The Perfusion-Based Model of AMD: Moving Towards a Unifying Hypothesis.
Age-related macular degeneration (AMD) is a complex disease wherein age, genetics, and environment play a role. How each of these factors contribute to the overall disease initiation and progression remains largely unelucidated. A renewed examination of the existing literature regarding the blood supply to the outer retina may provide novel insights. Hypoxia in the retinal pigment epithelium (RPE) can produce features of AMD, including photoreceptor degeneration. In the macula, the choriocapillaris has unique features making it susceptible to hypoperfusion, producing low-grade ischemia and chronic tissue hypoxia. The choriocapillaris experiences vascular loss and decreased blood flow early in AMD. Genetic risk, when viewed through a new lens, points to vascular insult as central to AMD pathophysiology. Complement-related risk genes are active in the vasculature, from large tributary vessels to small vessels of the choriocapillaris. HtrA serine peptidase 1 (HTRA1) is associated with cerebral small vessel disease and localizes to the choriocapillaris in AMD. Ageing can be interpreted as inevitable atherosclerosis from large to small vessels of the cerebral system. Western diets, smoking, and a rising prevalence of metabolic syndrome in people over age 60 are confirmed to accelerate both atherosclerosis and AMD. A perfusion-based model for complement-related, soft drusen-associated AMD is proposed while also explaining a second phenotype of non-complement related subretinal drusenoid deposit-associated AMD. Common to both phenotypes of AMD is chronic hypoperfusion causing decreased oxygen exchange and waste removal at the neurovascular unit of the choriocapillaris, RPE, and photoreceptors. Understanding AMD as an end-organ vascular disease may move us towards a unifying hypothesis.