The APOE ε2 allele is associated with risk of neovascular age-related macular degeneration in a Russian cohort

Age-related macular degeneration (AMD) is a progressive disease that leads to blindness and is the cause of visual impairment in an aging population. Apolipoprotein E (ApoE) is one of the key proteins in lipoprotein metabolism. ApoE is expressed in the retina and is found in drusen in AMD patients. ApoE isoforms are significant genetic determinants of AMD risk (ε2 > ε3 > ε4), wherein the effects of APOE alleles vary by ethnic group. APOE genotype may also influence response to treatment. Here we examine the effect of APOE alleles on the risk of neovascular AMD and response to anti-VEGF treatment in patients from the population of Western Siberia. Genotyping of the rs429358 and rs7412 polymorphisms of the APOE gene was carried out in patients with neovascular AMD (n = 315) and the control group (n = 317) using allele-specific PCR. To assess the association of APOE alleles with treatment response, 275 patients were categorized into three groups of treatment response (good, weak, no response) after three loading injections of aflibercept. We revealed a significant association between the ε2 allele and neovascular AMD: carriers of ε2 had a 1.5- fold higher risk of AMD compared with carriers of other allelic variants (OR = 1.536; 95% CI: 1.075–2.195). The results indicate a moderate association of the ε2 allele with the development of neovascular AMD in the Russian population. However, no association was found between APOE genotype and short-term response to anti-VEGF therapy. 

1. Abyadeh M., Gupta V., Paulo J.A., Sheriff S., Shadfar S., Fitzhenry M., Amirkhani A., Gupta V., Salekdeh G.H., Haynes P.A., Graham S.L., Mirzaei M. Apolipoprotein ε in brain and retinal neurodegenerative diseases. Aging Dis. 2023;14(4):1311-1330. doi 10.14336/AD.2023.0312-1

2. Adams M.K., Simpson J.A., Richardson A.J., English D.R., Aung K.Z., Makeyeva G.A., Guymer R.H., Giles G.G., Hopper J., Robman L.D., Baird P.N. Apolipoprotein E gene associations in age-related macular degeneration: the Melbourne Collaborative Cohort Study. Am J Epidemiol. 2012;175(6):511-518. doi 10.1093/aje/kwr329

3. Amoaku W.M., Chakravarthy U., Gale R., Gavin M., Ghanchi F., Gibson J., Harding S., Johnston R.L., Kelly S.P., Lotery A., Mahmood S., Menon G., Sivaprasad S., Talks J., Tufail A., Yang Y. Defining response to anti­VEGF therapies in neovascular AMD. Eye (Lond.). 2015;29(6):721-731. doi 10.1038/eye.2015.48

4. Anderson D.H., Ozaki S., Nealon M., Neitz J., Mullins R.F., Hageman G.S., Johnson L.V. Local cellular sources of apolipoprotein E in the human retina and retinal pigmented epithelium: implications for the process of drusen formation. Am J Ophthalmol. 2001;131(6): 767-781. doi 10.1016/s0002-9394(00)00961-2

5. Bakbak B., Ozturk B.T., Zamani A.G., Gonul S., Iyit N., Gedik S., Yıldırım M.S. Association of apolipoprotein E polymorphism with intravitreal ranibizumab treatment outcomes in age-related macular degeneration. Curr Eye Res. 2016;41(6):862-866. doi 10.3109/02713683.2015.1067325

6. Chan M.L., Meyer O.L., Farias S.T., Whitmer R.A., Rajan K., Olichney J., Johnson D., Mungas D. APOE effects on late life cognitive trajectories in diverse racial/ethnic groups. J Int Neuropsychol Soc. 2023;29(2):126-135. doi 10.1017/S1355617722000030

7. Fernández-Vega B., García M., Olivares L., Álvarez L., González-Fernández A., Artime E., Fernández-Vega Cueto A., Cobo T., CocaPrados M., Vega J.A., González-Iglesias H. The association study of lipid metabolism gene polymorphisms with AMD identifies a protective role for APOE-E2 allele in the wet form in a Northern Spanish population. Acta Ophthalmol. 2020;98(3):e282-e291. doi 10.1111/aos.14280

8. Fritsche L.G., Igl W., Bailey J.N., Grassmann F., Sengupta S., BraggGresham J.L., Burdon K.P., … Lee K.E., Hunter D.J., Sardell R.J., Mitchell P., Heid I.M. 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. doi 10.1038/ng.3448

9. Fursova A.Zh., Derbeneva A.S., Vasilyeva M.A., Nikulich I.F., Tarasov M.S., Gamza Yu.A., Chubar N.V., Gusarevich O.G., Dmitrieva E.I., Telegina D.V., Kozhevnikova O.S. Current data on the age-related macular degeneration pathophysiology: focus on growth factors and neurotrophins. Adv Gerontol. 2023;13:105-115. doi 10.1134/S2079057024600162

10. Gupta D., Chawla S. Association of apolipoprotein E (APOE) gene polymorphism with age-related macular degeneration (AMD) in Indian patients. Cureus. 2025;17(6):e85441. doi 10.7759/cureus.85441

11. Hu M.L., Quinn J., Xue K. Interactions between apolipoprotein E metabolism and retinal inflammation in age­related macular degeneration. Life (Basel). 2021;11(7):635. doi 10.3390/life11070635

12. Huebbe P., Rimbach G. Evolution of human apolipoprotein E (APOE) isoforms: gene structure, protein function and interaction with dietary factors. Ageing Res Rev. 2017;37:146-161. doi 10.1016/j.arr.2017.06.002

13. Kozhevnikova O.S., Fursova A.Z., Derbeneva A.S., Nikulich I.F., Devyatkin V.A., Kolosova N.G. Pharmacogenetic association between allelic variants of the autophagy-related genes and anti-vascular endothelial growth factor treatment response in neovascular agerelated macular degeneration. Biomedicines. 2023;11(11):3079. doi 10.3390/biomedicines11113079

14. Levy O., Lavalette S., Hu S.J., Housset M., Raoul W., Eandi C., Sahel J.A., Sullivan P.M., Guillonneau X., Sennlaub F. APOE isoforms control pathogenic subretinal inflammation in age­related macular degeneration. J Neurosci. 2015;35(40):13568-13576. doi 10.1523/JNEUROSCI.2468-15.2015

15. Lin J.B., Halawa O.A., Husain D., Miller J.W., Vavvas D.G. Dyslipidemia in age-related macular degeneration. Eye (Lond). 2022;36(2): 312-318. doi 10.1038/s41433-021-01780-y

16. Liuska P.J., Rämö J.T., Lemmelä S., Kaarniranta K., Uusitalo H., Lahtela E., Daly M.J., Harju M., Palotie A., Turunen J.A.; for the FinnGen Study†. Association of APOE haplotypes with common agerelated ocular diseases in 412,171 individuals. Invest Ophthalmol Vis Sci. 2023;64(14):33. doi 10.1167/iovs.64.14.33

17. Ramadan A., Foda B.M., Sabry N.A., Refaat O., Saleh A.A., Fawzy A. Association analysis of ApoE gene polymorphisms among Egyptian patients with Alzheimer’ disease. Gene Rep. 2019;14:65-71. doi. org/10.1016/j.genrep.2018.10.017

18. Rasmussen K.L., Tybjærg-Hansen A., Nordestgaard B.G., FrikkeSchmidt R. Associations of Alzheimer disease-protective APOE variants with age-related macular degeneration. JAMA Ophthalmol. 2023;141(1):13-21. doi 10.1001/jamaophthalmol.2022.4602

19. Sun E., Lim A., Liu X., Snellingen T., Wang N., Liu N. Apolipoprotein E gene and age-related macular degeneration in a Chinese population. Mol Vis. 2011;17:997-1002

20. Viturino M.G., Neto J.M., Bajano F.F., Costa S.M., Roque A.B., Borges G.F., Ananina G., Rim P.H., Medina F.M., Costa F.F., Vasconcellos J.P., Melo M.B. Evaluation of APOE polymorphisms and the risk for age-related macular degeneration in a Southeastern Brazilian population. Exp Biol Med (Maywood). 2021;246(10):1148-1155. doi 10.1177/1535370220985466

21. Wickremasinghe S.S., Xie J., Lim J., Chauhan D.S., Robman L., Richard son A.J., Hageman G., Baird P.N., Guymer R. Variants in the APOE gene are associated with improved outcome after anti-VEGF treatment for neovascular AMD. Invest Ophthalmol Vis Sci. 2011; 52(7):4072-4079. doi 10.1167/iovs.10-6550

22. Wisniewski T., Drummond E. APOE-amyloid interaction: therapeutic targets. Neurobiol Dis. 2020;138:104784. doi 10.1016/j.nbd.2020.104784

23. Xiying M., Wenbo W., Wangyi F., Qinghuai L. Association of apolipoprotein E polymorphisms with age-related macular degeneration subtypes: an updated systematic review and meta-analysis. Arch Med Res. 2017;48(4):370-377. doi 10.1016/j.arcmed.2017.08.002

24. Zhong L., Xie Y.Z., Cao T.T., Wang Z., Wang T., Li X., Shen R.C., Xu H., Bu G., Chen X.F. A rapid and cost­effective method for genotyping apolipoprotein E gene polymorphism. Mol Neurodegener. 2016;11:2. doi 10.1186/s13024-016-0069-4