Rezumat
Introduction Apolipoprotein E (APOE) gene significantly affects lipid metabolism and CVD susceptibility, with its isoforms exerting different effects on cholesterol levels and cardiovascular health. Of particular concern is the APOE4 allele, which is linked to dyslipidemia, elevated LDL-C levels, and increased oxidative stress, thereby heightening the risk for coronary artery disease (CAD) and stroke. This review explores the complex relationship between APOE genotypes, lipid metabolism, and CVD risk, with a specific focus on the APOE4 allele.
Materials and Methods This review followed a systematic literature review (SLR) methodology in accordance with PRISMA guidelines. Implementing a pre-defined eligibility and screening criteria, 48 studies were included in the review.
Results It highlights the influence of dietary fat intake on lipid profiles and the potential for targeted nutritional interventions in individuals carrying the APOE4 allele to mitigate genetic risk. Despite evidence linking APOE4 to impaired lipid clearance and cardiovascular pathology, research examining the interplay of genetics, nutrition, and metabolism in CVD remains limited.
Conclusion This paper emphasizes the importance of personalized dietary strategies tailored to an individual's APOE genotype to improve lipid metabolism, reduce CVD risk, and enhance overall cardiovascular health. By better understanding the genetic-nutritional relationship, clinicians and researchers can design more effective preventive and therapeutic strategies for individuals at higher genetic risk for CVD.
Referințe
1. World Health Organization. Cardiovascular diseases (CVDs) Fact Sheet. Updated 2025/2026. Available at: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds
2. Shahjehan RD, Bhutta BS. Coronary Artery Disease. In: StatPearls. StatPearls Publishing; 2024. Accessed June 2, 2025. https://www.ncbi.nlm.nih.gov/books/NBK564304/.
3. Scudeler TL, da Costa LMA, Nunes RAB, et al. Association between low-density lipoprotein cholesterol levels and all-cause mortality in patients with coronary artery disease: a real-world analysis using data from an international network. Sci Rep. 2024;14(1):29201. https://doi.org/10.1038/s41598-024-80578-w
4. Ozen E, Lovegrove JA, Jackson KG. Association between body composition and cardiometabolic disease risk: role of dietary fat intake and APOLIPOPROTEIN E genotype on this relationship. Proc Nutr Soc. 2024;83(OCE1):1-9. https://doi.org/10.1017/S0029665124000053.
5. Feingold KR. The effect of diet on cardiovascular disease and lipid and lipoprotein levels. In: Feingold KR, Anawalt B, Blackman MR, et al, eds. Endotext. MDText.com, Inc.; 2021.
6. Yang LG, March ZM, Stephenson RA, Narayan PS. Apolipoprotein E in lipid metabolism and neurodegenerative disease. Trends Endocrinol Metab. 2023;34(8):430-445. https://doi.org/10.1016/j.tem.2023.05.002.
7. Field CJ, Robinson L. Dietary fats. Adv Nutr. 2019;10(4):722-724. https://doi.org/10.1093/advances/nmz052.
8. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240(4852):622-630. https://doi.org/10.1126/science.3283935.
9. Marais AD. Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease. Pathology. 2019;51(2):165-176. https://doi.org/10.1016/j.pathol.2018.11.002.
10. Marrzoq LFA, Sharif FA, Abed AA. Relationship between ApoE gene polymorphism and coronary heart disease in Gaza Strip. J Cardiovascular Dis Res. 2011;2(1):29-35. https://doi.org/10.4103/0975-3583.78584
11. Phillips MC. Apolipoprotein E isoforms and lipoprotein metabolism. IUBMB Life. 2014;66(9):616-623. https://doi.org/10.1002/iub.1314.
12. Beeri MS, Rapp M, Silverman J, et al. Coronary artery disease is associated with Alzheimer disease neuropathology in APOE4 carriers. Neurology. 2006;66(9):1399-1404. https://doi.org/10.1212/01.wnl.0000210447.19748.0b.
13. Husain MA, Laurent B, Plourde M. APOE and Alzheimer’s disease: from lipid transport to physiopathology and therapeutics. Front Neurosci. 2021;15:630502. https://doi.org/10.3389/fnins.2021.630502.
14. Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med. 2016;94(7):739-746. https://doi.org/10.1007/s00109-016-1427-y.
15. Hazarika L, Sen S, Doshi J. Molecular docking analysis of arjunolic acid from Terminalia arjuna with a coronary artery disease target APOE4. Bioinformation. 2021;17(11):949-954. https://doi.org/10.6026/97320630017949.
16. Hazarika L, Sen S, Doshi J. Computational Studies and Scaffold Search for APOE4 as Coronary Artery Disease Target by Virtual Screening. Comput Biol Bioinform. 2022;10(2):49-59. https://doi.org/ 10.11648/j.cbb.20221002.11.
17. Hazarika L, Sen S, Zawar A, Doshi J. Identification of APOE4 modulators, targeted therapeutic candidates in Coronary Artery Disease, using Molecular Docking studies. bioRxiv. Published online February 2, 2021. https://doi.org/10.11648/j.jddmc.20210702.11.
18. Marcel YL, Vezina C, Milne RW. Cholesteryl ester and apolipoprotein E transfer between human high density lipoproteins and chylomicrons. Biochim Biophys Acta. 1983;750(2):411-417. https://doi.org/10.1016/0005-2760(83)90047-4.
19. Chou CY, Jen WP, Hsieh YH, Shiao MS, Chang GG. Structural and functional variations in human apolipoprotein E3 and E4. J Biol Chem. 2006;281(19):13333-13344. https://doi.org/10.1074/jbc.M511077200.
20. Lalazar A, Mahley RW. Human apolipoprotein E: receptor binding activity of truncated variants with carboxyl-terminal deletions. J Biol Chem. 1989;264(15):8447-8450. Accessed June 2, 2025. https://pubmed.ncbi.nlm.nih.gov/2542277/.
21. Safieh M, Korczyn AD, Michaelson DM. ApoE4: an emerging therapeutic target for Alzheimer’s disease. BMC Med. 2019;17(1):64. https://doi.org/10.1186/s12916-019-1299-4.
22. Mahley RW, Rall SC Jr. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 2000;1:507-537. https://doi.org/10.1146/annurev.genom.1.1.507.
23. Rall SC Jr, Weisgraber KH, Mahley RW. Human apolipoprotein E: the complete amino acid sequence. J Biol Chem. 1982;257(8):4171-4178. Accessed June 2, 2025. https://pubmed.ncbi.nlm.nih.gov/7068630/.
24. Rezeli M, Zetterberg H, Blennow K, et al. Quantification of total apolipoprotein E and its specific isoforms in cerebrospinal fluid and blood in Alzheimer’s disease and other neurodegenerative diseases. EuPA Open Proteomics. 2015;8:137-143. https://doi.org/10.1016/j.euprot.2015.06.001.
25. Weisgraber KH. Apolipoprotein E: structure-function relationships. Adv Protein Chem. 1994;45:249-302. https://doi.org/10.1016/s0065-3233(08)60642-7.
26. Mahley RW. Central nervous system lipoproteins: ApoE and regulation of cholesterol metabolism. Arterioscler Thromb Vasc Biol. 2016;36(7):1305-1315. https://doi.org/10.1161/ATVBAHA.116.307023.
27. Frieden C, Garai K. Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease. Proc Natl Acad Sci U S A. 2012;109(23):8913-8918. https://doi.org/10.1073/pnas.1207022109.
28. Li H, Dhanasekaran P, Alexander ET, Rader DJ, Phillips MC, Lund-Katz S. Molecular mechanisms responsible for the differential effects of apoE3 and apoE4 on plasma lipoprotein–cholesterol levels. Arterioscler Thromb Vasc Biol. 2013;33(4):687-693. https://doi.org/10.1161/ATVBAHA.112.301193.
29. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA. 1997;278(16):1349-1356. https://doi.org/10.1001/jama.1997.03550160069041.
30. Leduc V, Domenger D, De Beaumont L, Lalonde D, Bélanger-Jasmin S, Poirier J. Function and comorbidities of apolipoprotein E in Alzheimer's disease. Int J Alzheimer Dis. 2011;2011:974361. https://doi.org/10.4061/2011/974361.
31. Ashiq S, Ashiq K. The association of apolipoprotein-E (APOE) gene polymorphisms with coronary artery disease: a systematic review and meta-analysis. Egypt J Med Hum Genet. 2021;22(1):4. https://doi.org/10.1186/s43042-021-00135-2.
32. Chen J, Li Q, Wang J. Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A. 2011;108(36):14813-14818. https://doi.org/10.1073/pnas.1106420108.
33. Moriarty PM. Association of ApoE and HDL-C with cardiovascular and cerebrovascular disease: potential benefits of LDL-apheresis therapy. Clin Lipidol. 2009;4(3):311-329. https://doi.org/10.2217/clp.09.21.
34. Minihane AM, Jofre-Monseny L, Olano-Martin E, Rimbach G. ApoE genotype, cardiovascular risk and responsiveness to dietary fat manipulation: symposium on ‘Molecular basis for diseases’. Proc Nutr Soc. 2007;66(2):183-197. https://doi.org/10.1017/S0029665107005435.
35. Das M, Pal S, Ghosh A. Apolipoprotein E gene polymorphism and dyslipidaemia in adult Asian Indians: a population based study from Calcutta, India. Indian J Hum Genet. 2008;14(3):87-91. https://doi.org/10.4103/0971-6866.45000.
36. Cahua-Pablo G, Cruz M, Moral-Hernández OD, et al. Elevated levels of LDL-C are associated with ApoE4 but not with the rs688 polymorphism in the LDLR gene. Clin Appl Thromb Hemost. 2016;22(5):465-470. https://doi.org/10.1177/1076029614568714.
37. Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988;8(1):1-21. https://doi.org/10.1161/01.ATV.8.1.1.
38. Minihane A, Jofre-Monseny L, Olano-Martin E, Rimbach G. ApoE genotype, cardiovascular risk and responsiveness to dietary fat manipulation: symposium on ‘Molecular basis for diseases’. Proceedings of the Nutrition Society. 2007;66(2):183–197. https://doi.org/10.1017/s00296651070054
39. Weisgraber KH. Apolipoprotein E distribution among human plasma lipoproteins: role of the cysteine-arginine interchange at residue 112. J Lipid Res. 1990;31(8):1503-1511. https://doi.org/10.1016/S0022-2275(20)42621-5.
40. Feingold KR. Introduction to lipids and lipoproteins. In: Feingold KR, Anawalt B, Blackman MR, et al, eds. Endotext. MDText.com, Inc.; 2024.
41. Jackson KG, Maitin V, Leake DS, Yaqoob P, Williams CM. Saturated fat-induced changes in Sf 60–400 particle composition reduces uptake of LDL by HepG2 cells. J Lipid Res. 2006;47(2):393-403. https://doi.org/10.1194/jlr.M500382-JLR200.
42. Kris-Etherton PM, Petersen K, Van Horn L. Convincing evidence supports reducing saturated fat to decrease cardiovascular disease risk. BMJ Nutr Prev Health. 2018;1(1):23-26. https://doi.org/10.1136/bmjnph-2018-000009.
43. Leren P. The Oslo diet-heart study: eleven-year report. Circulation. 1970;42(5):935-942. https://doi.org/10.1161/01.CIR.42.5.935.
44. Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Trans fatty acids and cardiovascular disease. N Engl J Med. 2006;354(15):1601-1613. https://doi.org/10.1056/NEJMra054035.
45. Chowdhury R, Warnakula S, Kunutsor S, et al. Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis. Ann Intern Med. 2014;160(6):398-406. https://doi.org/10.7326/M13-1788.
46. Ramsden CE, Zamora D, Leelarthaepin B, et al. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ. 2013;346:e8707. https://doi.org/10.1136/bmj.e8707.
47. Li Y, Hruby A, Bernstein AM, et al. Saturated fats compared with unsaturated fats and sources of carbohydrates in relation to risk of coronary heart disease: a prospective cohort study. J Am Coll Cardiol. 2015;66(14):1538-1548. https://doi.org/10.1016/j.jacc.2015.07.055.
48. Sacks FM, Lichtenstein AH, Wu JH, et al. Dietary fats and cardiovascular disease: a presidential advisory from the American Heart Association. Circulation. 2017;136(3):e1-e23. https://doi.org/10.1161/CIR.0000000000000510
49. Gunness P, Gidley MJ. Mechanisms underlying the cholesterol-lowering properties of soluble dietary fibre polysaccharides. Food Funct. 2010;1(2):149-155. https://doi.org/10.1039/C0FO00080A.
50. Calpe-Berdiel L, Escolà-Gil JC, Blanco-Vaca F. New insights into the molecular actions of plant sterols and stanols in cholesterol metabolism. Atherosclerosis. 2009;203(1):18-31. https://doi.org/10.1016/j.atherosclerosis.2008.06.026.
51. Weingärtner O, Böhm M, Laufs U. Controversial role of plant sterol esters in the management of hypercholesterolaemia. Eur Heart J. 2009;30(4):404-409. https://doi.org/10.1093/eurheartj/ehn580.
52. Hendriks HF, Weststrate JA, van Vliet T, Meijer GW. Spreads enriched with three different levels of vegetable oil sterols and the degree of cholesterol lowering in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr. 1999;53(4):319-327. https://doi.org/10.1038/sj.ejcn.1600728.
53. Makhmudova U, Schulze PC, Lütjohann D, Weingärtner O. Phytosterols and cardiovascular disease. Curr Atheroscler Rep. 2021;23(11):68. https://doi.org/10.1007/s11883-021-00964-x.
54. Farvid MS, Ding M, Pan A, et al. Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation. 2014;130(18):1568-1578. https://doi.org/10.1161/CIRCULATIONAHA.114.010236.
55. Siri-Tarino PW, Sun Q, Hu FB, Krauss RM. Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease. Am J Clin Nutr. 2010;91(3):535-546. https://doi.org/10.3945/ajcn.2009.27725.
56. Reiner Ž. Resistance and intolerance to statins. Nutr Metab Cardiovasc Dis. 2014;24(10):1057-1066. https://doi.org/10.1016/j.numecd.2014.05.009.
57. Choi JY, Na JO. Pharmacological strategies beyond statins: ezetimibe and PCSK9 inhibitors. J Lipid Atheroscler. 2019;8(2):183-192. https://doi.org/10.12997/jla.2019.8.2.183.
58. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):e285-e350. https://doi.org/10.1016/j.jacc.2018.11.003.
59. Wehner GJ, Jing L, Haggerty CM, et al. Routinely reported ejection fraction and mortality in clinical practice: where does the nadir of risk lie? Eur Heart J. 2020;41(12):1249-1257. https://doi.org/10.1093/eurheartj/ehz550.
60. Ordovas JM, Lopez-Miranda J, Mata P, Perez-Jimenez F, Lichtenstein AH, Schaefer EJ. Gene-diet interaction in determining plasma lipid response to dietary intervention. Atherosclerosis. 1995;118(suppl):S11-S27. https://doi.org/10.1016/0021-9150(95)90069-1.
61. Flock MR, Green MH, Kris-Etherton PM. Effects of adiposity on plasma lipid response to reductions in dietary saturated fatty acids and cholesterol. Adv Nutr. 2011;2(3):261-274. https://doi.org/10.3945/an.111.000422.
62. Yang B, Mallett S, Takwoingi Y, Davenport CF, Hyde CJ, Whiting PF, et al. QUADAS-C: a tool for assessing risk of bias in comparative diagnostic accuracy studies. Ann Intern Med. 2021;174(11):1592–9. https://doi.org/10.7326/M21-2234.

Această lucrare este licențiată în temeiul Creative Commons Attribution 4.0 International License.
Copyright (c) 2026 Chandan DAS, Bishakha BORA, Nabanita PAUL, Lima HAZARIKA
