ApoE基因多态性与大动脉粥样硬化型脑梗死及卒中后认知障碍的相关性研究

doi:10.20223/j.cnki.1000-8535.2025.03.007

摘要/Abstract

摘要： 目的探讨载脂蛋白E（ApoE）基因多态性与卒中后认知障碍的相关性,即大动脉粥样硬化型脑梗塞的严重程度。方法采用病例——对照研究的方法,收集九江学院附属医院神经内科的100例急性缺血性脑卒中且病因分型为大动脉粥样硬化型患者（脑梗死组）和50例性别、年龄匹配的非缺血性脑卒中患者（对照组）。检测患者的 ApoE 基因型、血脂、美国国立卫生院卒中量表（NIHSS）、卒中后6个月简易智力状态检查量表（MMSE）等,采用多因素方差分析等统计学方法分析他们之间的关联性。结果 ApoE 3/4基因型频率与Ɛ3、Ɛ4等位基因频率,在脑梗死组别中高于对照组（P<0.05）。同时,携带Ɛ3等位基因患者的低密度脂蛋白水平高于携带Ɛ2、Ɛ4等位基因的患者;进一步分析发现含Ɛ3等位基因的脑梗死患者NIHSS评分更高、卒中后认知障碍更严重（P<0.05）。结论 ApoE基因型为Ɛ3/4、等位基因Ɛ3、Ɛ4更易罹患大动脉粥样硬化型脑梗死,提示该基因型是脑梗死的易感基因,脑梗死后认知障碍患者Ɛ3等位基因的频率较高,可能是卒中后认知障碍的易感因素。

关键词: ApoE基因多态性, 大动脉粥样硬化型, 脑梗死, 卒中后认知障碍, 易感基因, 等位基因

Abstract: Objective To explore the relationship between ApoE gene polymorphisms and post-stroke cognitive impairment,the severity of large artery atherosclerotic cerebral infarction．Methods A case-control research study was conducted,gathering data from 100 individuals diagnosed with large artery atherosclerotic cerebral infarction according to the TOAST classification,who admitted to the Neurology Department of the Affiliated Hospital of Jiujiang University．Additionally,50 non-ischemic stroke patients,matched for gender and age,were included as the control group．The patients were assessed for ApoE genotype,blood lipid,NIHSS,and MMSE scale at 6 months post-stroke,and statistical methods were used to analyze their associations．Results Significant differences were observed in the ApoE 3/4 genotype frequency and Ɛ3、Ɛ4 allele frequency between patients with cerebral infarction and the control group,with a notably higher incidence of cerebral infarction in the former．Furthermore,patients carrying the Ɛ3 allele exhibited significantly higher LDL levels than those carrying Ɛ2 or Ɛ4．The analysis also revealed that patients with the Ɛ4 allele experienced higher NIHSS and severer post-stroke cognitive impairment．Conclusions The findings suggest that the ApoE genotype Ɛ3/4 and allele Ɛ3、Ɛ4 may predispose individuals to develop large atherosclerotic cerebral infarction,indicating a susceptibility gene for cerebral infarction．Additionally,the Ɛ3 allele was associated with a higher frequency of cognitive deficits after cerebral infarction,implying that it may be a predisposing factor for post-stroke cognitive impairment．

Key words: ApoE gene polymorphism, large artery atherosclerotic, cerebral infarction, post-stroke cognitive impairment, susceptibility gene, allele gene

夏忠斌, 桂敏, 谈丹丹, 柴竞艳, 官燕琴, 鲍兵, 吴向斌. ApoE基因多态性与大动脉粥样硬化型脑梗死及卒中后认知障碍的相关性研究[J]. 广州医药, 2025, 56(3): 338-345.

XIA Zhongbin, GUI Min, TAN Dandan, CHAI Jingyan, GUAN Yanqin, BAO Bing, WU Xiangbin. Correlation of ApoE gene polymorphisms with large artery atherosclerotic cerebral infarction and post-stroke cognitive impairment[J]. Guangzhou Medical Journal, 2025, 56(3): 338-345.

参考文献

[1] 中华医学会神经病学分会,中华医学会神经病学分会脑血管病学组.中国缺血性卒中和短暂性脑缺血发作二级预防指南2022[J].中华神经科杂志,2022,55(10):1071-1110.
[2] HUI C,TADI P,KHAN S M,et al.Ischemic stroke[J].Florida:StatPearls,2024.
[3] PARADOWSKI B,MACIEJAK A.TOAST classification of subtypes of ischaemic stroke:diagnostic and therapeutic procedures in stroke:A four-year observation[J].Cerebrovasc Dis,2005,20(5):319-324.
[4] ROJSANGA W,SAWANYAWISUTH K,CHOTMONGKOL V,et al.Clinical risk factors predictive of thrombotic stroke with large cerebral infarction[J].Neurol Int,2019,11(2):7941.
[5] 谷文龙,黄玉宇,王红武,等.代谢综合征与心血管疾病和痴呆的关系[J].广州医药,2017,48(4):51-55,59.
[6] BOEHME A K,ESENWA C,ELKIND M S V.Stroke risk factors,genetics,and prevention[J].Circ Res,2017,120(3):472-495.
[7] LANFRANCO M F,SEPULVEDA J,KOPETSKY G,et al.Expression and secretion of apoE isoforms in astrocytes and microglia during inflammation[J].Glia,2021,69(6):1478-1493.
[8] WINDHAM I A,COHEN S.The cell biology of APOE in the brain[J].Trends Cell Biol,2024,34(4):338-348.
[9] KUMAR A,KUMAR P,PRASAD M,et al.Association between apolipoprotein epsilon4 gene polymorphism and risk of ischemic stroke:A meta-analysis[J].Ann Neurosci,2016,23(2):113-121.
[10] YE B S,KIM H J,YOON C,et al.P2-071:Effects of APOE-ε4 on lacunar infarcts,white matter lesions and brain amyloid:A study among people with subcortical vascular cognitive impairment[J].Alzheimers Dement,2013,9(4S_Part_9):369-370.
[11] QUAN M,LV H,LIU Z,et al.MST1 suppresses disturbed flow induced atherosclerosis[J].Circ Res,2022,131(9):748-764.
[12] ZHANG H,ZHAO X,WANG C,et al.A preliminary study of the association between apolipoprotein E promoter methylation and atherosclerotic cerebral infarction[J].J Stroke Cerebrovasc Dis,2019,28(4):1056-1061.
[13] NELSON K,FUSTER V,RIDKER P M.Low-dose colchicine for secondary prevention of coronary artery disease:JACC review topic of the week[J].J Am Coll Cardiol,2023,82(7):648-660.
[14] XU D,XIE L,CHENG C,et al.Triglyceride-rich lipoproteins and cardiovascular diseases[J].Front Endocrinol,2024(15):1409653.
[15] SACKS F M,FURTADO J D,JENSEN M K.Protein-based HDL subspecies:Rationale and association with cardiovascular disease,diabetes,stroke,and dementia[J].Biochim Biophys Acta Mol Cell Biol Lipids,2022,1867(9):159182.
[16] MARAIS A D.Apolipoprotein E in lipoprotein metabolism,health and cardiovascular disease[J].Pathology,2019,51(2):165-176.
[17] RASMUSSEN K L,TYBJAERG-HANSEN A,NORDESTGAARD B G,et al.APOE and dementia - resequencing and genotyping in 105,597 individuals[J].Alzheimers Dement,2020,16(12):1624-1637.
[18] DAS S,KAUL S,JYOTHY A,et al.Association of APOE(E2,E3 and E4)gene variants and lipid levels in ischemic stroke,its subtypes and hemorrhagic stroke in a South Indian population[J].Neurosci Lett,2016(628):136-141.
[19] ZHAO T,ZHONG T,ZHANG M,et al.Alzheimer's disease:Causal effect between obesity and APOE gene polymorphisms[J].Int J Mol Sci,2023,24(17):13531.
[20] WANG Q Y,WANG W J,WU L,et al.Meta-analysis of APOE ε2/ε3/ε4 polymorphism and cerebral infarction[J].J Neural Transm,2013,120(10):1479-1489.
[21] YAN H Q,YUAN Y,ZHANG P,et al.Association of the ApoE gene polymorphism and dietary factors with cerebral infarction and circulating lipid concentrations[J].Genet Mol Res,2015,14(1):665-670.
[22] ZHONG Z,WU H,YE M,et al.Association of APOE gene polymorphisms with cerebral infarction in the Chinese population[J].Med Sci Monit,2018(24):1171-1177.
[23] KHALIL Y A,RABES J P,BOILEAU C,et al.APOE gene variants in primary dyslipidemia[J].Atherosclerosis,2021(328):11-22.
[24] MIAO G,ZHUO D,HAN X,et al.From degenerative disease to malignant tumors:Insight to the function of ApoE[J].Biomed Pharmacother,2023(158):114127.
[25] CHENG Y W,LIAO Y C,CHEN C H,et al.Contribution of the APOE genotype to cognitive impairment in individuals with NOTCH3 cysteine-altering variants[J].J Am Heart Assoc,2023,12(22):e032689.
[26] DAVIDSON Y,GIBBONS L,PURANDARE N,et al.Apolipoprotein E epsilon4 allele frequency in vascular dementia[J].Dement Geriatr Cogn Disord,2006,22(1):15-19.
[27] KLAGES J D,FISK J D,ROCKWOOD K.APOE genotype,vascular risk factors,memory test performance and the five-year risk of vascular cognitive impairment or Alzheimer's disease[J].Dement Geriatr Cogn Disord,2005,20(5):292-297.
[28] NOGUCHI S,MURAKAMI K,YAMADA N.Apolipoprotein E genotype and Alzheimer's disease[J].Lancet,1993,342(8873):737.
[29] MONTAGNE A,NATION D A,SAGARE A P,et al.APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline[J].Nature,2020,581(7806):71-76.
[30] 罗伏钢,陈梅芳,章隆,等.ApoE基因多态性与脑梗死后血管性痴呆的关联性研究[J].中华全科医学,2018,16(6):874-877.
[31] STOCKER H,PERNA L,WEIGL K,et al.Prediction of clinical diagnosis of Alzheimer's disease,vascular,mixed,and all-cause dementia by a polygenic risk score and APOE status in a community-based cohortprospectively followed over 17 years[J].Mol Psychiatry,2021,26(10):5812-5822.
[32] XIONG M,JIANG H,SERRANO J R,et al.APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function[J].Sci Transl Med,2021,13(581):eabd7522.
[33] NORDESTGAARD L T,CHRISTOFFERSEN M,FRIKKE-SCHMIDT R.Shared risk factors between dementia and atherosclerotic cardiovascular disease[J].Int J Mol Sci,2022,23(17):9777.