What Causes Macular Drusen?

Drusen is a German word meaning “geode.” Since they are the defining feature of age-related macular degeneration (AMD), it’s important to understand what causes them to form. Understanding these mechanisms may lead to treatments that decrease the risk of disease progression.

Drusen are the defining feature of AMD. They are tiny deposits under the retina that the eye doctor can see during an exam. They can also be photographed with a retina camera or using an imaging device called optical coherence tomography (OCT), which shows a cross-section of the retina and underlying drusen.

The Size and Number of Drusen are Important

Drusen are about the width of a pinhead and are composed of a mixture of proteins and lipids (naturally occurring molecules that include fats). They often cause no symptoms, but can occasionally cause visual distortion if they are very large and near the center of the retina.

The size and number of drusen are very important, as larger numbers of drusen, as well as drusen of larger size, indicate a higher risk for some vision loss in the future. Whereas the chance of a person with a few small drusen losing some central vision from AMD in a five-year timeframe is only a few percent, the chance may be as high as 50 percent over the same timeframe for certain people with many intermediate and large-size drusen.

Drusen Contain a Complex Mixture of Proteins and Fats

To begin to discover why drusen form, researchers first investigated the contents of drusen. They are a complex mixture of proteins and fats. Several of the proteins are involved in immunity. These proteins normally function in a part of the immune system called the complement cascade, which can regulate white blood cells and poke holes in the membranes of invading bacteria. However, in patients with AMD, several complement proteins accumulate in drusen. The possibility that abnormal activity of the complement cascade is involved in AMD is strengthened by genetic studies showing that people with DNA sequence changes in several complement genes have an increased risk of AMD.

Beta Amyloid

Another protein in drusen is beta-amyloid. This protein is also found outside of neurons in the brains of patients with Alzheimer’s disease, suggesting that the mechanisms of AMD and Alzheimer’s disease may be related. However, most patients with AMD do not have Alzheimer’s disease. So far, therapies aimed at preventing beta-amyloid formation or promoting the removal of amyloid beta in AMD have failed in clinical trials.

Cholesterol

Lipids, including certain forms of cholesterol, also accumulate in drusen, and genetic studies implicate lipids in AMD. A small study enrolling patients with very large drusen near the center of the retina showed that relatively high doses of a cholesterol-lowering statin drug were associated with drusen shrinkage and vision improvement. However, other recent large scale retrospective studies have shown that statin use at typically prescribed doses does not significantly slow formation of drusen. Further studies are needed before this approach can be widely recommended.

Pseudodrusen

Recently, researchers have come to recognize a second kind of deposit that, while appearing similar to drusen, occurs in a different place within the retina. While trypical drusen forms underneath the retinal pigment epithelium (RPE), this new kind of deposit, called “reticular pseudodrusen” or “subretinal drusenoid deposits,” collects in the narrow space between the RPE and light-sensing photoreceptors. Found in about 30-40% of eyes with intermediate AMD and most that have developed GA, “pseudodrusen” contain a different mixture of fats compared to ordinary drusen. This suggests they form through similar but distinct processes compared to traditional drusen.

Cleaning Up Drusen

In February 2023, the U.S. Food and Drug Administration (FDA) approved Syfovre for the treatment of geographic atrophy (GA), the severe or late-stage form of dry AMD. Later that year, the FDA approved Izervay as the second treatment for GA. Both work by blocking the complement cascade, and both are delivered as injections.

Dr. Pamela Weber spoke with BrightFocus Foundation in 2025 about both options, including information about what to discuss with your healthcare team when deciding whether to pursue treatment.

Another treatment approach aiming to reduce drusen is light therapy, which uses special colors of red and near-infrared light to help cells in the eye make more energy. A clinical study of a device called the Valeda® Light Delivery System showed that people with intermediate dry AMD who received light therapy had reduced drusen that was accompanied by slower disease progression and improved vision on eye charts.

Dr. Richard Rosen was featured on a 2025 Molecular Chat episode where he discussed light therapy in more detail.

In addition to these treatments, research continues to increase understanding of how drusen form and what could be done to slow or stop them. A study in mice showed that inhibiting the activity of a certain type of white blood cell, called macrophage, leads to the formation of drusen-like deposits in the retina. Since macrophages normally clean up unwanted debris or “garbage” outside of cells, the study suggests that macrophages clean up drusen before they accumulate to a clinically detectable size. Impaired macrophage function may contribute to drusen accumulation in patients.

Other studies have used cultured retinal pigment epithelial cells, the cells overlying drusen, grown in plastic dishes. Over weeks to months, these isolated cells excrete material that builds up underneath the cells and, in many ways, resembles drusen. This excreted material is probably some of the “garbage” that macrophages need to clean up to prevent drusen formation.

Mutated Enzymes

Another line of research has shown that patients with a rare form of hereditary drusen, as well as mice that model this disease, have a mutation in an enzyme that normally helps to maintain the normal structure of the membrane underneath the RPE cells, called Bruch’s membrane. So this indicates that proper maintenance of this membrane is important.

Drusen: Putting the Research Pieces Together

Taken together, these findings suggest that drusen form because RPE cells extrude (force out) unwanted or damaged proteins and lipids, which can then accumulate in Bruch’s membrane. Proteins from the complement cascade, along with minerals such as calcium, phosphate, zinc, and iron, then stick to this material, enlarging it and holding it together. Impaired macrophage function could contribute due to failure to clean up the “garbage.”

Whether the drusen are a cause or consequence of the disease process is unclear, but it seems likely that they are at least partly causal, as they can disrupt the flow of materials between the RPE and bloodstream, and they can distort the single layer of RPE cells. This may disrupt the blood-retina barrier function of the RPE. Consistent with this, a recent study from my laboratory suggests that eyes containing drusen leak blood components into the retina.

Since drusen are the defining feature of AMD, and their number and size are associated with the risk of vision loss from AMD, an increased understanding of drusen is likely to lead to new vision-saving drugs or treatments.