It is not known what specifically causes AMD. There has been a great deal of research on AMD in recent years in order to understand the course of events that underlie its emergence. Below we summarize the major theories that scientists have developed and are evaluating.

Lack of anti-oxidants
Several characteristics of the retina make it potentially susceptible to damage from oxygen. Cellular membranes of the retina have a high concentration of polyunsaturated lipids, which are particularly prone to react with oxygen and form damaged molecules. The photoreceptors and retinal pigment epithelium are exposed to unusually high concentrations of oxygen in the choroidal circulation. Finally, the lifetime exposure to light may enhance the reactivity of normal components with oxygen, compared to other tissues. The fact that the retina, particularly the macula, has high concentrations of compounds like lutein and zinc, suggests that it has developed its own natural defense mechanisms against damage from oxygen. Oxygen-damaged lipids are known to be involved in other diseases, so it is possible that they play a role in initiating AMD. On the basis of this theory, scientists have sought evidence that damaged lipids are found in diseased retina and that anti-oxidant compounds (e.g., vitamin E) protect the retina from disease.

Build-up of abnormal material in the retinal pigment epithelium
An important function of the retinal pigment epithelium is to bite off and digest the outer tips of the photoreceptors everyday. Compared to other cells in the body, the retinal pigment epithelium has the largest amount of material to digest and dispose. Much of that material ends up in distinctive granules called lipofuscin, which shine upon exposure to the right color of light. Lipofuscin accumulates with age, and its fluorescence becomes more prominent in retinal pigment epithelium cells that eventually die. Therefore, it is thought that lipofuscin contains compounds directly toxic to cells.

Genetic factors
All diseases involve a balance of inherited susceptibility and environmental influences. The relative balance of genetics and environment is not yet known for AMD. Nevertheless, there are several ways in which genetics may play a role in AMD.

First, it is known that there is a hereditable component to the disease, because identical twins and close relatives of affected individuals are more likely to develop AMD than those without relatives with the disease. Therefore, scientists have sought to identify large families of older adults who exhibit signs of the disease, so that detailed analysis of their DNA may be performed. It is possible that there is a whole battery of genes whose activity differs in patients with AMD. Recently several genes have been identified that appear to increase one’s susceptibility to AMD, and thus they are called genetic susceptibility factors. These genes include complement factor H, factor B, LOC387715, LRP, VEGF, and VLDLR.

Second, there are many rare inherited retinal diseases that affect younger adults, and a substantial number of the mutated genes have been identified. It is possible that at least some cases of macular degeneration in older adults may involve mutations of the same genes that cause disease in younger adults. So far, this has not turned out to be true, but many other genes remained to be considered.

Neovascularization: angiogenic factors and damage to Bruch’s membrane
Because neovascularization (formation of new blood vessels) accounts for the most sudden and severe loss of vision due to AMD, scientists have been particularly interested in understanding the basis of abnormal growth of new blood vessels in the eye. Current evidence from animal studies indicates that the retinal pigment epithelium actively secretes growth factors to maintain the proper health of the choroidal vessels. However, choroidal vessels do not break through Bruch’s membrane unless it is damaged. Bruch’s membrane thickens with debris and becomes calcified in older adults, which may weaken its structure, but how this happens is not yet clear.

Inflammation
Recent research from the laboratory, as well as epidemiological studies, have suggested that inflammation in the retina may contribute to the development of AMD. Inflammation could theoretically interfere with the normal function of cells in the RPE and elsewhere in the retina.

Hemodynamic model
The sclera (white of the eye) and Bruch’s membrane accumulate lipids with age. According to this theory, stiffening of sclera and Bruch’s membrane would increase blood pressure in the choriocapillaris, and the accumulated lipids damage Bruch’s membrane. Deficiencies in the choroidal vasculature or increased resistance in the capillaries could lead to ischemia (lack of oxygen) at the retinal pigment epithelium. These cells may respond by secreting factors that cause blood vessels to multiply to make up for the low oxygen. The combination of increased blood pressure, damage in Bruch’s membrane, and poor oxygenation of the retinal pigment epithelium could lead to neovascularization.

Response-to-retention of a “bad cholesterol” particle produced in the eye
This is a new theory based on work done here at UAB and also based on well-studied principles in cardiovascular disease. In the coronary arteries that supply the heart, cholesterol builds up in the vessel wall, due to the influx of cholesterol-carrying particles from the blood. Local cells respond to the build-up by secreting factors that destabilize the vessel wall, causing rupture and hemorrhage. Cholesterol also builds up in Bruch’s membrane and drusen, but it is possible that the cholesterol comes from the retinal pigment epithelium rather than the blood.