Age-Related Macular Degeneration: Mechanisms, Clinical Course, and Therapeutic Landscape

 

Abstract

Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in older adults. The disease encompasses a slowly progressive atrophic (dry) form and an exudative neovascular (wet) form. AMD results from multi-layered dysfunction within the photoreceptor–retinal pigment epithelium (RPE)–Bruch’s membrane–choriocapillaris unit. Oxidative stress, mitochondrial injury, complement dysregulation, impaired autophagy, lipid accumulation, chronic para-inflammation, epithelial–mesenchymal transition (EMT), and glial remodeling collectively drive structural degeneration. Emerging evidence further highlights rod–cone vulnerability differences, the role of subretinal drusenoid deposits (reticular pseudodrusen), gut–retina immune signalling, synaptic neurodegeneration, and microglia–Müller glia crosstalk in progression. Anti-VEGF therapy revolutionized wet AMD management, while complement-directed therapies now provide disease-modifying benefit in geographic atrophy. However, no treatment halts the fundamental degenerative cascade. Future directions target mitochondrial rescue, autophagy restoration, neuroprotection, and anti-fibrotic strategies.

---

1) Clinical Overview

AMD typically begins with subtle central blurring, impaired contrast sensitivity, and metamorphopsia. Dry AMDconstitutes ~85–90% of cases, with drusen and RPE pigmentary changes progressing to geographic atrophy (GA), characterized by irreversible RPE and photoreceptor loss [1–4]. Wet AMD develops when hypoxia- and inflammation-driven VEGF signaling induces choroidal neovascularization (CNV), producing intraretinal/subretinal fluid and hemorrhage; vision loss may be rapid without prompt anti-VEGF therapy [3,4].

---

2) The RPE–Photoreceptor–Choriocapillaris Functional Unit

The macula demands high oxygen and ATP, rendering it uniquely vulnerable to oxidative injury. The RPE sustains photoreceptors via phagocytosis of photoreceptor outer segments, retinoid recycling, barrier maintenance, and metabolic support. When oxidative stress and inflammation impair RPE mitochondrial efficiency, proteostasis and autophagy fail, photoreceptors lose metabolic support, and choriocapillaris perfusion deteriorates [5–8].

---

3) Oxidative Stress and Mitochondrial Dysfunction

RPE mitochondria demonstrate cumulative mtDNA damage, impaired respiratory chain function, and heightened ROS production in AMD [7,8]. This generates a feedback loop linking oxidative injury to reduced ATP, lysosomal vulnerability, inflammasome activation, and apoptosis. Smoking and poor antioxidant intake magnify this susceptibility [7–9].

Clinical implication: This explains why AREDS2 antioxidant supplementation benefits intermediate AMD, but does not reverse advanced atrophy.

---

4) Lipofuscin, A2E, and drusen formation

RPE lysosomal degradation of photoreceptor outer segments produces bisretinoids, including A2E, which accumulate as lipofuscin. Photo-oxidized A2E disrupts lysosomes and inhibits autophagy, promoting drusen—extracellular deposits containing oxidized lipids, apolipoproteins, and complement proteins [5,9]. Drusen load correlates with future risk of GA and CNV [10].

---

5) Complement Dysregulation

Genetic variants affecting complement regulation (e.g., CFH, C3, CFI) heighten susceptibility to chronic para-inflammation in the macula [2,4,11]. Complement activation products localize in drusen and Bruch's membrane, while membrane-attack complexes damage the RPE [2,4].

Clinical translation: This mechanistic insight underpins C3 and C5-directed therapies that slow GA progression.

---

6) Impaired Autophagy / Proteostasis Failure

Autophagy and mitophagy are required to remove damaged mitochondria and lipofuscin precursors. Chronic oxidative stress inhibits lysosomal acidification and autophagic flux, leading to accumulation of damaged organelles and activation of inflammasome-dependent RPE death pathways [5,7].

---

7) RPE EMT and Subretinal Fibrosis

Under chronic stress, RPE cells undergo epithelial–mesenchymal transition (EMT), losing barrier function and contributing to fibrosis, especially in chronic wet AMD [1,12]. EMT explains reduced visual outcomes even when exudation is controlled.

---

8) Rod–Cone Vulnerability and Macular Neuropathy

Rod photoreceptors degenerate earlier than cones in AMD, likely due to differences in oxygen dependence and outer segment turnover [13]. Early rod loss manifests clinically as night vision difficulty and delayed dark adaptation, often preceding acuity changes.

Clinical pearl: Testing dark adaptation detects progression earlier than Snellen acuity.

---

9) Subretinal Drusenoid Deposits (Reticular Pseudodrusen)

Reticular pseudodrusen represent subretinal (not sub-RPE) lipid-rich deposits associated with choroidal vascular insufficiency, thin choroid phenotype, and higher risk of GA and CNV [14].

OCT recognition: Hyperreflective ribbon-like deposits above the RPE.

Clinical takeaway: Presence of SDD indicates faster progression risk than soft drusen alone.

---

10) The Gut–Retina Axis

Systemic low-grade inflammation can influence retinal immune tone. Altered gut microbiome composition, Western diet patterns, and increased gut permeability promote circulating inflammatory mediators that can prime complement activation and microglial reactivity in the retina [15].

Clinical translation: Mediterranean-style diet is protective not just nutritionally, but immunologically.

---

11) Neuroprotection and Synaptic Degeneration

AMD is not only a photoreceptor disease; synaptic remodeling and inner retinal neuron dysfunction occur even before cell death [16]. Loss of glutamatergic homeostasis and impaired neurotrophic support contribute to functional impairment.

This supports development of neuroprotective therapeutics (BCF2 mimetics, neurotrophins, photobiomodulation).

---

12) Microglia and Müller Glia Crosstalk

Activated microglia migrate into the subretinal space, releasing cytokines that exacerbate RPE stress. Müller gliarespond by altering metabolic support and gliotic remodeling [17]. This glia-driven immune loop amplifies degeneration even when vascular leakage is controlled.

Emerging therapeutic angle: Target microglial activation state rather than simply inhibiting cytokines.

---

13) Geographic Atrophy

GA involves progressive loss of RPE, photoreceptors, and choriocapillaris, driven by complement activation, mitochondrial failure, proteostasis collapse, and glial-mediated neuroinflammatory persistence [4,7,10].

Disease-modifying therapy:

• C3 inhibitors

• C5 inhibitors

These slow lesion expansion, but do not restore tissue.

---

14) Neovascular AMD

VEGF-mediated angiogenesis under hypoxic and inflammatory conditions produces CNV [3,4].

Anti-VEGF therapy remains first-line:

• Ranibizumab

• Aflibercept

• Bevacizumab

• Faricimab / longer-acting agents

However, fibrosis and EMT limit long-term visual recovery.

---

15) Future Directions

---

References 

1. Wang N, et al. Biomolecules. 2025;15(6):771.

2. Piri N, Kaplan HJ. Biomolecules. 2023;13(5):832.

3. Tisi A, et al. Cells. 2021;10(1):64.

4. Borchert GA, et al. Cells. 2023;12(11):2092.

5. Kaarniranta K, et al. Autophagy. 2023;19(2):388-400.

6. Somasundaran S, et al. Clin Exp Ophthalmol. 2020;48(8):1043-1058.

7. Kinnunen K, et al. Acta Ophthalmol. 2012;90(2):125-135.

8. Hyttinen JMT, et al. Int J Mol Sci. 2024;25(4):4136.

9. Luo T, et al. Invest Ophthalmol Vis Sci. 2025;66(5):30.

10. Coleman HR, et al. Lancet. 2008;372(9652):1835-45.

11. Golestaneh N, et al. Cell Death Dis. 2018;9(2):253.

12. Simo R, et al. Prog Retin Eye Res. 2022;91:101094.

13. Curcio CA, et al. Prog Retin Eye Res. 2000;19(4):421-464.

14. Spaide RF, et al. Retina. 2010;30(9):1336-44.

15. Zinkernagel MS, et al. Prog Retin Eye Res. 2020;76:100845.

16. Cehajic-Kapetanovic J, et al. IOVS. 2023;64(15):45.

17. Karlstetter M, et al. J Neuroinflammation. 2015;12:5.