Age-related macular degeneration (AMD) is a disease that causes atrophic or exudative changes in the macula due to age-related changes. It is considered a multifactorial disease involving genetic predisposition and environmental factors such as aging, smoking, sunlight exposure, obesity, and high-fat diet.
Conventionally, AMD was defined as age-related macular abnormalities within a 6,000 μm diameter centered on the fovea in individuals aged 50 years or older. However, the 2024 Japanese clinical guidelines removed the age criterion from the diagnostic criteria and classify AMD into early AMD, intermediate AMD, late AMD, and end-stage AMD1). Late AMD includes neovascular AMD with MNV and atrophic AMD with GA. AMD is a major cause of visual impairment in Japan1).
Japanese epidemiological studies have shown that AMD and its precursor lesions increase with aging. Smoking is an important modifiable risk factor for AMD, and smoking cessation guidance is important from the perspective of prevention and progression control1)2).
There are racial differences, with higher prevalence in Caucasians and Asians, and lower in Hispanics and African Americans2). The prevalence of atrophic AMD is reported to be 0.66–1.34% in Western studies, and in those aged 85 years or older, it is reported to be four times more frequent than neovascular AMD. This is likely to become a major issue in Japan as the population ages. Worldwide, approximately 200 million people are affected by AMD, and this number is projected to increase to approximately 288 million by 20402). The prevalence of late AMD increases exponentially with age, from 0.1% in those aged 50–59 years to 4.3% in those aged 80 years or older2).
The latest Japanese clinical practice guidelines (2024) classify AMD into the following four stages based on the Beckman classification1).
| Stage | Characteristics |
|---|---|
| Early AMD | One or more medium soft drusen (63 to <125 μm) |
| Intermediate AMD | Large drusen (≥125 μm), RPE abnormalities, subretinal drusenoid deposits |
| Late AMD | Presence of macular neovascularization (MNV) (including PNV) or geographic atrophy |
| End-stage AMD | Fibrotic scar or severe vision loss due to cystoid macular degeneration |
Small (hard) drusen (<63 μm) are considered physiological aging changes and are not included in early AMD. However, if numerous (20 or more) hard drusen are present, the risk of developing AMD is high1). The 5-year progression rate for intermediate AMD is approximately 18%, but the risk increases markedly in the presence of reticular pseudodrusen (5-year risk 72% with pigmentary abnormalities + large drusen + reticular pseudodrusen)2).
Neovascular AMD
Macular neovascularization (MNV): New blood vessels originating from the choroid or retinal vessels develop in the macula, causing sudden vision loss.
Types: Classified into type 1 MNV (sub-RPE), type 2 MNV (supra-RPE), type 3 MNV (retinal angiomatous proliferation, RAP), and PCV (type 1 MNV with polypoidal lesions)1).
Characteristics in Japan: About half of neovascular AMD cases are pachychoroid neovasculopathy (PNV), and drusen are seen in only about 30% of cases1).
Atrophic AMD
Geographic atrophy (GA): Characterized by well-demarcated atrophy of the RPE, photoreceptors, and choriocapillaris.
Natural course: Begins around the fovea and expands in a horseshoe shape, then ring-shaped. Growth rate is 1.28–2.6 mm²/year3).
MNV during progression: MNV may develop during the course of geographic atrophy; if exudative changes appear, it should be evaluated and treated as neovascular AMD.
This disease requires attention for bilaterality. If one eye has late-stage AMD, the fellow eye is at risk of developing MNV. The ARMS2 genotype has been reported as a predictor of fellow eye involvement1). Regular eye examinations and self-checking with an Amsler grid are recommended.
Early stages begin with metamorphopsia (distorted vision) and central scotoma. As it progresses, visual acuity may drop below 0.1. In cases of massive hemorrhage, sudden severe vision loss can occur.
In cases of unilateral onset, it is often not noticed in daily life. The severity of symptoms varies depending on the location and size of MNV, and the extent of subretinal fluid, hemorrhage, and fibrous scarring. In the neovascular type, the time to legal blindness tends to be shorter than in the atrophic type, and prompt consultation is recommended when metamorphopsia appears.
Yellow-white small round elevated lesions seen in the macula, consisting of polymorphous material (membranous debris, unesterified cholesterol, complement, etc.) accumulated between the RPE basement membrane and the inner collagenous layer of Bruch’s membrane. They are considered the origin of chronic inflammation, which is the core of AMD pathology.
Geographic atrophy is a well-demarcated area of RPE atrophy through which choroidal vessels are visible. The lesion begins in the perifoveal area, expands in a horseshoe shape to a ring shape, and progresses to the fovea. The median time to foveal involvement is 2.5 years3). The growth rate is 1.28–2.6 mm²/year; in ranibizumab trial data, GA area increased from an average of 8.07 to 12.05 mm² over 2 years3). Multifocal GA has a faster growth rate than unifocal GA3).
Rapid atrophy progression may occur when a large drusenoid PED regresses. Hyperautofluorescence patterns at the border of the atrophic area on fundus autofluorescence are useful for predicting the rate of progression.
The Amsler grid (a self-check sheet with grid lines) can be used to self-detect metamorphopsia and scotomas. However, early stages are often asymptomatic, making regular eye exams essential. Especially when only one eye is affected, it is not uncommon for patients to be unaware in daily life.
AMD is a multifactorial disease, developing from a combination of genetic predisposition and environmental/behavioral factors.
AREDS2 supplements (lutein, zeaxanthin, vitamins C and E, zinc, copper) reduce the risk of progression from intermediate to late AMD by about 25% 2). However, their effectiveness for early AMD or primary prevention has not been established. Beta-carotene increases the risk of lung cancer in smokers, so smokers should choose products containing lutein/zeaxanthin 1).
The diagnostic criteria for neovascular AMD are as follows 1).
The diagnostic criteria for atrophic AMD (geographic atrophy) are considered to be all of the following 1).
| Item | Criteria |
|---|---|
| Size | Diameter ≥250 μm |
| Shape | Round, oval, lobular, or geographic |
| Border | Sharp |
| RPE changes | Hypopigmented or depigmented changes |
| Choroid | Medium and large vessels clearly visible |
OCT simultaneously evaluates disease stage, MNV type, exudative activity, and the extent of GA atrophy. In AMD-related atrophy, OCT is positioned as the foundational imaging for diagnosis and staging, with fundus photography and FAF used complementarily 11).
| Evaluation target | Key OCT findings | Interpretation points |
|---|---|---|
| Early/intermediate AMD | Soft drusen, large drusen, subretinal drusenoid deposits, drusenoid PED, RPE irregularity | Assess disease stage and risk of progression to late AMD 1). |
| Type 1 MNV/PNV | Double layer sign, low irregular RPE elevation, fibrovascular PED, choroidal thickening | Leakage may be inconspicuous on FA due to sub-RPE location; use OCTA or ICGA to confirm the vascular network 1). |
| Type 2 MNV | Medium-to-high reflectivity structure above RPE, subretinal hyperreflective material, subretinal fluid, fibrin | Corresponds to classic MNV; tends to cause rapid vision loss and metamorphopsia 1). |
| Type 3 MNV (RAP) | Intraretinal hyperreflective focus, cystoid macular edema, PED with bump sign | Be cautious in cases with bilateral multiple soft drusen; evaluate neovascular activity originating from within the retina 1). |
| PCV | sharp-peaked / thumb-like PED, notched or multilobular PED, sub-RPE ring-like lesion, double-layer sign | OCT findings are clues to suspect PCV, but multimodal evaluation including ICGA is important for definitive diagnosis14). |
| Exudative activity | Intraretinal fluid (IRF), subretinal fluid (SRF), sub-RPE fluid, hemorrhage, fibrin | These are key findings for deciding initiation, continuation, and dose interval adjustment of anti-VEGF therapy1). |
| GA / AMD-related atrophy | cRORA, iRORA, RPE thinning or disruption, outer retinal atrophy, hypertransmission into choroid | cRORA is a complete atrophy finding on OCT that meets criteria such as hypertransmission ≥250 μm, RPE damage, and photoreceptor degeneration11). |
When exudative changes from MNV (IRF, SRF, sub-RPE fluid, fibrin, hemorrhage, etc.) are observed, it is judged as “active”1). Noninvasive evaluation with OCT has become mainstream. Since the site of high disease activity in MNV is not necessarily at the fovea, scanning the entire macula for evaluation is recommended1).
Macular abnormalities with MNV require differentiation from the following diseases.
OCTA has high accuracy for MNV detection with sensitivity 0.87 and specificity 0.972), and is increasingly used as a non-invasive test. It may be superior to fluorescein angiography especially for detecting type 1 MNV1). However, ICGA remains essential for PCV diagnosis, and OCTA is not a complete replacement.
There is no evidence-based treatment for early AMD2). For intermediate AMD or higher, in addition to smoking cessation and dietary improvement, supplementation based on the AREDS2 formulation is recommended1).
Supplement formulation used in AREDS21):
Beta-carotene was replaced with lutein/zeaxanthin because it increases lung cancer risk in smokers1). The AREDS2 formulation reduces the risk of progression from intermediate to late AMD by approximately 25%.
The first-line treatment for neovascular AMD is intravitreal injection of anti-VEGF agents 1). For subfoveal MNV, anti-VEGF monotherapy is recommended as initial treatment.
Ranibizumab
Dose: 0.5 mg intravitreal injection
Loading phase: 3 injections at 1-month intervals
Maintenance phase: Pro re nata (PRN) dosing. In the MARINA study, visual acuity improved by 6.6 letters compared to a 14.9-letter decline in the sham group 1).
Biosimilar: Ranibizumab biosimilar is available.
Aflibercept
Dose: 2.0 mg intravitreal injection
Loading phase: 3 injections at 1-month intervals
Maintenance phase: Fixed dosing every 2 months or treat-and-extend regimen. If no exudative recurrence, the interval is extended by 2 weeks (up to 3 months); if recurrence occurs, the interval is shortened by 2 weeks 1).
PCV: Polyp regression rate of 40–50%, superior to ranibizumab (20–30%).
Brolucizumab / Faricimab
Brolucizumab: 6 mg injection. Dosing every 8–12 weeks is possible. Caution is needed for intraocular inflammation including retinal vasculitis and vascular occlusion 1).
Faricimab: VEGF-A + Ang-2 bispecific antibody. Administered every 8 to 16 weeks. In the TENAYA/LUCERNE studies, it was non-inferior to aflibercept1)10).
There are three main dosing regimens1):
For type 2 MNV or PCV lesions that do not involve the fovea, laser photocoagulation of the entire MNV is an option. Irradiation parameters are determined professionally based on lesion size, location, and equipment used. However, laser photocoagulation irreversibly damages the RPE and is not suitable for MNV near the fovea1).
Treatment options for PCV are as follows1):
PDT uses verteporfin, with laser irradiation tailored to the lesion area. After treatment, patients are instructed to avoid photosensitivity reactions for a certain period.
Long-term PDT may worsen macular atrophy, and it is advisable to avoid it in cases with thin choroid or pre-existing macular atrophy. PDT is not recommended for type 3 MNV1).
When the response to anti-VEGF therapy is poor (treatment-resistant cases) or diminishes over time (acquired resistance), switching to another agent may be effective 1). Drug changes may also be considered based on treatment burden (frequency of visits and injections). In end-stage AMD with inactive fibrotic scarring or atrophic changes, aggressive treatment is not indicated, and observation is considered 1).
For type 3 MNV (RAP), anti-VEGF therapy is the mainstay. PDT may worsen macular atrophy and is not recommended for type 3 MNV 1).
Massive submacular hemorrhage causes acute vision loss. If treated early, pneumatic displacement may improve vision.
The goal of treatment for geographic atrophy is to slow the enlargement of atrophy, not to restore lost vision or eliminate atrophic lesions. Previously, management focused on lifestyle modification, AREDS2, anti-VEGF therapy for incident MNV, and low-vision care. However, on September 19, 2025, avacincaptad pegol sodium (Izaybe intravitreal injection 20 mg/mL) was approved in Japan for the indication of “slowing the progression of geographic atrophy in atrophic age-related macular degeneration” 13).
This drug is administered as 2 mg/0.1 mL avacincaptad pegol sodium intravitreally once monthly for the first 12 months, then every 2 months thereafter. Indication decisions should individually assess lesion location, enlargement rate, fellow eye status, risk of MNV development, injection-related complications, and visit burden 13). If MNV develops during follow-up, anti-VEGF therapy for neovascular AMD should be considered 1).
For patients with progressive vision loss, low-vision care including visual aids such as tinted glasses and magnifiers, as well as support for daily activities, is important 1).
The induction phase typically involves three injections at one-month intervals. During the subsequent maintenance phase, the treat-and-extend method (gradually extending intervals) is recommended. The ALTAIR study (Japanese subjects) confirmed efficacy over 96 weeks 1). With faricimab, some cases can maintain intervals of up to 16 weeks 10).
For geographic atrophy, treatments aimed at slowing lesion enlargement have emerged. In Japan, avacincaptad pegol sodium was approved on September 19, 2025 13). However, it is not a treatment that restores vision; indications are determined after evaluating foveal involvement, MNV complications, injection risks, and visit burden. AREDS2 supplements reduce the risk of progression to late AMD but have not been shown to suppress the progression of geographic atrophy itself. When vision loss progresses, low vision care becomes important.
The pathology of AMD begins with damage to RPE cells. Drusen accumulate between the RPE basement membrane and the inner collagenous layer of Bruch’s membrane. Drusen components include membranous debris, unesterified cholesterol, and complement, serving as a source of chronic inflammation. Oxidative stress, lipid metabolism abnormalities, and activation of the innate immune system are complexly involved, leading to disruption of the homeostasis of the RPE-Bruch’s membrane-choriocapillaris complex. Subsequently, the pathway diverges into two.
Aged RPE cells exhibit a senescence-associated secretory phenotype (SASP), with increased expression of SA-β-gal, p53, p21, and p16 7). This senescent RPE phenotype is consistent with findings in patients with atrophic AMD, and selective elimination by senolytics is attracting attention as a therapeutic target.
Genetic polymorphisms in CFH, C3, and ARMS2 are associated with susceptibility to AMD 2). Dysregulation of complement pathways (classical, alternative, and lectin pathways) drives the expansion of geographic atrophy 3). Inhibiting complement C3 is expected to suppress the entire terminal pathway downstream of C5, while inhibiting C5 is expected to prevent the formation of the membrane attack complex (MAC).
Anegondi et al. (2025) analyzed data from the lampalizumab trial and showed that faster growth rates of geographic atrophy lead to faster BCVA decline, with approximately 75% losing 5 or more letters, approximately 50% losing 10 or more letters, and approximately 25% losing 15 or more letters over 2 years 3).
Pachychoroid is a condition characterized by dilation of large choroidal vessels (pachyvessels) and increased choroidal vascular permeability 1). Central serous chorioretinopathy (CSC) is a representative pachychoroid disease, and MNV arising from CSC or pachychoroid pigment epitheliopathy (PPE) is called pachychoroid neovasculopathy (PNV). The CFH gene has also been reported to be involved in the development of pachychoroid and CSC 1).
Ribatti et al. (2024) reported that tryptase secreted by choroidal mast cells induces Bruch’s membrane degradation, leading to RPE death, and the release of VEGF-A, FGF-2, IL-8, and NGF promotes angiogenesis 5).
Non-exudative MNV is biologically active even when asymptomatic, with persistent area enlargement 4).
Wang et al. (2023) reported in an SS-OCTA study of 45 eyes that growing MNV (area increase ≥50%) had a significantly shorter time to exudative conversion than non-growing MNV (13.60 months vs. 31.11 months, HR 12.51), and smoking history was significantly correlated with MNV area increase (P=0.021) 4).
Geographic atrophy often begins around the fovea, and the fovea shows relative resistance to atrophy 3). This results in horseshoe-shaped or ring-shaped GA. The median time to foveal involvement is 2.5 years, during which high-contrast visual acuity is preserved, but daily visual functions such as dark-adapted sensitivity and reading speed are impaired early 8).
In geographic atrophy, drugs targeting the complement pathway have been clinically implemented to slow lesion progression. Pegcetacoplan in the OAKS/DERBY trials and avacincaptad pegol in the GATHER2 trial have been reported to suppress the enlargement of GA lesions9)12). In Japan, avacincaptad pegol sodium was approved in 202513).
However, neither drug showed a significant difference in trials where visual acuity improvement was a prespecified endpoint, leaving the “structure-function dissociation” as a remaining challenge3)8). The European Medicines Agency (EMA) required demonstration of functional benefit and did not approve pegcetacoplan8).
On the other hand, not all complement system and visual cycle targeted drugs have shown efficacy, and careful evaluation from both structural and functional perspectives continues for the pharmacological treatment of geographic atrophy8).
In a review by Dinah et al. (2026), BCVA was found to insufficiently capture the functional impact of geographic atrophy, and microperimetry, low-luminance visual acuity (LLVA), and reading speed were recommended as alternative measures8). Establishing a comprehensive, multimodal functional assessment will be key for future clinical trials.
Ji et al. (2025) reported a case of dry AMD treated with photobiomodulation therapy (red to near-infrared light 650–1,300 nm)6). Over 8 months, the drusen area in the right eye decreased by 58% and completely disappeared in the left eye. Visual acuity improved from 20/30 to 20/20 in the left eye and remained 20/25 in the right eye. However, this is a case report, and further validation is needed to establish it as a standard treatment.
Chung & Kim (2022) reported that the MDM2 inhibitor Nutlin-3a is a promising novel approach for selectively eliminating senescent RPE cells7). The development of mitochondria-specific senolytics remains a future challenge.
Stem cell therapy using RPE cell transplantation is in the research stage, with multiple trials ongoing. Gene therapy targeting complement factors is also being investigated.
Genetic polymorphisms in CFH, ARMS2, and C3 are associated with the risk of developing AMD. Genetic testing may enable prediction of prognosis, such as the development of AMD in the fellow eye1). However, at present, treatment strategies based on genetic testing are not standardized2), and routine testing is not recommended.
Atrophic AMD progresses slowly, but when geographic atrophy reaches the fovea, visual acuity drops to 0.1 or less. The median time to legal blindness (visual acuity 20/200 or worse) has been reported as 6.2 years3). Analysis of lampalizumab trial data showed that mean BCVA decreased from 66 to 57 letters (approximately 20/50 to 20/80 equivalent) over 2 years3).
Faster growth of geographic atrophy is associated with more rapid BCVA decline; in eyes with a single subfoveal lesion, the fastest-growing group showed a loss of approximately 4 lines (17.75 letters) over 2 years3). In contrast, the slowest-growing group lost only 1.69 letters over 2 years. Even when the fovea is preserved, scotopic sensitivity, contrast sensitivity, and reading speed are impaired early, so visual acuity alone underestimates functional impact8).
Additionally, there is a certain probability of developing MNV and transitioning to neovascular AMD, leading to more severe vision loss.
Control of MNV with anti-VEGF drugs has significantly improved visual prognosis. In the 5-year follow-up of the CATT study, 50% of eyes achieved visual acuity of 20/40 or better15). However, if left untreated, severe vision loss occurs, leaving fibrotic or atrophic scars in the macula. In cases with massive hemorrhage from MNV, extensive visual field defects and more severe visual impairment, including complete blindness, can occur.
Complete cure of MNV is impossible, and without appropriate treatment and long-term management, it can easily lead to irreversible vision loss 1). Even if MNV activity temporarily subsides, it may recur over the long term, and repeated exudation can lead to atrophic changes or fibrous scarring. Considering that MNV also occurs at a high rate in the fellow eye, continued treatment and regular monitoring are essential 1). Active low-vision care is recommended for patients with severe visual impairment.
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