amd is found on chromosome 10q26 at loc 387715. an insertion/deletion polymorphism at this site reduces expression of the arms2 gene though destabilization of its mrna through deletion of the polyadenylation signal. arms2 protein may localize to the mitochondria and participate in energy metabolism, though much remains to be discovered about its function. other gene markers of progression risk includes tissue inhibitor of metalloproteinase 3 (timp3), suggesting a role for extracellular matrix metabolism in amd progression. variations in cholesterol metabolising genes such as the hepatic lipase, cholesterol ester transferase, lipoprotein lipase and the atp-binding cassette a1 correlate with disease progression. the early stigmata of disease, drusen, are rich in cholesterol, offering face validity to the results of genome-wide association studies. stages in amd there is a progressive accumulation of characteristic yellow deposits, called drusen (buildup of extracellular proteins and lipids), in the macula (a part of the retina), between the retinal pigment epithelium and the underlying choroid. this accumulation is believed to damage the retina over time. amyloid beta, which builds up in alzheimer's disease brains, is one of the proteins that accumulate in amd, which is a reason why amd is sometimes called "alzheimer's of the eye" or "alzheimer's of the retina". amd can be divided into 3 stages: early, intermediate, and late, based partially on the extent (size and number) of drusen. amd-like pathology begins with small yellow deposits (drusen) in the macula, between the retinal pigment epithelium and the underlying choroid. most people with these early changes (referred to as age-related maculopathy) still have good vision. people with drusen may or may not develop amd. in fact, the majority of people over age 60 have drusen with no adverse effects. the risk of developing symptoms is higher when the drusen are large and numerous, and associated with the disturbance in the pigmented cell layer under the macula. large and soft drusen are thought to be related to elevated cholesterol deposits. early amd early amd is diagnosed based on the presence of medium-sized drusen, about the width of an average human hair. early amd is usually asymptomatic. intermediate amd intermediate amd is diagnosed by large drusen and/or any retinal pigment abnormalities. intermediate amd may cause some vision loss, but, like early amd, it is usually asymptomatic. recently, subgroups of intermediate amd have been identified, which have a very high risk of progression toward late amd. this subgroup (depending on the precise definitions) is termed nascent ga and/or irora (incomplete retinal pigment epithelium and outer retinal atrophy). these 'high-risk' subgroups of intermediate amd can be used to inform patients of theirs prognosis. in addition, these can be applied in clinical trials as endpoints. late amd in late amd, enough retinal damage occurs that, in addition to drusen, people will also begin to experience symptomatic central vision loss. the damage can either be the development of atrophy or the onset of neovascular disease. late amd is further divided into two subtypes based on the types of damage: geographic atrophy and wet amd (also called neovascular amd). dry amd dry amd (also called nonexudative amd) is a broad designation, encompassing all forms of amd that are not neovascular (wet amd). this includes early and intermediate forms of amd, as well as the advanced form of dry amd known as geographic atrophy. dry amd patients tend to have minimal symptoms in the earlier stages; visual function loss occurs more often if the condition advances to geographic atrophy. dry amd accounts for 80–90% of cases and tends to progress slowly. in 10–20% of people, dry amd progresses to the wet type. geographic atrophy geographic atrophy (also called atrophic amd) is an advanced form of amd in which progressive and irreversible loss of retinal cells leads to a loss of visual function. there are multiple layers that make up the retina, and in geographic atrophy, there are three specific layers that undergo atrophy: the choriocapillaris, retinal pigment epithelium, and the overlying photoreceptors. the three layers that undergo atrophy in geographic atrophy are all adjacent to each other. the photoreceptors are the most superficial and they are the cells that are responsible for converting energy from the light from the outside world, into an electrical signal to be sent to the brain. there are several functions of the retinal pigment epithelium. one of the main functions of the retinal pigment epithelium is to minimize oxidative stress. it does so by absorbing light, and thus preventing it from getting to the underlying layers. the layers underlying the retinal pigment epithelium are very vascularlized so they have very high oxygen tension. thus, if light was to get to those layers, many free radicals would form and cause damage to nearby tissues. the deepest layer that undergoes atrophy in geographic atrophy is called the choriocappilaris. it is a capillary network that provides nutrients to the retinal pigment epithelium. the pathophysiology of geographic atrophy is still uncertain. some studies questioned whether it was due to a deficient retinal pigment epithelium, leading to increased oxidative stress. other studies have looked for inflammatory causes of damage. thus far, the medical community is still not certain. recent studies have begun to look at each layer individually. they found that decrease blood flow in the choriocapillaris precedes atrophy of the retinal pigment epithelium and the overlying photoreceptors. since the choriocapillaris is a vascular layer, this may be used as an argument for why geographic atrophy could be a disease due to decreased blood flow. wet amd neovascular or exudative amd, the "wet" form of advanced amd, causes vision loss due to abnormal blood vessel growth (choroidal neovascularization) in the choriocapillaris, through bruch's membrane. it is usually, but not always, preceded by the dry form of amd. the proliferation of abnormal blood vessels in the retina is stimulated by vascular endothelial growth factor (vegf). because these blood vessels are abnormal, these are also more fragile than typical blood vessels, which ultimately leads to blood and protein leakage below the macula. bleeding, leaking, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors and rapid vision loss if left untreated. diagnosis super resolution microscopic investigation of human eye tissue affected by amd diagnosis of age-related macular degeneration depends on signs in the macula, not necessarily vision. early diagnosis of amd can prevent further visual deterioration and potentially improve vision. diagnosis of dry (or early stage) amd may include the following clinical examinations as well as procedures and tests: the transition from dry to wet amd can happen rapidly, and if it is left untreated can lead to legal blindness in as little as six months. to prevent this from occurring and to initiate preventive strategies earlier in the disease process, dark adaptation testing may be performed. a dark adaptometer can detect subclinical amd at least three years earlier than it is clinically evident. there is a loss of contrast sensitivity, so that contours, shadows, and color vision are less vivid. the loss in contrast sensitivity can be quickly and easily measured by a contrast sensitivity test like pelli robson performed either at home or by an eye specialist. when viewing an amsler grid, some straight lines appear wavy and some patches appear blank when viewing a snellen chart, at least 2 lines decline in dry macular degeneration, which occurs in 85–90 percent of amd cases, drusen spots can be seen in fundus photography using an electroretinogram, points in the macula with a weak or absent response compared to a normal eye may be found farnsworth-munsell 100 hue test and maximum color contrast sensitivity test (mccs) for assessing color acuity and color contrast sensitivity optical coherence tomography is now used by most ophthalmologists in the diagnosis and the follow-up evaluation of the response to treatment with antiangiogenic drugs. diagnosis of wet (or late stage) amd may include the following in addition to the above tests: preferential hyperacuity perimetry changes (for wet amd). preferential hyperacuity perimetry is a test that detects drastic changes in vision and involves the macula being stimulated with distorted patterns of dots and the patient identification of where in the visual field this occurs. in wet macular degeneration, angiography can visualize the leakage of bloodstream behind the macula. fluorescein angiography allows for the identification and localization of abnormal vascular processes. histology pigmentary changes in the retina – in addition to the pigmented cells in the iris (the colored part of the eye), there are pigmented cells beneath the retina. as these cells break down and release their pigment, dark clumps of released pigment and later, areas that are less pigmented may appear exudative changes: hemorrhages in the eye, hard exudates, subretinal/sub-rpe/intraretinal fluid drusen, tiny accumulations of extracellular material that build up on the retina. while there is a tendency for drusen to be blamed for the progressive loss of vision, drusen deposits can be present in the retina without vision loss. some patients with large deposits of drusen have normal visual acuity. if normal retinal reception and image transmission are sometimes possible in a retina when high concentrations of drusen are present, then, even if drusen can be implicated in the loss of visual function, there must be at least one other factor that accounts for the loss of vision. management treatment of amd varies depending on the category of the disease at the time of diagnosis. in general, treatment is aimed at slowing down the progression of amd. as of 2018, there are no treatments to reverse the effects of amd. early-stage and intermediate-stage amd is managed by modifying known risk factors such as smoking cessation, management of hypertension and atherosclerosis and making dietary modifications. for intermediate-stage amd, management also includes antioxidant and mineral supplementation. advanced-stage amd is managed based on the presence of choroidal neovascularization (cnv): dry amd (no cnv present) or wet amd (cnv present). no effective treatments exist for dry amd. the cnv present in wet amd is managed with vascular endothelial growth factor (vegf) inhibitors. daily use of an amsler grid or other home visual monitoring tools can be used to monitor for development of distorted vision, which may be a sign of disease progression. dietary supplements the age related eye disease studies 1 and 2 (areds) showed that those with bilateral early or intermediate amd, or intermediate amd in one eye and advanced amd in the other eye may benefit from specific vitamin and mineral supplementation. the specific vitamins and minerals in areds-1 are vitamin c (500 mg), zinc (80 mg), vitamin e (400 iu), copper (2 mg) and beta-carotene (15 mg). in the areds-2 formulation, lutein (10 mg) and zeaxanthin (2 mg) replaced beta-carotene due to the risk of lung cancer in smokers taking beta-carotene. these specific micronutrient supplementations were associated with a lower risk of progression to more severe forms of amd and greater visual acuity at 5 years. there is no evidence that micronutrient supplementation prevents amd progression in those with severe disease or prevents disease onset in those without amd. dry amd there is no cure for dry amd. while there is increasing academic and pharmaceutical interest in developing complement inhibitors to treat ophthalmic inflammation, with several clinical trials underway for dry amd, the first such agent to complete phase 3 trials in amd (the anti-factor d agent, lampalizumab) did not significantly improve the rate of disease progression. nevertheless, strategies targeting different aspects of the complement system are ongoing. wet amd ranibizumab, aflibercept, brolucizumab and faricimab are approved vegf inhibitors for the treatment of cnv in wet amd. all three drugs are administered via intravitreal injection, meaning they are injected directly into the eye. bevacizumab is another vegf inhibitor that has been shown to have similar efficacy and safety as the previous two drugs, however, is not currently indicated for amd. amd can also be treated with laser coagulation therapy. a randomized control trial found that bevacizumab and ranibizumab had similar efficacy, and reported no significant increase in adverse events with bevacizumab. a 2014 cochrane review found that the systemic safety of bevacizumab and ranibizumab are similar when used to treat neovascular amd, except for gastrointestinal disorders. bevacizumab however is not fda approved for treatment of macular degeneration. a controversy in the uk involved the off-label use of cheaper bevacizumab over the approved, but expensive, ranibizumab. ranibizumab is