Complement activation levels are related to disease stage in AMD
Open accessAbstract
Purpose: To study the levels of complement activation in different disease stages of AMD and the influence of genetic polymorphisms in complement genes. Methods: We included 797 patients with AMD and 945 controls from the European Genetic Database. Patients were grouped into five AMD stages: early AMD, intermediate AMD, central geographic atrophy, active choroidal neovascularization or inactive choroidal neovascularization. Differences in complement activation, as defined by the systemic C3d/C3 ratio, between AMD stages were evaluated using general linear modeling. In addition, we evaluated the influence of 18 genetic AMD polymorphisms in complement genes and their effect on complement activation. Differences in complement activation between stages were evaluated stratifying by complement associated haplotypes. Results: Complement activation levels differed significantly between AMD disease stages. As compared with controls, the C3d/C3 ratio was higher in patients with intermediate AMD (P < 0.001) and central geographic atrophy (P = 0.001). Two polymorphisms in CFH (rs10922109 and rs570618) and one in CFB (rs116503776) were significantly associated with complement activation. The association between AMD disease stage and complement activation was more pronounced in patients with haplotypes associated with the highest complement activation. Conclusions: In general, consecutive AMD disease stages showed increasing levels of complement activation, especially in individuals with a genetic burden in complement genes. These findings contribute to the discussion on the pathogenesis of AMD in relation to complement activation and might suggest refinement in patient selection and the optimum window of treatment with complement inhibitors. Prospective studies are needed to confirm these results.
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C3d and APOE correlate with increased AMD risk.
“both of which are more abundant in the aged retina and correlate with increased AMD risk (23–25).”
From Retinal polyunsaturated fatty acid supplementation reverses aging-related vision decline in mice (2025) · cites this paper as [25]
The Results and Discussion (page not available in our copy) associate a higher systemic C3d/C3 ratio with certain AMD stages compared with controls. They do not establish that C3d or APOE is more abundant in the aged retina, or that APOE correlates with increased AMD risk; the study measures disease-stage association rather than prospective risk. (LLM, conf=0.85)
Experimental — accuracy not yet measuredComplement component C3d is elevated in age-related macular degeneration (AMD).
“which has been shown to be elevated in AMD (24, 25)”
From Retinal polyunsaturated fatty acid supplementation reverses aging-related vision decline in mice (2025) · cites this paper as [25]
The Results report higher systemic complement activation in intermediate AMD, central geographic atrophy, and active choroidal neovascularization than in controls. However, the paper evaluates activation using the C3d/C3 ratio, not an elevation in C3d alone, and the finding does not apply uniformly to every AMD stage (Results; Complement, CRP, and Triglyceride Measurements; pages unavailable). (LLM, conf=0.86)
Experimental — accuracy not yet measuredC3d and APOE are more abundant in the aged retina.
“both of which are more abundant in the aged retina and correlate with increased AMD risk (23–25).”
From Retinal polyunsaturated fatty acid supplementation reverses aging-related vision decline in mice (2025) · cites this paper as [25]
The Results report an association between age and systemic complement activation, but do not establish that C3d is more abundant in aged retinal tissue. Searches for APOE and retinal C3d abundance found no passage addressing either protein’s abundance in the aged retina; the paper measures the systemic C3d/C3 ratio instead. (LLM, conf=0.76)
Experimental — accuracy not yet measuredLevels of circulating complement activation products may be associated with the severity of AMD.
“There is evidence suggesting that levels of circulating complement activation products may be associated with the severity of AMD”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [215]
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“demonstrated higher systemic levels of activated complement in patients with intermediate AMD (who demonstrated the highest serum complement activation), geographic atrophy and inactive neovascular AMD compared to patients with active nAMD [20].”
BackgroundMethodResultInfluentialRegulation of oxidative stress and inflammatory responses in human retinal pigment epithelial cells
Bhattarai, N. (2022) · Acta Ophthalmologica · doi:10.1111/aos.15275 · Cited by 27 · see citing works
Schäfer, N., Wolf, H. N., Enzbrenner, A., Schikora, J., Reichenthaler, M., Enzmann, V., & Pauly, D. (2020) · Antioxidants · doi:10.3390/antiox9090793 · Cited by 24 · see citing works
“This results in high levels of anaphylatoxins C3a and C5a, which have been associated with physiological and pathological processes in the retina [27,70,71]: Eye morphogenesis [31], sub-RPE depositions [32], pro-inflammatory RPE reaction [33–35], PI3/Akt-pathway activation [29], and ER stress-mediated lipid accumulati…”
BackgroundLearning from Fifteen Years of Genome-Wide Association Studies in Age-Related Macular Degeneration
Strunz, T., Kiel, C., Sauerbeck, B. L., & Weber, B. H. F. (2020) · Cells · doi:10.3390/cells9102267 · Cited by 24 · see citing works
Carozza, G., Zerti, D., Tisi, A., Ciancaglini, M., Maccarrone, M., & Maccarone, R. (2023) · Reviews in the Neurosciences · doi:10.1515/revneuro-2023-0130 · Cited by 24 · see citing works
“…with cardiovascular disease, previous cataract surgery, chronic kidney disease, hypertension, hyperthyroidism, diabetes, Parkinson ’ s and Alzheimer ’ s disease, genetic predisposition and racial background are classi fi ed as risk factors, as detailed elsewhere (Heesterbeek et al. 2020b).”
BackgroundRecent developments of neuroprotective agents for degenerative retinal disorders
Wu, J., Ou, K., Li, Y., Liu, L., Li, H., Cox, K. H. M., Liu, J., & Dick, A. D. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.335140 · Cited by 22 · see citing works
“Several other genetic variants in complement genes, such as CFB/C2, C3, C5and CFI, have since been associated with AMD (Heesterbeek et al., 2020).”
BackgroundInfluentialAssociation of plasma trace element levels with neovascular age-related macular degeneration
Heesterbeek, T. J., Rouhi, M., Church, S. J., Lechanteur, Y. T. E., Lorés‐Motta, L., Kouvatsos, N., Clark, S. J., Bishop, P. N., Hoyng, C. B., den Hollander, A. I., et al. (2020) · Experimental Eye Research · doi:10.1016/j.exer.2020.108324 · Cited by 22 · see citing works
Self-citationThe complement system in lipid-mediated pathologies
Alić, L., Dendinovic, K., & Papac-Miličević, N. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1511886 · Cited by 19 · see citing works
Alternative Complement Pathway Inhibition by Lampalizumab
Edmonds, R., Steffen, V., Honigberg, L. A., & Chang, M. (2023) · Ophthalmology Science · doi:10.1016/j.xops.2023.100286 · Cited by 20 · see citing works
Li, C., Zhou, L., Sun, H., & Yang, M. S. (2024) · Clinical Interventions in Aging · doi:10.2147/cia.s463297 · Cited by 20 · see citing works
“65 In AMD patient plasma, there is an increased concentration of activated products such as C3a, C3b, Ba, Bb, C5a, and CFH. 66 Elevated complement C5a levels significantly stimulate T cells to produce IL-22 and IL-17, promoting the onset of AMD-related inflammation.”
A critical review on air pollutant exposure and age-related macular degeneration
Liu, L., Li, C., Yu, H., & Yang, X. (2022) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2022.156717 · Cited by 21 · see citing works
Shukla, P., Russell, M. W., Muste, J. C., Shaia, J. K., Kumar, M., Nowacki, A. S., Hajj‐Ali, R. A., Singh, R. P., & Talcott, K. E. (2024) · Ophthalmology Retina · doi:10.1016/j.oret.2024.01.026 · Cited by 18 · see citing works
Sitnilska, V., Enders, P., Cursiefen, C., Fauser, S., & Altay, L. (2020) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s00417-020-04910-6 · Cited by 18 · see citing works
Self-citationOCULAR SURFACE TEMPERATURE DIFFERENCES IN RETINAL VASCULAR DISEASES
Rosenblatt, H. N., Prat, D. L., Moisseiev, J., Alhalel, A., Huna-Baron, R., Skaat, A., Pilus, S., Levi, L., & Leshno, A. (2021) · Retina · doi:10.1097/iae.0000000000003278 · Cited by 17 · see citing works
Annamalai, B., Parsons, N., Nicholson, C., Obert, E., Jones, B., & Rohrer, B. (2021) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.62.4.11 · Cited by 16 · see citing works
Kozhevnikova, O. S., Фурсова, А. Ж., Derbeneva, A. S., Nikulich, I. F., Сергеевич, Т. М., Devyatkin, V. A., Rumyantseva, Y. V., Telegina, D. V., & Kolosova, N. G. (2022) · Biomedicines · doi:10.3390/biomedicines10071658 · Cited by 16 · see citing works
Complement Inhibition for Geographic Atrophy: A Tempting Target with Mixed Results
Lin, J. B., Halawa, O. A., Miller, J. W., & Vavvas, D. G. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10132890 · Cited by 14 · see citing works
de Jong, S., de Breuk, A., Volokhina, E. B., Bakker, B., Garanto, A., Fauser, S., Katti, S. K., Hoyng, C. B., Lechanteur, Y. T. E., van den Heuvel, L. P., et al. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddab256 · Cited by 14 · see citing works
“It was previously reported that complement activation measured as C3d/C3 ratio increased with AMD progression (13).”
BackgroundSelf-citationLan, L., Wang, S., Duan, S., Zhou, X., & Li, Y. (2022) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2022/1259093 · Cited by 13 · see citing works
Treating patients with geographic atrophy: are we there yet?
Antonio‐Aguirre, B., & Arévalo, J. F. (2023) · International Journal of Retina and Vitreous · doi:10.1186/s40942-023-00493-6 · Cited by 13 · see citing works
“Studies have shown that patients with iAMD and late AMD exhibit higher levels of complement activation compared to both con-trol individuals and those with early AMD [71].”
BackgroundBiber, J., Jabri, Y., Glänzer, S., Dort, A., Hoffelner, P., Schmidt, C. Q., Bludau, O., Pauly, D., & Grosche, A. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03045-3 · Cited by 11 · see citing works
“Both findings suggest a reduced pro-inflammatory complement activity as the turnover of C3b to iC3b and downstream C3 fragments was enhanced [12, 23].”
BackgroundThomsen, A. K., Steffensen, M. A., Hinnerskov, J. M. V., Nielsen, A. T., Vorum, H., Honoré, B., Nissen, M. H., & Sørensen, T. L. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03273-7 · Cited by 11 · see citing works
Retinal polyunsaturated fatty acid supplementation reverses aging-related vision decline in mice
Gao, F., Tom, E., Rydz, C., Cho, W., Kolesnikov, A. V., Sha, Y., Papadam, A., Jafari, S., Joseph, A., Ahanchi, A., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.ads5769 · Cited by 10 · see citing works
The Relationship between Complements and Age-Related Macular Degeneration and Its Pathogenesis
Chu, L., Bi, C., Wang, C., & Zhou, H. (2024) · Journal of Ophthalmology · doi:10.1155/2024/6416773 · Cited by 10 · see citing works
“C3 is the most abundant, and its cleavage products, C3a and C3b, are also the hubs for the activation of the entire complement system [124].”
BackgroundRole of Complement in the Onset of Age-Related Macular Degeneration
Piri, N., & Kaplan, H. J. (2023) · Biomolecules · doi:10.3390/biom13050832 · Cited by 12 · see citing works
“In contrast, the level of systemic complement activation in wet AMD is relatively low [12,70].”
InfluentialCell-Type-Specific Complement Profiling in the ABCA4−/− Mouse Model of Stargardt Disease
Jabri, Y., Biber, J., Díaz‐Lezama, N., Grosche, A., & Pauly, D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228468 · Cited by 10 · see citing works
Systemic Complement Activation Profiles in Nonexudative Age-Related Macular Degeneration
Lin, J. B., Serghiou, S., Miller, J. W., & Vavvas, D. G. (2022) · Ophthalmology Science · doi:10.1016/j.xops.2022.100118 · Cited by 9 · see citing works
“CFH* 312 (253-420) mg/ml Lynch et al(22) C3ay 34 (20-75) ng/ml sC5b-9y 141 (87-220) ng/ml”
Chaudhary, V., Chair, R. E. T. I. A. (. E. T. I. N. A. ). S. G., Bhandari, M., Wykoff, C. C., Sivaprasad, S., Thabane, L., Kaiser, P. K., Sarraf, D., Bakri, S. J., Garg, S. J., et al. (2022) · Eye · doi:10.1038/s41433-022-02221-0 · Cited by 9 · see citing works
Vujosevic, S., Limoli, C., & Kozak, I. (2024) · Eye · doi:10.1038/s41433-024-03341-5 · Cited by 9 · see citing works
“This suggests that AMD might be a manifestation of chronic, low-grade systemic complement activation, especially in aging individuals with complement gene variants [36, 132].”
Ong, J., Selvam, A., Driban, M., Zarnegar, A., Silva, S. I. M. M. A. D., Joy, J. G., Rossi, E. A., Geest, J. P. V., Sahel, J., & Chhablani, J. (2025) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2025.101358 · Cited by 9 · see citing works
“Overactivity of the complement cascade caused by environmental factors such as advanced age and smoking or by genetic mutations can result in inflammation that disturbs BM.(Gaya da Costa et al., 2018; Heesterbeek et al., 2020; Paun et al., 2015; Ristau et al., 2014).”
Armento, A., Merle, D. A., & Ueffing, M. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-27681-1_2 · Cited by 8 · see citing works
Genetic and molecular biomarkers for geographic atrophy
Riley-Gillis, B. M., Huh, H., Shen, J., & den Hollander, A. I. (2023) · Acta Ophthalmologica · doi:10.1111/aos.15803 · Cited by 8 · see citing works
Nusinovici, S., Zhou, L., Wang, X., Tham, Y. C., Wang, X., Wong, T. Y., Chakravarthy, U., & Cheng, C. (2024) · Ophthalmology Science · doi:10.1016/j.xops.2024.100538 · Cited by 8 · see citing works
“Higher levels of complement activation (C3d/C3 ratio) have been found in patients with intermediate AMD and late dry AMD, compared with both controls and early AMD groups, 15 suggesting that this excessive activation of the complement cascade is at play after the onset of the disease.”
The Role of the Complement Pathway in Clinical Progression of Geographic Atrophy
Edmonds, R., Steffen, V., Honigberg, L. A., & Chang, M. (2023) · Ophthalmology Science · doi:10.1016/j.xops.2023.100301 · Cited by 8 · see citing works
“Altered levels of complement activation in serum samples were associated with the SNPs rs10922109 and rs570618 (CFH gene) and rs116503776 (CFB gene).(13) However, 15 other selected”
BackgroundResultInfluentialSystemic complement activation levels in Stargardt disease
Dhooge, P. P. A., Runhart, E. H., Li, C. H. Z., Angelino, C. M. D. K., Hoyng, C. B., Molen, R. G. V. D., & den Hollander, A. I. (2021) · PLoS ONE · doi:10.1371/journal.pone.0253716 · Cited by 7 · see citing works
“amplifies the complement response in AMD [40].”
BackgroundSelf-citationYu, H. J., & Wykoff, C. C. (2021) · BioDrugs · doi:10.1007/s40259-021-00481-y · Cited by 7 · see citing works
Lynch, A. M., Grove, N. C., Wagner, B. D., Palestine, A. G., Holers, V. M., Frazer‐Abel, A. A., Gnanaraj, R., Lisker-Cervantes, A., Patnaik, J. L., de Carlo, T. E., et al. (2025) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2025.1608 · Cited by 5 · see citing works
A systematic review on age-related macular degeneration: New insights from multi-omics studies
Castro-Fernández, D. C., Cañizo-Outeiriño, A., Cuartero‐Martínez, A., Gil‐Martínez, M., Mondelo‐García, C., González‐Barcia, M., Álvarez-Barrios, A., & Fernández‐Ferreiro, A. (2026) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2026.02.001 · Cited by 4 · see citing works
de Carlo, T. E., Marin, A. I., Gill, Z. S., Gnanaraj, R., Patnaik, J. L., Poppelaars, F., Lynch, A. M., Palestine, A. G., Mathias, M. T., Manoharan, N., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-31051-9 · Cited by 2 · see citing works
“Various research groups 10–14 , including ours 7–9 , have proposed that systemic inflammation is involved in the pathogenesis of AMD.”
Redox Regulation of Complement Pathway Activation in Aging and Related Diseases
Ferdowsi, S., Arjuna, S., Sudharshan, S. J., & Zennadi, R. (2025) · Antioxidants · doi:10.3390/antiox15010029 · Cited by 2 · see citing works
“The ratio of C3d/C3 is significantly higher in AMD patients, indicating sustained complement activation [228].”
Elloumi, Y., & Kachouri, R. (2023) · International Conference on Image Processing Theory, Tools and Applications (IPTA) · doi:10.1109/ipta59101.2023.10320012 · Cited by 2 · see citing works
“(b) [10].”
Genotype-Phenotype Correlations and Genetic Risk Assessment in Age-Related Macular Degeneration
Jaskoll, S., Kramer, A., Elbaz-Hayoun, S., Rinsky, B., Grunin, M. A., Tiosano, L., Vofo, B. N., Shwartz, Y., & Chowers, I. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-76550-6_4 · Cited by 2 · see citing works
Altay, L., Lemke, J., Schröder–Braunstein, J., Gietzelt, C., Sitnilska, V., Schaub, F., Cursiefen, C., Enders, P., & Fauser, S. (2021) · Ophthalmologica · doi:10.1159/000516885 · Cited by 2 · see citing works
Self-citationZhu, M., Wu, B., Chenzhao, C., Chen, H., & Xiong, W. (2024) · PubMed Central · doi:10.11817/j.issn.1672-7347.2024.240062 · Cited by 1 · see citing works
Jones, A., Sun, A., Yang, H., Latuszek, A., Negron, N., Shi, P., Fury, W., Lehmann, G. L., Hu, Y., & Sagdullaev, B. T. (2025) · Experimental Eye Research · doi:10.1016/j.exer.2025.110433 · Cited by 1 · see citing works
Effect of Pegcetacoplan on Aqueous Humor Proteome in Geographic Atrophy: A Prospective Exploration
Trivizki, O., Wykoff, C. C., Smoor, M. A., Rabinovitch, D., Zhou, A., Cao, J. A., Lechanteur, Y. T. E., van den Heuvel, L., van Gool, A. J., Gloerich, J., et al. (2025) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.66.15.24 · Cited by 1 · see citing works
“Additionally, elevated complement activation markers have been detected in the systemic circulation, 2,8 many complement components are found in drusen, 9 and the membrane attack complex (MAC) is significantly increased in the choroid of AMD patients.”
Self-citationSalkar, A., Palanivel, V., Basavarajappa, D. K., Heng, B., Schulz, A. M., Gupta, V. K., Graham, S. L., Mirzaei, M., & You, Y. (2026) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-01905 · Cited by 2 · see citing works
“Complement activation increases with AMD progression, especially in patients carrying high-risk complement factor H and complement factor B variants (Heesterbeek et al., 2020).”
Analysis of hemopexin plasma levels in patients with age-related macular degeneration.
Lauwen, S., Bakker, B., de Jong, E. K., Fauser, S., Hoyng, C. B., Lefeber, D. J., & den Hollander, A. I. (2022) · PubMed Central · Cited by 1 · see citing works
Self-citationGene Editing: New Opportunities for the Treatment of Age-related Macular Degeneration
<p>Tianshuo Zhang, S. T. (2025) · Frontiers in Medical Science Research · doi:10.25236/fmsr.2025.070207 · Cited by 1 · see citing works
Common and rare variants in patients with early onset drusen maculopathy
de Breuk, A., Lechanteur, Y. T. E., Astuti, G., Corominas, J., Klaver, C. C. W., Hoyng, C. B., & den Hollander, A. I. (2022) · Clinical Genetics · doi:10.1111/cge.14212 · Cited by 1 · see citing works
“Higher complement activation levels are reported in AMD patients compared to control individuals.(28) Therefore, we expect that nonsense 420 de BREUK ET AL.”
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Lu, F., Zhang, J., Lu, J., Jiang, W., Fei, Z., Xiao, Q., & Wang, Z. (2026) · Medicine · doi:10.1097/md.0000000000046598
Forest, T. E. D. C., Grove, N. C., Cordaro, N. J., Veturi, Y. A., Wagner, B. D., Manoharan, N., Lisker-Cervantes, A., Bearce, B., McNamara, S., Lynch, A. M., et al. (2026) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.67.12.69
- Authors
- Heesterbeek, T. J., Lechanteur, Y. T. E., Lorés-Motta, L., Schick, T., Daha, M. R., Altay, L., Liakopoulos, S., Smailhodzic, D., den Hollander, A. I., Hoyng, C. B., de Jong, E. K., & Klevering, B. J.
- Affiliations
- Radboud University Medical Center (NL)
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
- University Hospital Cologne (DE)
- Leiden University Medical Center (NL)
- Corresponding author
- Klevering, B. Jeroen
- ORCID
- Venue
- Investigative Opthalmology & Visual Science
- Published
- 2020-03-16
- Volume
- 61
- Issue
- 3
- Pages
- 18
- ISSN
- 0146-0404 (ISSN-L)
- 1552-5783
- PMC
- PMC7401663
- OpenAlex
- W3010752005
- Cited by
- 76
- References
- 51
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 13 · 2023: 12 · 2022: 13 · 2021: 15 · 2020: 8
- FWCI
- 9.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Investigative Ophthalmology & Visual Science (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Leiden Repository (Leiden University) (submittedVersion, cc-by-nc-nd)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by-nc-nd)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Radboud Universiteit
- Radboud Universitair Medisch Centrum
- Oogfonds
- Algemene Nederlandse Vereniging ter voorkoming van Blindheid
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- age-related macular degeneration, complement activation, disease stage, choroidal neovascularization, complement factor H, CFB, complement inhibitors, AMD pathogenesis
- MeSH terms
- Aged, C-Reactive Protein, Complement Activation, Complement C3, Haplotypes, Humans, Macular Degeneration, Middle Aged, Severity of Illness Index, Triglycerides, Complement C3d, Case-Control Studies, Polymorphism, Single Nucleotide, Databases, Genetic
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