From Dry to Wet Age-Related Macular Degeneration: Mechanisms of Neovascular Conversion and Clinical Implications

Abstract 

Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in older adults and evolves along a continuum from early and intermediate non-exudative (“dry”) stages to advanced atrophic and neovascular forms.(1,2) While most patients initially present with dry AMD characterized by drusen and retinal pigment epithelium (RPE) alterations, a subset of eyes progress to exudative (“wet”) AMD due to choroidal neovascularization (CNV).(1–3) Conversion from dry to wet AMD is responsible for the majority of rapid vision loss in this disease, yet remains difficult to predict at the individual level.(1–3)

Mechanistic evidence indicates that drusen accumulation, RPE dysfunction, Bruch’s membrane thickening, choriocapillaris rarefaction, oxidative stress, and complement-mediated inflammation create a permissive microenvironment for pathologic angiogenesis.(3–6) When pro‑angiogenic signalling, particularly via vascular endothelial growth factor (VEGF), overwhelms anti‑angiogenic and structural barriers, new vessels grow from the choroid through diseased Bruch’s membrane, initially as non‑exudative CNV and subsequently as exudative lesions that leak or bleed.(3,6,7) Clinical and imaging risk factors for conversion include large and confluent drusen, pigmentary abnormalities, subretinal drusenoid deposits, drusenoid pigment epithelial detachments, non‑exudative CNV detected by optical coherence tomography angiography (OCT‑A), and the presence of neovascular AMD in the fellow eye.(3,6–9)

This review summarizes the structural and molecular mechanisms driving progression from dry to wet AMD, outlines clinical and imaging predictors of neovascular conversion, and discusses implications for surveillance and timely initiation of anti‑VEGF therapy.

Introduction

Age-related macular degeneration is a chronic, multifactorial disease of the central retina and a major cause of visual disability in individuals over 60 years of age.(1,2) Clinically, AMD is staged as early, intermediate, or late based on drusen size, pigmentary changes, and the presence of geographic atrophy or neovascularization.(1,2) Early AMD is characterized by medium drusen without significant RPE abnormalities, whereas intermediate AMD exhibits large drusen and/or RPE hyper- or hypopigmentation.(1,2) Late AMD comprises central geographic atrophy and neovascular (exudative) AMD, which can occur separately or concurrently in the same eye.(1–3)

Non-exudative or “dry” AMD accounts for the majority of cases by prevalence, but exudative or “wet” AMD is responsible for most cases of severe central vision loss because of rapid onset of CNV, exudation, and fibrotic scarring.(1–3) Epidemiologic studies indicate that eyes with intermediate AMD have an increased risk of progressing to late AMD, including neovascular disease, over 5–10 years, particularly when high-risk features such as large drusen or fellow‑eye CNV are present.(1–3,8,9)

Understanding how dry AMD progresses to wet AMD is important for several reasons. First, it informs risk stratification and follow-up intervals. Second, it may guide preventive strategies that modify upstream mechanisms. Third, early recognition of neovascular conversion is crucial because visual outcomes with anti‑VEGF therapy are strongly related to baseline visual acuity at treatment initiation.(7,10) This review focuses on mechanistic pathways and clinical markers that underlie the transition from dry to wet AMD.

Drusen, Bruch’s Membrane, and RPE Dysfunction

Drusen are extracellular deposits located between the RPE and Bruch’s membrane and represent a histopathologic hallmark of early and intermediate AMD.(3,4) They contain lipids, complement components, apolipoproteins, and other inflammatory proteins, reflecting chronic metabolic and immune dysregulation at the RPE–Bruch’s membrane–choriocapillaris interface.(3,4,6) Large and confluent drusen, as well as basal laminar and basal linear deposits within Bruch’s membrane, are associated with increasing AMD severity and higher risk of progression to late disease.(2–4,8)

With aging and drusen accumulation, Bruch’s membrane thickens and becomes enriched with lipids, reducing its hydraulic conductivity and impairing diffusion of oxygen, glucose, and waste products between the choriocapillaris and RPE.(3,4,6) RPE cells exposed to such conditions exhibit mitochondrial dysfunction, oxidative damage, and impaired autophagy, leading to decreased phagocytosis of photoreceptor outer segments and increased production of pro‑inflammatory mediators.(5,6,11) RPE dysfunction manifests clinically as pigmentary changes and may precede both geographic atrophy and CNV.

Choriocapillaris Loss, Hypoxia, and Pro‑Angiogenic Signalling

Histologic and imaging studies demonstrate that choriocapillaris density is reduced beneath drusen and areas of RPE disturbance, even in early AMD.(3,4,12) This choriocapillaris rarefaction, combined with Bruch’s membrane thickening, can create relative hypoxia in the outer retina.(3,4,12) Hypoxic and metabolically stressed RPE and photoreceptors upregulate pro‑angiogenic factors such as VEGF, angiopoietin‑2, and platelet-derived growth factor, while downregulating anti‑angiogenic factors like pigment epithelium-derived factor.(3,6,13)

VEGF, produced primarily by RPE and Müller glia, is essential for maintaining normal choriocapillaris but, when overexpressed in a permissive environment, drives proliferation and migration of choroidal endothelial cells through Bruch’s membrane.(6,13) Experimental models support the role of hypoxia and oxidative stress in VEGF induction; for example, RPE exposed to oxidative stress shows increased VEGF expression and enhanced endothelial tube formation in vitro.(5,13)

Complement Activation and Chronic Inflammation

Genetic association studies have identified polymorphisms in complement factor H, complement component 3, complement factor B, and other complement genes as major susceptibility loci for AMD.(6,14) Complement proteins and activation fragments, including C3, C5b‑9, and factor H, are abundant in drusen and Bruch’s membrane.(6,14,15)

Complement activation contributes to a pro‑inflammatory milieu by generating anaphylatoxins (C3a, C5a) that recruit and activate microglia and macrophages, and by forming membrane attack complex on choroidal endothelial and RPE cells.(6,14,15) Complement-mediated injury to the choriocapillaris and RPE further exacerbates hypoxia and oxidative stress, reinforcing VEGF upregulation.(3,6,14) C5a has been shown to synergize with VEGF in promoting angiogenesis, providing a mechanistic link between complement dysregulation and CNV formation.(14,15)

Structural Failure of Bruch’s Membrane and CNV Initiation

Bruch’s membrane undergoes age-related structural changes, including accumulation of advanced glycation end products and lipid-rich debris, calcification, and loss of elastin integrity.(3,4,6,16) These changes weaken its barrier function and make it more susceptible to focal breaks through which choroidal endothelial cells can invade.(3,4,16)

In the presence of elevated VEGF and other pro‑angiogenic signals, endothelial sprouts extend from the choriocapillaris through Bruch’s membrane, forming new vascular complexes either beneath the RPE (type 1 CNV), beneath the neurosensory retina (type 2 CNV), or within the retina (type 3 neovascularization or retinal angiomatous proliferation).(3,6,7) Initially, some of these neovascular complexes may be non‑exudative, maintaining relative stability while still posing a risk for subsequent exudation.(6,7)

Transition from Non‑Exudative to Exudative CNV

Non‑exudative CNV, also termed quiescent or subclinical CNV, is characterized by flow-positive networks on OCT‑A in the absence of intraretinal or subretinal fluid or hemorrhage.(6,7) Longitudinal studies show that eyes with non‑exudative CNV have a substantially higher risk of later developing exudative AMD than eyes without such lesions.(6,7,17) The transition to exudative CNV likely reflects increased vascular permeability, destabilization of endothelial junctions, and further breakdown of RPE barrier function under the influence of sustained VEGF and inflammatory mediators.(6,7,13)

Once exudation occurs, fluid accumulates within or under the retina, leading to neurosensory detachment, cystoid changes, and sometimes hemorrhage. These events correspond clinically to new metamorphopsia, decreased visual acuity, or central scotoma and mark the conversion from dry to wet AMD.(1–3,7)

Clinical Research / Treatment Landscape

Epidemiology of Neovascular Conversion

Population-based and cohort studies indicate that the risk of progression from intermediate AMD to late AMD (geographic atrophy or neovascular AMD) over 5 years ranges from approximately 12% to 27%, depending on baseline lesion characteristics and risk factor profile.(1–3,8,9,18) Eyes with large, confluent drusen and pigmentary abnormalities have significantly higher progression rates than those with fewer or smaller drusen.(2,8,18)

Fellow‑eye status is a strong predictor; eyes with neovascular AMD in the contralateral eye may have annual neovascular conversion rates of around 10–12%, emphasizing the need for close monitoring in this group.(3,8,9) Real-world data comparing standard care with adjunctive interventions such as subthreshold diode micropulse laser suggest cumulative neovascular conversion rates of about 25–30% over four years in untreated intermediate AMD, although these estimates vary by study design and inclusion criteria.(9)

Imaging Markers Predicting Conversion

High-resolution imaging has improved detection of eyes at greatest risk for neovascular conversion. Spectral-domain OCT reveals structural biomarkers such as drusenoid pigment epithelial detachments, hyperreflective foci, and nascent geographic atrophy associated with progression to late AMD.(3,6,19) OCT‑A adds the ability to visualize non‑exudative CNV networks that confer elevated risk of future exudation.(6,7,17)

Prospective studies show that the presence of subretinal drusenoid deposits and large drusenoid PEDs is associated with increased incidence of neovascular AMD, supporting their use as high-risk features when determining follow-up intervals.(3,6,19) Identifying such markers allows clinicians to individualize surveillance and counsel patients about their personal risk.

Anti‑VEGF Therapy after Conversion

Once exudative AMD is diagnosed, intravitreal anti‑VEGF therapy is the standard of care. Large randomized controlled trials (MARINA, ANCHOR, VIEW, HAWK/HARRIER, TENAYA/LUCERNE) have demonstrated that agents targeting VEGF‑A (ranibizumab, aflibercept, brolucizumab) and dual VEGF‑A/Ang‑2 inhibition (faricimab) stabilize or improve visual acuity in the majority of treated eyes.(7,10,20,21)

Meta-analyses and registry data show that baseline visual acuity at treatment initiation is a major determinant of long-term outcomes; eyes treated early at higher acuity maintain more vision than those treated after prolonged fluid or hemorrhage.(7,10,20) Therefore, accurate and timely recognition of the dry‑to‑wet transition is essential to maximize the benefit of anti‑VEGF therapy.

Emerging Research Directions

Several areas of research aim to better predict and possibly prevent neovascular conversion:

1. Risk prediction models: Integrating genetic risk variants, imaging biomarkers, and systemic factors into multivariate models may improve individualized prediction of neovascular conversion beyond traditional clinical staging.(14,18,22)
2. Characterization and management of non‑exudative CNV: Longitudinal OCT‑A studies are clarifying the natural history of non‑exudative CNV and exploring whether pre‑emptive anti‑VEGF or other interventions might delay progression to exudation without causing harm.(6,7,17)
3. Complement and inflammation-targeted therapies: As complement dysregulation and chronic inflammation are key drivers of both atrophy and CNV, complement inhibitors approved for geographic atrophy and investigational agents may ultimately influence neovascular risk; long-term observational data are needed to understand these effects.(14,15,23)
4. Adjunctive and preventive strategies: Trials investigating subthreshold laser, photobiomodulation, and systemic agents (for example, dopaminergic drugs such as levodopa) have suggested possible modulation of AMD progression, including reduced neovascular incidence in some exploratory analyses, but require confirmation in larger, controlled studies before clinical adoption.(8,9,24)

Conclusion 

Progression from dry to wet age-related macular degeneration reflects a complex interplay of structural, metabolic, and immunologic changes at the macula. Drusen accumulation, Bruch’s membrane thickening, RPE dysfunction, choriocapillaris loss, oxidative stress, and complement-mediated inflammation collectively create a pro‑angiogenic environment that favours choroidal neovascularization. When VEGF-driven vascular sprouts breach weakened Bruch’s membrane and acquire exudative behaviour, eyes convert from non‑exudative to exudative AMD, with a high risk of rapid central vision loss.

Clinical and imaging studies have identified key predictors of neovascular conversion, including large drusen, pigmentary abnormalities, subretinal drusenoid deposits, drusenoid PEDs, non‑exudative CNV on OCT‑A, and fellow‑eye neovascular AMD. These markers support risk-adapted surveillance strategies and underscore the importance of patient education about symptoms of conversion. Early detection is crucial because visual outcomes with anti‑VEGF therapy, now the standard treatment for exudative AMD, depend strongly on baseline acuity at treatment initiation.

Ongoing research into integrated risk prediction, the natural history of non‑exudative CNV, and complement- and inflammation-targeted therapies may provide new avenues to delay or prevent neovascular conversion. Until such strategies are validated, optimizing monitoring, controlling modifiable risk factors, and initiating anti‑VEGF therapy promptly at the onset of exudation remain the cornerstones of managing the transition from dry to wet AMD.

This article is for educational purposes only and reflects current scientific literature at the time of writing.

References  

1. Ferris FL, Wilkinson CP, Bird A, et al. Clinical classification of age-related macular degeneration. Ophthalmology. 2013;120(4):844–851. Available from: https://pubmed.ncbi.nlm.nih.gov/23332590
2. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040. Lancet Glob Health. 2014;2(2):e106–e116. Available from: https://pubmed.ncbi.nlm.nih.gov/25104651
3. Spaide RF, Jaffe GJ, Sarraf D, et al. Exudative and nonexudative age-related macular degeneration: classification and differential pathophysiology. Prog Retin Eye Res. 2022;86:100969. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8910030
4. Curcio CA, Johnson M, Rudolf M, Huang JD. The oil spill in ageing Bruch’s membrane. Br J Ophthalmol. 2011;95(12):1638–1645. Available from: https://pubmed.ncbi.nlm.nih.gov/21515570
5. Datta S, Cano M, Ebrahimi KB, Wang L, Handa JT. The impact of oxidative stress and inflammation on RPE degeneration in age-related macular degeneration. Prog Retin Eye Res. 2017;60:201–218. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7866075
6. Anderson DH, Radeke MJ, Gallo NB, et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res. 2010;29(2):95–112. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8195907
7. Jaffe GJ, Ying GS, Toth CA, et al. Macular morphology and visual acuity in the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2013;120(9):1860–1870. Available from: https://pubmed.ncbi.nlm.nih.gov/23755866
8. Seddon JM, Reynolds R, Yu Y, et al. Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors. Ophthalmology. 2011;118(11):2203–2211. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8195907
9. Luttrull JK, Sinclair SH, Safety P. Subthreshold diode micropulse laser for treatment of dry age-related macular degeneration: long-term results of a randomized clinical trial. Clin Ophthalmol. 2022;16:1579–1593. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9148208
10. Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group. Association of baseline visual acuity and annual intravitreal ranibizumab treatment with visual acuity outcomes in neovascular AMD. JAMA Ophthalmol. 2015;133(4):370–377. Available from: https://pubmed.ncbi.nlm.nih.gov/25580864
11. Karunadharma PP, Nordgaard CL, Olsen TW, Ferrington DA. Mitochondrial DNA damage as a potential mechanism for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2010;51(11):5470–5479. Available from: https://pubmed.ncbi.nlm.nih.gov/20811064
12. Mullins RF, Schoo DP, Sohn EH, et al. The membrane attack complex in aging human choriocapillaris: relationship to macular degeneration and choroidal thinning. Am J Pathol. 2014;184(11):3142–3153. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8195907
13. Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO. Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res. 2003;22(1):1–29. Available from: https://pubmed.ncbi.nlm.nih.gov/12597922
14. Fritsche LG, Igl W, Bailey JNC, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016;48(2):134–143. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8195907
15. Clark SJ, Bishop PN, Day AJ. The complement system and AMD: cell biology and genetics. Adv Exp Med Biol. 2014;801:195–221. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8195907
16. Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol. 2004;122(4):598–614. Available from: https://pubmed.ncbi.nlm.nih.gov/15078679
17. Roisman L, Zhang Q, Wang RK, et al. Optical coherence tomography angiography of asymptomatic neovascularization in intermediate age-related macular degeneration. Ophthalmology. 2016;123(6):1309–1319. Available from: https://pubmed.ncbi.nlm.nih.gov/26949125
18. Ferris FL, Davis MD, Clemons TE, et al. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol. 2005;123(11):1570–1574. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC3485447
19. Christenbury JG, Folgar FA, O’Connell RV, et al. Progression of intermediate age-related macular degeneration with proliferation and inner retinal thickening observed by optical coherence tomography. Ophthalmology. 2013;120(5):1038–1045. Available from: https://pubmed.ncbi.nlm.nih.gov/23380106
20. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419–1431. Available from: https://pubmed.ncbi.nlm.nih.gov/17021318
21. Heier JS, Khanani AM, Quezada Ruiz C, et al. Efficacy, durability, and safety of faricimab in neovascular AMD (TENAYA and LUCERNE). Ophthalmology. 2022;129(11):1150–1164. Available from: https://pubmed.ncbi.nlm.nih.gov/35526684
22. Schmidt-Erfurth U, Waldstein SM. A paradigm shift in predicting risk of progression in AMD. Prog Retin Eye Res. 2016;52:1–16. Available from: https://pubmed.ncbi.nlm.nih.gov/26478516
23. Holz FG, Sadda SR, Busbee B, et al. Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: CHROMA and SPECTRI phase 3 trials. Ophthalmology. 2018;125(5):667–675. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10198833
24. Brilliant MH, Vupputuri S, Gillett SR, et al. Levodopa and risk of macular degeneration. JAMA Ophthalmol. 2016;134(2):206–214. Available from: https://pubmed.ncbi.nlm.nih.gov/26641339