Kadınlarda Alzheimer Hastalığına Duyarlılığı Artıran Östrojen Reseptörü Alfa (ERα) Gen Polimorfizmi rs2228480

Abstract

Amaç: Alzheimer hastalığı (AD), beta-amiloid ve tau birikimi ile hafıza kaybı ve günlük yaşamda bozulmaya yol açan nörodejeneratif bir hastalıktır ve kadınlarda daha sık görülür. Bu farklılık temel alınarak çalışmada, AD’li kadınlarda östrodiol (E2) düzeyleri ve ESR1 genindeki rs2228480 ve rs2295190 polimorfizmleri incelenerek kalıtsal yatkınlık araştırılmıştır. Gereç ve Yöntemler: Çalışmaya 66 AD tanısı almış ve 62 herhangi bir hastalığı olmayan kadın bireyler dahil edildi. E2 düzeyi katılımcılardan alınan plazma örneklerinde Elektrokemilüminesans immünoassay “ECLIA” yöntemi ile ölçüldü. Tam kandan izole edilen DNA örneklerinde ESR1’deki rs2228480 ve rs2295190 polimorfizmlerinin genotiplendirilmesi RT-PCR cihazı ve TaqMan hidroliz probları kullanılarak gerçekleştirildi. Bulgular: rs2228480 polimorfizmi için, GA ve AA genotiplerine sahip hastaların, GG genotiplerine kıyasla AD'lı kadınlarda artmış risk gösterdiği bulundu (OR = 3,1; %95 CI: 1,33 – 6,82; p = 0,007). Ancak, AD'lı kadın hastalar ve kontroller arasında rs2228480 polimorfizminin genotip dağılımında anlamlı bir fark bulunmadı. Ayrıca E2 yönünden de çalışma grupları arasında bir fark gözlenmedi. Sonuç: ESR1 rs2228480 polimorfizmi ile AD arasında anlamlı bir ilişki olduğuna ve bu polimorfizmin AD geliştirme riskini artırmada rol oynayabileceği kanısındayız. Ancak daha kesin veriler elde etmek için daha geniş kadın kohortlarıyla yapılacak kapsamlı çalışmalara ihtiyaç vardır.

Keywords

• Kadın
• Alzheimer hastalığı
• ESR1
• E2
• Polimorfizm

Estrogen Receptor Alpha Polymorphism rs2228480 Increases Alzheimer’s Disease Susceptibility in Women

Abstract

Aim: Alzheimer's disease (AD) is a neurodegenerative disease characterized by beta-amyloid and tau accumulation, leading to memory loss and impairment in daily life. It is more common in women. Considering this difference, the current research explored the hereditary predisposition through examining estradiol (E2) levels and the rs2228480 and rs2295190 polymorphisms in the ESR1 gene in women with AD. Material and Methods: The study included 66 women diagnosed with AD and 62 women without any disease. E2 levels were measured in plasma samples from the participants using the electrochemiluminescence immunoassay (ECLIA) method. Genotyping of the rs2228480 and rs2295190 polymorphisms in ESR1 was performed in DNA samples isolated from whole blood using RT-PCR and TaqMan hydrolysis probes. Results: For the rs2228480 polymorphism, patients with the GA and AA genotypes were found to have an increased risk in women with AD compared to those with the GG genotype (OR = 3.1; 95% CI: 1.33–6.82; p = 0.007). However, no significant difference was found in the genotype distribution of the rs2228480 polymorphism between female AD patients and controls. Furthermore, no difference was observed between the study groups in terms of E2. Conclusion: We believe that there is a significant association between the ESR1 rs2228480 polymorphism and AD; therefore, this polymorphism may play a role in increasing the risk of developing AD. However, comprehensive studies with larger cohorts of women are needed to obtain more definitive data.

Keywords

• Women
• Alzheimer
• ESR1
• E2
• Polymorphism

References

1. Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S et al. Preclinical Alzheimer's disease: definition, natural history, and diagnostic criteria. Alzheimer's & Dementia 2016; 12: 292-323.
2. Mucke L, Selkoe D. Cold Spring Harbor Perspect Med 2012; 2: a006338.
3. Burke SL, Hu T, Fava NM, Li T, Rodriguez MJ, Schuldiner KL et al. Sex differences in the development of mild cognitive impairment and probable Alzheimer’s disease as predicted by hippocampal volume or white matter hyperintensities. J Women Aging 2019; 31: 140-64.
4. Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B, Bush WS et al. Sex differences in the genetic predictors of Alzheimer’s pathology. Brain 2019; 142: 2581-9.
5. Ferretti MT, Iulita MF, Cavedo E, Chiesa PA, Schumacher Dimech A, Santuccione Chadha A et al. Sex differences in Alzheimer disease—the gateway to precision medicine. Nat Rev Neurol 2018; 14: 457-69.
6. Arnold M, Nho K, Kueider-Paisley A, Massaro T, Huynh K, Brauner B et al. Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome. Nat Commun 2020; 11: 1148.
7. Toro CA, Zhang L, Cao J, Cai D. Sex differences in Alzheimer’s disease: Understanding the molecular impact. Brain Res 2019; 1719: 194-207.
8. Gür E, Fertan E, Kosel F, Wong AA, Balcı F, Brown RE. Sex differences in the timing behavior performance of 3xTg-AD and wild-type mice in the peak interval procedure. Behav Brain Res 2019; 360: 235-43.

9. Altmann A, Tian L, Henderson VW, Greicius MD, Investigators AsDNI. Sex modifies the APOE‐related risk of developing Alzheimer disease. Ann Neurol 2014; 75: 563-73.
10. Rocca WA, Grossardt BR, Shuster LT. Oophorectomy, estrogen, and dementia: a 2014 update. Mol Cell Endocrinol 2014; 389: 7-12.
11. Lin KA, Choudhury KR, Rathakrishnan BG, Marks DM, Petrella JR, Doraiswamy PM et al. Marked gender differences in progression of mild cognitive impairment over 8 years. Alzheimers Dement (Amst) 2015; 1: 103-10.
12. Sahab-Negah S, Hajali V, Moradi HR, Gorji A. The impact of estradiol on neurogenesis and cognitive functions in Alzheimer’s disease. Cell Mol Neurobiol 2020; 40: 283-99.
13. Wang X, Feng S, Deng Q, Wu C, Duan R, Yang L. The role of estrogen in Alzheimer’s disease pathogenesis and therapeutic potential in women. Mol Cell Biochem 2025; 480: 1983-98.
14. Rettberg JR, Yao J, Brinton RD. Estrogen: a master regulator of bioenergetic systems in the brain and body. Front Neuroendocrinol 2014; 35: 8-30.
15. Uddin MS, Rahman MM, Jakaria M, Rahman MS, Hossain MS, Islam A et al. Estrogen signaling in Alzheimer’s disease: molecular insights and therapeutic targets for Alzheimer’s dementia. Mol Neurobiol 2020; 57: 2654-70.
16. Banks WA. Brain meets body: the blood-brain barrier as an endocrine interface. Endocrinology 2012; 153: 4111-9.
17. Maioli S, Leander K, Nilsson P, Nalvarte I. Estrogen receptors and the aging brain. Essays Biochem 2021; 65: 913-25.
18. Corbo RM, Gambina G, Ruggeri M, Scacchi R. Association of estrogen receptor α (ESR1) Pvu II and Xba I polymorphisms with sporadic Alzheimer’s disease and their effect on apolipoprotein E concentrations. Dement Geriatr Cogn Disord 2006; 22: 67-72.
19. Ji Y, Urakami K, Wada-Isoe K, Adachi Y, Nakashima K. Estrogen receptor gene polymorphisms in patients with Alzheimer’s disease, vascular dementia and alcohol-associated dementia. Dement Geriatr Cogn Disord 2000; 11: 119-22.
20. Olsen L, Rasmussen HB, Hansen T, Bagger YZ, Tankó LB, Qin G et al. Estrogen receptor alpha and risk for cognitive impairment in postmenopausal women. Psychiatr Genet 2006; 16: 85-8.
21. Xie J, Ding Y, Li X, Pu R, Liu W, Li P et al. Association of ESR1 gene polymorphisms with the susceptibility to Hepatitis B virus infection and the clinical outcomes. J Med Virol 2023; 95: e28510.
22. Rezende LM, Marson FAL, Lima CSP, Bertuzzo CS. Variants of estrogen receptor alpha and beta genes modify the severity of sporadic breast cancer. Gene 2017; 608: 73-8.
23. Doherty JA, Rossing MA, Cushing-Haugen KL, Chen C, Van Den Berg DJ, Wu AH et al. ESR1/SYNE1 polymorphism and invasive epithelial ovarian cancer risk: an Ovarian Cancer Association Consortium study. Cancer Epidemiol Biomarkers Prev 2010; 19: 245-50.
24. Arnal JF, Lenfant F, Metivier R, Flouriot G, Henrion D, Adlanmerini M et al. Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications. Physiol Rev 2017; 97: 1045-87.
25. Rusidzé M, Adlanmérini M, Chantalat E, Raymond-Letron I, Cayre S, Arnal JF et al. Estrogen receptor-α signaling in post-natal mammary development and breast cancers. Cell Mol Life Sci 2021; 78: 5681-705.
26. Rosner W, Hankinson SE, Sluss PM, Vesper HW, Wierman ME. Challenges to the measurement of estradiol: an endocrine society position statement. J Clin Endocrinol Metab 2013; 98: 1376-87.
27. Denver N, Khan S, Homer NZ, MacLean MR, Andrew R. Current strategies for quantification of estrogens in clinical research. J Steroid Biochem Mol Biol 2019; 192: 105373.
28. Snyder HM, Asthana S, Bain L, Brinton R, Craft S, Dubal DB et al. Sex biology contributions to vulnerability to Alzheimer's disease: a think tank convened by the Women's Alzheimer's Research Initiative. Alzheimers Dement 2016; 12: 1186-96.
29. Wang H, Wang J, Zeng Y, Yang H, Chen W, Shen Q et al. Association of psychosocial state with subsequent risk of dementia: a prospective cohort study based on the UK Biobank. Alzheimers Res Ther 2024; 16: 225.
30. Glover CM. Alzheimer's & Dementia: Behavior & Socioeconomics of Aging–Purpose, Vision, and Guidance. Wiley Online Library 2025; p. e12010.
31. Sheikhi K, Momenabadi V, Khosravi S, Souri A, Goodarzi E. Burden of risk factors attributable to Alzheimer’s disease and other dementia and its relationship with the Socio-Demographic index in Asia. BMC Neurol 2025; 25: 247.
32. Jack CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013; 12: 207-16.
33. Wang L, Li P, Hou M, Zhang X, Cao X, Li H. Construction of a risk prediction model for Alzheimer’s disease in the elderly population. BMC Neurol 2021; 21: 271.
34. Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell 2019; 179: 312-39.
35. Hrelia P, Sita G, Ziche M, Ristori E, Marino A, Cordaro M et al. Common protective strategies in neurodegenerative disease: focusing on risk factors to target the cellular redox system. Oxid Med Cell Longev 2020; 2020: 8363245.
36. Siddappaji KK, Gopal S. Molecular mechanisms in Alzheimer's disease and the impact of physical exercise with advancements in therapeutic approaches. AIMS Neurosci 2021; 8: 357.
37. Azad NA, Al Bugami M, Loy-English I. Gender differences in dementia risk factors. Gend Med 2007; 4: 120-9.
38. Mielke MM. Sex and gender differences in Alzheimer’s disease dementia. Psychiatr Times 2018; 35: 14.
39. Nebel RA, Aggarwal NT, Barnes LL, Gallagher A, Goldstein JM, Kantarci K et al. Understanding the impact of sex and gender in Alzheimer's disease: a call to action. Alzheimers Dement 2018; 14: 1171-83.
40. Mielke MM, Vemuri P, Rocca WA. Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol 2014; 6: 37-48.
41. Kilim SR, Chandala SR. A comparative study of lipid profile and oestradiol in pre-and post-menopausal women. J Clin Diagn Res 2013; 7: 1596.
42. Carlson LE, Sherwin BB. Relationships between mood and estradiol (E2) levels in Alzheimer's disease (AD) patients. J Gerontol B Psychol Sci Soc Sci 2000; 55: P11-18.
43. Kaydok E, Ozmen E, Sari I, Cakıroglu GS, Tas A, Silig Y et al. A significant association between rs2295190 polymorphism of the ESR1 gene and fibromyalgia syndrome. Cell Mol Biol 2022; 68: 182-7.
44. Ma H, Wu W, Yang X, Liu J, Gong Y. Genetic effects of common polymorphisms in estrogen receptor alpha gene on osteoarthritis: a meta-analysis. Int J Clin Exp Med 2015; 8: 13446.
45. Bai XH, Su J, Mu YY, Zhang XQ, Li HZ, He XF. Association between the ESR1 and ESR2 polymorphisms and osteoporosis risk: an updated meta-analysis. Medicine 2023; 102: e35461.
46. Li T, Zhao J, Yang J, Ma X, Dai Q, Huang H et al. A meta-analysis of the association between ESR1 genetic variants and the risk of breast cancer. PLoS One 2016; 11: e0153314.
47. Wang Y, He Y, Qin Z, Jiang Y, Jin G, Ma H et al. Evaluation of functional genetic variants at 6q25.1 and risk of breast cancer in a Chinese population. Breast Cancer Res 2014; 16: 422.
48. Candelaria NR, Liu K, Lin CY. Estrogen receptor alpha: Molecular mechanisms and emerging insights. J Cell Biochem 2013; 114: 2203-8.