Pathophysiology of AMD

Age-related macular degeneration (AMD) is a progressively deteriorating eye condition primarily impacting the macula, the central portion of the retina responsible for high-acuity vision. AMD can be present in either one or both eyes and spares peripheral vision. Disease progression can lead to increasing difficulty with reading, recognizing faces, driving, and seeing in dim light, ending in permanent central vision loss.¹

AMD is the leading cause of vision loss and blindness in developed countries for people aged 65 and older, with 18.34 million Americans over 40 living with early-stage AMD and 1.49 million with late-stage AMD.² Many people fear vision loss due to its impact on quality of life, daily activities, and independence.³

Changes to the retina are a normal part of the aging process. The retinal pigment epithelium (RPE) supports the function of the retinal photoreceptor cells by removing metabolic wastes and transporting them through Bruch’s membrane to the choroidal vasculature. Yellow deposits composed of lipids, proteins, and cellular debris under the retina, known as drusen, can build up in the interface between RPE and Bruch’s membrane. Drusen are visible through an ophthalmoscope.^4,5

AMD is characterized by the increasing presence and size of drusen, pigmentary changes in the RPE, atrophy of retinal cells, and potentially growth of abnormal blood vessels under the retina, known as choroidal neovascularization.^4,5

Atrophic (“dry” or non-exudative) AMD

Representing the more common presentation of AMD (80%-90% of AMD cases), the atrophic type consists of the slow degeneration of RPE and retinal photoreceptors. The advanced form can present as geographic atrophy, which is a gradual deterioration of the retinal cells, leading to retinal thinning and vision loss. More uncommonly, neovascular AMD can present in 10%-20% of people with late-stage atrophic AMD.^1,2,5,8–10

Neovascular (“wet” or exudative) AMD

With a more aggressive disease progression, deterioration of vision can be rapid and severe with neovascular AMD (nAMD) with a worse prognosis than associated with atrophic AMD. Despite only accounting for 10%-20% of AMD cases, nAMD is responsible for up to 90% of AMD-related legal blindness. These new blood vessels may then bleed and leak fluid, causing the macula to bulge or lift from its normally flat position (macular edema), thus distorting or destroying central vision. Elevated macular scar (disciform scar), edema, hemorrhage, or exudation can result.^1,2,5,8–10

Visual changes may include central dark spot(s) due to blood or fluid under the macula and metamorphopsia (straight lines appearing wavy and distorted) because the macula is no longer smooth. Sometimes complaints of metamorphopsia can include windows or doors appearing curved. Because visual changes may not be perceived despite the onset of neovascularization, periodic eye examinations are important for those at high risk.^1,2,5,8–10

While not fully understood, a number of factors are implicated in the pathogenesis of AMD:^{1,2,5,6,8,14–16,21}

Vascular changes

nAMD is characterized by abnormal angiogenesis within the choroid, subretinal space, and retina, driven by angiogenic signaling molecules, including vascular epithelial growth factor (VEGF). Continued damage to the RPE leads to further dysfunction of Bruch's membrane, which in some patients, is accompanied by a rise in VEGF, resulting in the growth of new vessels under the retinal pigment epithelium and the retina. These new, fragile vessels will leak, causing fluid to build up under the retina which can result in the detachment of retinal cones and pigment cells (RPE detachment) and sudden vision loss. Eventually, a disciform scar forms in the macula characterizing end-stage nAMD. Excessive fibrosis can lead to subretinal scarring, resulting in irreversible central vision loss.