a growing problem. Ninety percent of AMD patients have dry AMD, and 10% of AMD patients have wet AMD. Currently, an estimated 8 million Americans are affected with early AMD, and over 1 million will develop advanced AMD within the next 5 years (2).

Many changes in the macula could be due to normal aging. The focus of study has been which aging processes are implicated in the pathogenesis of senile macular degeneration or at what stage they become pathologic (3). The critical question to be answered is “Is AMD a normal process of aging or is it a disease by itself?” (4,5,6,7). Most of the authors defend the theory in which AMD is an advanced stage or perturbation of the normal process of eye senescence (3,4,8,9).

The pathophysiology of AMD is incompletely understood, but genetic tools offer new insights into the development and progress of AMD (10).


AMD is a multifactorial disease in which multiple genetic and environmental factors are involved.

Age: Age is the largest risk factor for AMD (11,12,13,14,15,16,17).

Smoking: The mechanism by which smoking might affect the retina is unknown; however, there exists a direct association between the risk of developing advanced AMD with the number of cigarettes smoked (18,19).

Sunlight exposure: Individuals who wore sunglasses regularly were less likely to develop soft drusen (20). Results from the Beaver Dam Study suggest that people who spent leisure time outdoors were at an increased risk of developing early AMD (21). On the other hand, some studies have shown little or no association between sunlight exposure and the risk of AMD (22,23,24).

White individuals: It is postulated that increased levels of melanin could increase the free radical scavenging potential of the retinal pigment epithelium (RPE) and Bruch’s membrane (BrM), thereby protecting against the risk of advanced AMD (25,26,27,28).

Female sex: Female gender might be a risk factor in individuals older than 75 years (29), with double the risk
of developing wet AMD in comparison with age-matched men. However, nonstatistically significant differences have been demonstrated (30).

Cholesterol levels, obesity, hypertension, cardiovascular disease, and increased dietary fat: These factors seem to be related to the risk of developing AMD, but different studies do not agree (31,32,33,34,35,36,37).

Genetics: Several studies show a genetic factor in the pathogenesis of the disease (38,39,40,41). The gene for apolipoprotein E (APOE) is the first identified susceptibility gene for AMD and has been also associated with other diseases of aging including Alzheimer’s disease. APOE epsilon 2 allele is associated with a 50% increased risk of AMD (42); however, APOE epsilon 4 allele is associated with 57% reduction in risk of wet AMD (43). Several loci have been also associated with AMD, including two major loci in the complement factor H (CFH) gene on 1q32 and the ARMS2/HTRA1 locus on the 10q26 gene cluster (44,45).

In short, genes influence many biologic pathways, but genetic susceptibility can be modified by environmental factors. Together, they are greatly predictive of onset and progression of disease (46,47).


The pathology of AMD is characterized by degenerative changes affecting outer retina (photoreceptors), RPE, BrM, and choriocapillaris. These structures, collectively called Ruysch’s complex (4,48), provide an optimal environment for retinal function—high-resolution and color vision (cones), and peripheral vision and vision at dusk (rods).

AMD can be classified according to its onset, distinguishing early and late AMD. Early pathologic changes in AMD involve basal deposits (laminar and linear) (49) in BrM, which cannot be distinguished by clinical evaluation. Late-stage AMD shows loss of RPE, decreased choriocapillaris density, and decreased lumen diameter of the choriocapillaris. There is no neovascularization in atrophic or dry AMD. In wet AMD, neovascularization, exudative change, and disciform scar formation are observed (50).


The RPE is a central element in the pathogenesis of AMD. It is a postmitotic, cuboidal monolayer of pigmented cells, which improves visual resolution and neutralizes photooxidative stress. The RPE has a very high metabolic rate and is rich in mitochondria. It is located between the neural retina and choroid. Because of its neuroectodermal origin, the RPE is considered part of the retina. The inner boundary (apical membrane) interdigitates with the outer segments of photoreceptors. The outer boundary (basolateral membrane) faces BrM forming the outer blood-retinal barrier (BRB). Functions of the RPE include regeneration of bleached visual pigments; formation and maintenance of two extracellular matrixes, the interphotoreceptor matrix and BrM; transport of nutrients, ions, and water between photoreceptors and the choriocapillaris; and phagocytosis of membranous discs of the outer segments of photoreceptors (51). Another pivotal function of the RPE is light absorption and protection against photo-oxidation. The RPE is also involved in the immune privilege of the eye through the secretion of immunosuppressant factors (52).


Transport through the RPE is bidirectional. From the sub-retinal space to choroid, the RPE transports electrolytes and water. From the blood to the photoreceptors, the RPE transports glucose and other nutrients.

Transport from blood to the photoreceptors encompasses glucose and other vital nutrients. The RPE absorbs glucose, retinol, ascorbic acid, and fatty acids in the blood and delivers them to the photoreceptor. For the transport of glucose, the RPE has high amounts of glucose transporter (GLUT) in both their apical and basolateral membranes. Another notable function of the RPE is transport of retinyl to ensure its supply to the retinal photoreceptors. In this process, many complex intermediate steps take place. A critical step involves an RPE enzyme that isomerizes all-trans-retinyl esters into 11-cis-retinal, which is essential for rod and cone function (33,53).

The delivery of the fatty acids such as docosahexaenoic acid and eicosapentaenoic acid to the photoreceptor is another important RPE function (54). These omega-3 fatty acids cannot be synthesized by the nervous tissue but are an essential component of the membranes of neurons and photoreceptors. They are synthesized in the liver from the precursor, linolenic acid, and are carried in the blood by plasma lipoproteins (33). In addition, docosahexaenoic acid is the precursor of the D1 neuroprotectin that protects RPE from oxidative stress (25,55). The main sources of omega-3 fatty acid are fish products. The Blue Mountain Eye Study and some case-control studies have found evidence of reduced risk of advanced AMD and in those who eat fish regularly (34,56,57).

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May 22, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on Pathogenesis and Pathophysiology of Age-Related Macular Degeneration

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