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🔬 Age-Related Macular Degeneration (AMD)

A Comprehensive Presentation - Basics to Recent Advances

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🏛️ SLIDE 1 - Introduction & Scope

• ~196 million people affected worldwide (2020), projected to rise to 288 million by 2040
• Causes quality of life decline comparable to end-stage prostate cancer or a bedridden stroke
• Advanced AMD costs billions in health resources annually
• Prevention and early treatment are top public health priorities

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🧬 SLIDE 2 - Anatomy of the Macula

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📊 SLIDE 3 - Classification & Staging

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🔬 SLIDE 4 - Pathogenesis (The "Deposit-Driven Disease")

Drusen Formation

• The RPE continuously recycles lipids, outer segment debris, and metabolites
• With aging, Bruch's membrane thickens and hydraulic conductivity falls
• Uncleared waste accumulates as soft drusen (the hallmark of AMD risk)
• Lipid content in Bruch's membrane increases exponentially after the 4th decade - phospholipids, triglycerides, free cholesterol
• Peroxidized lipids (from DHA, linolenic acid in photoreceptor outer segments) drive angiogenic cytokines, triggering neovascularization

Key Molecular Pathways

1. Complement dysregulation - inappropriate activation damages RPE and choriocapillaris
2. Lipid/cholesterol metabolism - lipid accumulation impairs RPE function
3. Oxidative stress - mitochondrial ROS damages the RPE
4. VEGF upregulation - hypoxic RPE secretes VEGF-A, driving choroidal neovascularization (CNV)
5. Inflammation/inflammasome - NLRP3 activation in RPE, macrophage infiltration

Drusen Subtypes

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🧪 SLIDE 5 - Risk Factors

Non-Modifiable

• Age - strongest risk factor. 5% of >75 yr olds have late AMD vs <0.1% in 50-55 yr olds
• Genetics - CFH, ARMS2/HTRA1, C3, CFB - heritability ~50-70%
• Ethnicity - White Europeans highest prevalence (~12%); African Americans lowest (~2.5%)
• Sex - slightly higher in females (partly longevity)
• Iris color/hyperopia - lighter iris, hyperopia = increased risk; myopia = protective

Modifiable

• Smoking - 2-4x increased risk; most powerful modifiable factor. Risk persists years after cessation. Up to 25% of female AMD cases attributable to smoking
• Diet - Mediterranean diet protective; omega-3 fatty acids, leafy greens (lutein/zeaxanthin) reduce risk
• AREDS supplements (Vitamins C, E, beta-carotene, zinc) reduce progression in intermediate AMD by ~25%
• Cardiovascular risk factors - HTN, obesity, sedentary lifestyle associated
• UV/blue light - some association, less consistent evidence

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🏥 SLIDE 6 - Clinical Presentation & Symptoms

Symptoms by Stage

• Often asymptomatic or mild
• Impaired dark adaptation (night vision difficulty) - often the first functional sign
• Subtle color/contrast changes
• Found incidentally on funduscopy

• Progressive central visual field loss
• Loss worsens as GA enlarges toward fovea
• Reading and facial recognition become difficult
• Bilateral in most patients

• Sudden metamorphopsia (visual distortion) - Amsler grid test positive
• Rapid central vision loss (days to weeks)
• Central scotoma
• Subretinal fluid/hemorrhage

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🔭 SLIDE 7 - Diagnosis & Imaging

Clinical Tools

• Identifies drusen, RPE changes, hemorrhage, exudate

• Was gold standard for CNV detection
• Hyperfluorescent leakage = active neovascularization
• Classifies CNV as classic (well-demarcated leakage), occult (late ill-defined), or mixed

• Better visualization of type 1 (sub-RPE) MNV and polypoidal choroidal vasculopathy
• Detects late hypofluorescence in GA

• Cross-sectional microstructural imaging at 5-10 µm resolution
• Identifies: drusen, subretinal fluid (SRF), intraretinal fluid (IRF), fibrovascular PED, RPE atrophy, EZ (ellipsoid zone) integrity
• Key OCT biomarkers for progression risk: hyperreflective foci (strongest single predictor), subretinal drusenoid deposits, drusen volume >0.03 mm³ in the central 3 mm circle

• Non-invasive, dye-free angiography
• Visualizes flow in all retinal layers
• Detects MNV subtypes precisely: Type 1 (sub-RPE plaque), Type 2 (subretinal "glomerulus"), Type 3 (intraretinal tuft)
• Detects "nascent" type 3 MNV as hyperreflective foci with flow

• Lipofuscin distribution maps
• Hypoautofluorescence = RPE loss (GA)
• Junctional hyperautofluorescence = active GA border (fastest growth zone)

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🩺 SLIDE 8 - Types of Macular Neovascularization (MNV)

• Wet AMD (diagram below) - abnormal vessels breach the RPE, leading to leakage and hemorrhage

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💊 SLIDE 9 - Treatment of Neovascular AMD (Wet AMD)

Pre-anti-VEGF Era (Historical)

• Laser photocoagulation - direct ablation of CNV; not useful for subfoveal lesions
• Photodynamic therapy (PDT) with Verteporfin - selective vessel closure; largely replaced but still used for polypoidal CVP
• Pegaptanib (Macugen) - first anti-VEGF (VEGF-165 selective); modest results; 2004 FDA approval

Anti-VEGF Era - The Revolution

Dosing Regimens

1. Monthly fixed - best outcomes, least practical
2. PRN (as needed) - fewer injections, slightly worse visual outcomes
3. Treat-and-Extend (T&E) - gold standard in practice; extends intervals if dry, contracts if recurrence
4. Individualized maintenance - based on monitoring

CATT Trial Key Findings (2yr data)

• Bevacizumab and ranibizumab were equivalent for visual acuity
• Continuous > PRN dosing (discontinuous dosing = ~2.4 letters less gained)
• Mean gain: ranibizumab monthly = +8.8 letters; bevacizumab monthly = +7.8 letters

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🧠 SLIDE 10 - Treatment of Geographic Atrophy (Dry AMD)

AREDS / AREDS2 Supplements

• AREDS formula: Vitamin C 500mg, Vitamin E 400 IU, Beta-carotene 15mg, Zinc 80mg
• 25% risk reduction of progression from intermediate to advanced AMD at 5 years
• AREDS2 replaced beta-carotene (lung cancer risk in smokers) with lutein/zeaxanthin 10/2mg

2023 - First-Ever FDA Approvals for GA: A Milestone

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🚀 SLIDE 11 - Advanced Drug Delivery Systems

Port Delivery System (PDS) with Ranibizumab (Susvimo)

• Surgically implanted sustained-release ocular device
• Placed in the pars plana, contains a drug reservoir
• Refilled in-office every ~6 months
• LADDER trial (Phase 2) and ARCHWAY trial (Phase 3) demonstrated non-inferiority to monthly ranibizumab
• FDA approved October 2021; voluntary withdrawal Feb 2022 (device issues); reapproved 2023

High-Concentration Formulations

• Aflibercept 8mg (Eylea HD) - higher dose allows q12-16wk dosing; FDA approved 2023 (PULSAR trial)

Sustained-Release Implants / Biodegradable Systems

• Graybug Vision sunitinib implant (Phase 2)
• Clearside Biomedical axitinib suprachoroidal injection
• Goal: 6-month or longer dosing intervals

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🧬 SLIDE 12 - Gene Therapy for AMD

• RGX-314 subretinal injection showed sustained anti-VEGF protein expression for 2+ years with reduced injection need
• Gene therapy for dry AMD: GT005 (Gyroscope/Novartis) - CFI gene for complement regulation; Phase 2 data showed safety, efficacy signals
• OCU410 - nuclear receptor RORa gene therapy for dry AMD; Phase 1/2 ongoing

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🔬 SLIDE 13 - Cell-Based Therapies & Regenerative Medicine

Stem Cell / RPE Cell Replacement

• OpRegen Phase 1/2 results: Patients with advanced GA showed signs of vision stabilization and improved RPE coverage on OCT
• Key challenge: immune rejection (allogeneic), engraftment efficiency, and host integration

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🖥️ SLIDE 14 - Multimodal Imaging & AI Diagnostics

The Imaging Revolution

• Intraretinal fluid (IRF) - strongest predictor of poor visual outcome
• Subretinal hyperreflective material (SHRM) - fibrovascular activity
• Hyperreflective foci (HRF) - strongest single OCT predictor of progression to late AMD
• Outer retinal atrophy (ORA) - precursor state to complete RPE and outer retinal atrophy (cRORA)

AI / Deep Learning in AMD

• Predict conversion from early to advanced AMD (outperforming clinical grading)
• Quantify GA area automatically
• Grade drusen and pigmentary changes
• Recommend retreatment decisions

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💉 SLIDE 15 - Clinical Trials Landscape (2023-2026)

Neovascular AMD - Emerging Agents

Geographic Atrophy - Pipeline Beyond Syfovre/Izervay

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🧬 SLIDE 16 - Multi-Omics & Genetics (Cutting Edge, 2026)

Genomics

• Over 50 independent genetic loci associated with AMD risk (GWAS meta-analyses)
• Top associations: CFH (Y402H variant), ARMS2/HTRA1 (chromosome 10q26), C3, C2/CFB, VEGFA, CETP, ABCA1
• Polygenic risk scores can identify individuals in the top 10% of genetic risk - potentially useful for screening

Transcriptomics / Proteomics

• Single-cell RNA sequencing of the human macula identified distinct RPE cell states in AMD
• Upregulation of complement genes, downregulation of RPE signature genes (BEST1, RPE65)
• Plasma proteomics: complement fragments C3d, Ba, Bb elevated even in early AMD

Metabolomics / Lipidomics

• Sphingolipid and ceramide dysregulation in AMD RPE
• Plasma DHA (docosahexaenoic acid) levels inversely correlate with AMD risk

Microbiome

• Gut microbiome dysbiosis (reduced Lactobacillus, increased Prevotella) associated with higher AMD risk - the gut-retina axis

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🔭 SLIDE 17 - Visual Rehabilitation & Low Vision

AREDS Role in Management

Low Vision Aids

• Optical magnifiers, stand magnifiers, electronic video magnifiers
• Screen-reading software, large-print materials
• Eccentric viewing training - teaches patients to use a preferred retinal locus (PRL) adjacent to the scotoma
• Contrast enhancement filters

Implantable Miniature Telescope (IMT - VisionCare Ophthalmic Technologies)

• Provides 2.2-2.7x magnification of the central visual field
• FDA approved for end-stage AMD (bilateral central GA or stable disciform scar)
• Requires pre-trial of external telescope to confirm benefit
• Monocular implant (one eye for central, fellow eye for peripheral vision)
• Phase 3 trial (21 participants, age 55+): 2/3 of participants gained 2+ lines of vision

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📊 SLIDE 18 - Summary: Treatment Algorithm

DIAGNOSIS OF AMD
      │
      ▼
  STAGE?
  ┌────────────────────────────────────────────────────┐
  │                                                    │
Early/Intermediate AMD              Advanced AMD
  │                                    │
  ▼                                    ├── Neovascular (Wet)
AREDS2 Supplements                    │       │
Monitor q6-12mo with OCT              │       ▼
Lifestyle modification                │   Anti-VEGF Intravitreal
(quit smoking, diet)                  │   (Faricimab, Aflibercept 8mg,
                                      │    Ranibizumab, Bevacizumab)
                                      │   Treat-and-Extend Protocol
                                      │
                                      └── Geographic Atrophy (Dry)
                                              │
                                              ▼
                                      Pegcetacoplan (Syfovre) or
                                      Avacincaptad pegol (Izervay)
                                      [Monthly or EOMonth injections]
                                      AREDS2 supplements
                                      Low Vision Rehabilitation
                                      Clinical Trial enrollment

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🌟 SLIDE 19 - Key Recent Advances Summary (2023-2026)

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📚 SLIDE 20 - Key References

1. Seddon JM, Sobrin L, Davoudi S. Epidemiology and Risk Factors for AMD. In: Ryan's Retina, 7th ed. Chapter 64.
2. Curcio CA. Pathogenesis of AMD. In: Ryan's Retina, 7th ed. Chapter 65.
3. Rosenfeld PJ et al. Neovascular AMD. In: Ryan's Retina, 7th ed. Chapter 67.
4. Bhisitkul RB. Pharmacotherapy of AMD. In: Ryan's Retina, 7th ed. Chapter 68.
5. CATT Research Group. Ranibizumab and Bevacizumab for Neovascular AMD. NEJM 2011.
6. Hanson RLW et al. OCT imaging biomarkers in nAMD: systematic review. Eye 2023. [PMID 36526863]
7. Vision Loss Expert Group. Global estimates of AMD blindness. Eye 2024. [PMID 38965321]
8. Yap DWT et al. Persistence of retinal fluid after anti-VEGF in nAMD. Ophthalmol Retina 2025. [PMID 39842717]
9. Castro-Fernández DC et al. Multi-omics in AMD: systematic review. Surv Ophthalmol 2026. [PMID 41643859]
10. AAO EyeWiki - Age-Related Macular Degeneration

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