No association between presenilin 1 (PS1) intronic polymorphism and sporadic Alzheimer's disease in Koreans

Summary. To investigate the possible involvement of an intronic polymorphism in the presenilin 1 (PS1) gene and its interactions with the aplolipoprotein E (APOE) or alpha-1 antichymotrypsin (ACT) polymorphisms in the manifestation of AD, we analyzed the PS1, APOE and ACT genotypes of 100 sporadic AD patients and 199 normal elderly controls in Koreans. The genotypic (χ² = 0.92, df = 2, P > 0.1) and allelic (χ² = 0.01, df = 1, P > 0.1) frequencies of the PS1 polymorphism in the late- and early-onset sporadic AD patients did not differ from those in the controls. And the occurrence of the APOE ε4 allele and ACT A allele did not influence the distribution of the PS1 intronic polymorphism. The PS1 intronic polymorphism didn't influence the age-at-onset of AD (F = 0.02, df = 2, P > 0.1). In conclusion, the PS1 intronic polymorphism did not modify the risk for sporadic AD, neither independently nor synergistically with the APOE ε4 allele or ACT A allele, in Koreans. Received December 24, 1999; accepted March 18, 2000     

早老素-2基因启动子区-1560A/del位点多态性与散发性阿尔茨海默病的相关性研究

目的探讨早老素-2（PSEN2）启动子区-1560A/del的多态性与散发性阿尔茨海默病（SAD）的相关性。方法用常规方法从被试者外周血细胞中提取基因组DNA,通过使用聚合酶链反应-限制性片断长度多态性方法（PCR-RFLP）检测早老素-2基因启动子区域-1560A/del位点的多态性。被试者均来自日本,包括348例SAD患者和年龄、性别相匹配的330例正常对照。观察PSEN2基因启动子区域的多态性分布,用卡方检验和逻辑回归分析进行统计。结果SAD患者组与对照组PSEN2基因的-1560A/del多态性的基因型与等位基因的总体分布无明显统计学意义。（χ^2=1.09,P〉0.05）。结论PSEN2基因启动子区域的-1560A/del多态性可能不是散发性AD发病的风险因素。     

No association between a 3' untranslated region polymorphism in the neprilysin gene and Alzheimer's disease in the Japanese population

Background: Alzheimer's disease (AD) is caused by neuronal cell death with aggregation of amyloid‐β (Aβ) in the brain cortex and hippocampus. Neprilysin (NEP) plays an important role mainly in the degradation of Aβ. The NEP‐knockout mouse shows low degradation of Aβ and is confirmed to have AD. The frequency of the C/C genotype of NEP159 C/T polymorphism in the 3’ untranslated region (UTR) of the NEP gene Apolipoprotein E (Apo E) ?4 group has been reported to be higher than that of the control group. In the present study, we screened for the polymorphism in our Japanese AD and control subjects. Furthermore, we searched for a new polymorphism in exon 1 and exon 24 in the NEP gene. Methods: 121 sporadic AD (SAD) patients were recruited from among the inpatients and outpatients of the hospital the authors work in. The 101 age‐matched control subjects were recruited from healthy volunteers with no history of dementia or other neuropsychiatric diseases. The NEP159 C/T polymorphism and Apo E were genotyped by the polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method and a new polymorphism was detected by the polymerase chain reaction–single strand conformation polymorphism (PCR–SSCP) method. Results: We confirmed that the frequency of the Apo E ?4‐allele was higher in the SAD group than in the control group. There was no significant difference in genotypic distribution of the NEP159 C/T polymorphism between the control and SAD groups. Conclusion: Our studies suggest that there is no genetic association between the NEP159 C/T polymorphism and the risk of Japanese SAD. Our results indicate that further genetic studies of the NEP gene should be performed in other ethnic groups.     

Association between apolipoprotein CI HpaI polymorphism and sporadic Alzheimer's disease in Chinese

OBJECTIVE: To investigate into the relationship of apolipoprotein CI (ApoCI) polymorphism with sporadic Alzheimer's disease (AD) in Chinese. SUBJECTS AND METHODS: A total of 257 AD patients and 242 age-matched elderly individuals were genotyped for the ApoCI HpaI and apolipoprotein E (ApoE) HhaI polymorphisms. RESULTS: The ApoCI A allele was associated with AD of moderate to severe dementia when patients were divided into two subgroups according to Clinical Dementia Rating scale, and the AA genotype was strongly associated with moderate to severe AD in ApoE epsilon4 allele carriers [odds ratio (OR) = 8.19, 95% confidential interval: 1.28-52.30, after adjusting for age and gender by logistic regression analysis], although in total no significant differences of allele or genotype frequency between patients and controls were found. CONCLUSION: The present study partially confirmed the previous findings, suggesting that the ApoCI A allele might contribute to the susceptibility to moderate to severe sporadic AD in Chinese.     

中国人群ApoE基因多态性与迟发性阿尔茨海默病关系的Meta分析

目的探讨中国人群载脂蛋白E(Apo E)基因多态性与迟发性阿尔茨海默病的关系。方法以载脂蛋白E基因(Apo E)、迟发性阿尔茨海默病(late onset Alzheimer's disease)、基因多态性(polymorphism)、China和Chinese等中英文词组,检索美国国立医学图书馆生物医学信息检索系统、荷兰医学文摘、EBSCO-CINAHL、Cochrane图书馆,以及中国生物医学文献数据库、中国知网中国知识基础设施工程、万方数据库等近20年发表的关于中国人群Apo E基因多态性与迟发性阿尔茨海默病关系的病例对照研究,采用Newcastle-Ottawa量表(NOS)进行文献质量评价,Rev Man 5.0统计软件进行Meta分析。结果共获得249篇文献,经剔除重复和不符合纳入标准者并补充相关文献,最终纳入13篇高质量临床研究(NOS评分≥5分),共3372例受试者(迟发性阿尔茨海默病患者1360例、对照者2012例)。Meta分析显示:携带Apo Eε4等位基因者发生迟发性阿尔茨海默病的风险高于携带Apo Eε3等位基因者(OR=3.710,95%CI:2.960~4.640;P=0.000);表现为Apo Eε3/ε4(OR=3.160,95%CI:2.390~4.180;P=0.000)、Apo Eε2/ε4(OR=3.410,95%CI:2.160~5.380;P=0.000)和Apo Eε4/ε4(OR=16.400,95%CI:8.200~32.810;P=0.000)基因型者发生迟发性阿尔茨海默病的风险高于Apo Eε3/ε3基因型者。结论携带Apo Eε4等位基因,以及Apo Eε3/ε4、Apo Eε2/ε4和Apo Eε4/ε4基因型是中国人群发生迟发性阿尔茨海默病的危险因素。     

Early-onset Alzheimer's disease with a de novo mutation in the presenilin 1 gene

A 32-year-old woman diagnosed with very rapidly progressing early-onset Alzheimer's disease (EOAD), age of onset 29 years, and S170F mutation in presenilin 1 gene (PSEN1) is presented. Neuroimaging conducted 2 years after the first symptoms was typical for the advanced stage of Alzheimer's disease (AD), showing cortical brain atrophy, particularly within hippocampus, frontal and temporal cortex. The unaffected parents of the proband are not carriers of the mutation. The paternity was confirmed by microsatellite typing, strongly suggesting de novo origin of S170F mutation. In silico modeling of S170F mutation impact on presenilin 1 (PS1) transmembrane structure indicates that the mutation considerably alters putative interactions of PS1 with other proteins within gamma-secretase complex.     

Apolipoprotein E polymorphism in various dementias in Taiwan Chinese population

Summary. To verify the association between APOE4 frequency and various dementias in Taiwan Chinese individuals, APOE genotypes were determined in patients with dementia of Alzheimer's type (AD), vascular dementia (VD), dementias due to other general medical conditions (OD), and dementia of Alzheimer's type with cerebral vascular disease (mixed type dementia; MD). Only AD patients exhibited higher APOE4 frequency (OR = 2.95, p = 0.001) than controls after Bonferroni correction to control the overall type I error rate for the multiple testing. No such difference was observed among VD, OD, MD and control groups. The lack of association between VD and APOE4 allele frequency suggests that APOE4 allele does not associate with cerebrovascular pathology related dementia in Taiwan Chinese. Received December 3, 2001; accepted April 9, 2002 Published online July 26, 2002 Acknowledgement This work was supported by Taichung Veterans General Hospital grant TCVGH 894001B. Authors' address: L.-J. Chuo, MD, Department of Psychiatry, Taichung Veterans General Hospital, Taichung, Taiwan, e-mail: ljchuo@vghtc.vghtc.gov.tw     

A presenilin 1 mutation (Arg278Ser) associated with early onset Alzheimer's disease and spastic paraparesis

Early onset familial Alzheimer’s disease (EOFAD) has been associated with mutations in three genes, of which presenilin 1 (PSEN1) mutations are the most frequent. Several families with an association of progressive dementia and spastic paraplegia caused by PSEN1 mutations have been described. Here we described a novel PSEN1 mutation that was associated with dementia and spastic paraplegia in a family with 5 affected individuals in three generations. The proband was a 44-year-old woman who presented with 5 years history of progressive difficulties in walking, cognition and visuospatial impairment. Her maternal grandmother, mother and two maternal aunts also had similar neurological presentation. Molecular genetic analysis showed a missense mutation predicted to substitute an arginine residue for a serine residue at position 278 in the PSEN1 polypeptide (Arg278Ser). The novel PSEN1 mutation identified in this patient adds to the diverse list of existing mutations causing EOFAD associated with spastic paraparesis.     

SORL1基因多态与阿尔茨海默病发病风险的Meta分析

目的 运用Meta分析的方法探讨SORL1基因rs2070045位点基因多态与阿尔茨海默病(AD)发病风险的关系.方法 应用SORL1、sortilin-related recepmr、Alzheimer等关键词,检索Medline、Cochrane网书馆和中国生物医学文献数据库(CBM)发表的文章并附以文献追溯方法.应用RevMan4.2软件进行统计分析.结果 三篇文献共11组不同种族人群纳入分析,共有AD组2927例.对照组3869例.AD组和对照组rs2070045位点基因多态现象巾GG+GT基因型频率与最常见的纯合子TT基因型频率比的合并比值比(OR)值为1.19,95%可信区间为1.08～1.31,Z=3.39,P=0.0007,等位基因频率合并OR值为1.17,95%可信区间为1.07～1.27,Z=3.67,P=0.0002.结论 SORL1基因rs2070045位点多态性与AD患病风险相关.     

Alzheimer病早期脑脊液tau蛋白与ApoE基因的关系

目的探讨Alzheimer病患者脑脊液tau蛋白与ApoE基因型的关系。方法对84例患者脑脊液微管相关蛋白(tau蛋白)应用ELISA法对进行定量,其中41例临床诊断为早期Alzheimer病(AD),23例伴其他类型的痴呆,6例为Down综合征患者;14例非痴呆患者为对照组。结果多变量ANOVA分析显示痴呆患者与ApoE等位基因者脑脊液tau蛋白升高,AD患者脑脊液tau蛋白浓度明显高于对照组。而非AD痴呆患者脑脊液tau蛋白浓度与AD患者和对照组无明显差异,伴ApoEε4等位基因的AD病人与不伴ε4等位基因的AD病人相比,tau蛋白浓度升高。结论脑脊液tau蛋白浓度升高提示携带ε4等位基因AD病人早期发生神经变性和神经纤维病理学改变,应用ELISA法检测脑脊液tau蛋白对诊断早期AD及与其他类型的痴呆相鉴别缺乏敏感性和特异性,应首先考虑ApoE基因类型。     

Case-control study of presenilin-1 intronic polymorphism in sporadic early and late onset Alzheimer's disease

OBJECTIVE: Presenilin-1 is a major causative gene for early onset familial Alzheimer's disease, and the apolipoprotein E epsilon4 allele is a major genetic risk factor known to influence late onset and sporadic early onset Alzheimer's disease. The presenilin-1 1/1 genotype has recently been reported to be associated with sporadic Alzheimer's disease. The purpose of this study is to determine whether Alzheimer's disease is associated with presenilin-1 gene polymorphism and the apolipoprotein E genotype in an extended case-control study. METHODS: An examination was conducted on 217 patients with Alzheimer's disease, along with an equal number of age and sex matched controls derived from the same community in a Japanese population, by using a chi2 test for homogeneity and a logistic regression analysis. A meta-analysis of data from the literature on allele frequencies in Alzheimer's disease and control populations was used for comparison with the Japanese allele frequencies obtained in this study. RESULTS: The presenilin-1 allele-1 frequencies were similar in patients with early onset Alzheimer's disease (0.61) and younger controls (0.61), and in those with late onset Alzheimer's disease (0.63) and elderly controls (0. 63). We found no evidence for a possible association between the presenilin-1 polymorphism and the apolipoprotein E epsilon4 allele. However, the meta-analysis showed that the association between the presenilin-1 1/1 genotype and Alzheimer's disease was significant (Peto odds ratio=1.16, 95% confidence interval=1.04-1.31). CONCLUSIONS: These results suggest a subtle but positive association of presenilin-1 gene polymorphism with Alzheimer's disease, although Japanese data in this study which failed to support such a relation would indicate an ethnic variation.     

载脂蛋白E基因多态性和急性脑损伤的关联研究

背景 急性脑损伤及其预后的影响因素是多方面的,如年龄、损伤程度与患者体质情况等,但其对外伤性脑损伤的预后结局仅作部分预测.近年来,有关遗传因素对脑损伤的影响和其预后的报道开始增多,关于载脂蛋白E在颅脑外伤预后中所起作用已引起人们的关注.在国外以往的研究中,关于载脂蛋白E基因多态性和脑损伤预后的研究结果也不相同.本研究初步探讨有关我国急性脑损伤及其预后与APOE基因之间的关系.方法 采用病例对照研究,选取94名车祸脑损伤患者和正常人作为研究对象,采用聚合酶链式反应(PCR)限制性片段长度多态性(RFLP)方法鉴定载脂蛋白E(APOE)基因型,探讨其等位基因及基因型同车祸脑损伤及其预后的关系.结果 车祸脑损伤患者中其等位基因ε2频率为0.1010,其基因型ε2/ε3的频率为0.1596明显高于正常人群ε2等位基因频率0.0050,及ε2/ε3基因型的频率0.0100(P＜0.05).同时,患者中,其未愈死亡组中ε2等位基因频率为0.1970及ε2/ε3基因型的频率为0.2727,明显高于好转治愈组ε2等位基因频率0.0508及ε2/ε3基因型的频率0.1017(P＜0.05),有统计学意义.结论 APOE基因的等位基因ε2基因型ε2/ε3初步可作为预示不良的预后参数.     

丝裂酶原活化蛋白激酶1基因多态性与中国汉族阿尔茨海默病的关联研究

目的:研究探讨丝裂酶原活化蛋白激酶1(MAPK1)基因在中国汉族阿尔茨海默病(AD)发生过程中的作用。方法:根据《美国精神障碍诊断和统计手册》(DSM-IV)和美国国立神经病、语言功能紊乱和脑卒中研究所及AD和相关疾病协会临床诊断标准(NINCDS-ADRDA),收集中国东部和西南部人群AD患者715例和健康对照者760人。选取MAPK1基因3个标签多态性位点rs2276006、rs1063311和rs2006893。采用SNa Pshot SNP分型技术对这3个SNP位点进行分析。结果:中国东部和西南部人群AD组与对照组间MAPK1基因各位点基因多态性及等位基因分布频率差异无统计学意义(P0.05);东部及西南部人群合并后AD组与对照组间MAPK1基因各位点基因多态性及等位基因分布频率差异无统计学意义(P0.05),连锁不平衡检验显示各SNP位点之间存在强连锁(D'0.95),单体型分析结果显示病例组与对照组间单体型估计频率差异无统计学意义(P0.05)。结论:MAPK1基因可能不是中国汉族AD的主要致病基因。     

Alzheimer病患者载脂蛋白E基因多态性及线粒体DAN4336突变的研究

目的　研究散发性Alzheimer病 (AD)患者载脂蛋白E (ApoE)基因型的分布以及线粒体DAN4 336基因突变情况 ,并对不同国家和地区AD患者ApoE基因型的分布频率进行对比。方法　采用聚合酶链反应 限制性片段长度多态性分析 (PCR RFLP)方法对 12 7例AD患者 (AD组 )和 138名正常老年人 (正常组 )ApoE基因型和mtDNA基因突变进行分析。结果　AD组携带 2个、1个和不含ApoE 4基因型的比例为 2 4 %、18 1%和 79 5 % ;正常组的比例分别为 0 7%、10 1%和 89 2 % ,两组比较差异有显著性 (P <0 0 5 ) ;两组均未出现mtDNA 4 336基因突变。AD组ε4 /4比例相对于西方研究报道要低 ,与部分亚洲国家研究相近。结论　ApoE 4等位基因可能是中国散发性AD发生的危险因素 ,ApoE基因型分布频率可能与人群选择、病例分辨和种族、地区差异有关。     

Association of alpha 2-macroglobulin polymorphisms and Alzheimer disease in Mainland Han Chinese

This study used case-control method to investigate roles of two α2-macroglobulin (A2M) polymorphisms, a 5-bp insertion/deletion (A2M-I/D) and an A→G substitution (A2M-A/G), in the development of sporadic Alzheimer disease (AD) in Mainland Han Chinese. Our results showed a trend of lower D-carrying genotype frequency in APOE-ε4 carrying AD patients than in corresponding control subjects (χ²=3.67, p=0.055). The ID/AA genotype frequency was lower in AD patients comparing with controls (χ²=4.04, p=0.044). In AD patients, the G-carrying genotype frequency was significantly higher in APOE-ε4 carrier subgroup than in APOE-ε4 non-carriers (χ²=7.38, OR=2.99, 95% CI: 1.33-6.71, p=0.007). These results indicated that A2M-D allele was probably a weak AD protective factor, and there was a possible interaction of APOE-ε4 and A2M-G alleles to increase AD risk in Mainland Han Chinese.     

Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland

Mutations in three causative genes have been identified in patients with an autosomal-dominant form of early-onset Alzheimer's disease (EOAD). To determine the spectrum of mutations in a group consisting of 40 Polish patients with clinically diagnosed familial EOAD and 1 patient with mild cognitive impairment (MCI) and family history of AD, we performed a screening for mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) genes. Four previously recognized pathogenic mutations in PSEN1 gene (H163R, M139V) and APP gene (T714A, V715A), and three novel putative mutations in PSEN1 gene (P117R and I213F) and PSEN2 gene (Q228L) were identified. The 34 patients with no mutations detected were older than the patients with mutations. A frequency of APOE4 allele was higher in this group. Frequency of mutations is relatively low (17%), possibly due to used operational definition of a patient with familial EOAD (a patient having at least one relative with early-onset dementia). It could be concluded that screening for mutations in the three genes could be included in a diagnostic program directed at patients with a positive family history or age of onset before 55 years.     

Apolipoprotein E type 4 allele and Alzheimer's disease: Effect on age at onset and relative risk in different age groups

The effect of the apolipoprotein E (apoE) genotype on the age at onset of Alzheimer's disease (AD) and the relative risk conferred by the apoE 4 allele were studied in 91 patients and 69 healthy age-matched controls. According to the age of presentation, which varied from 44 to 95 years, subjects were divided into four groups. The inheritance of at least one 4 allele was associated with a significant reduction of the age at onset by 7.7 years among patients who were 83 years or older when examined. A weaker inverse relationship between the 4 allele and the age at onset was also observed among patients who were aged 44–63 years at presentation. The effect of the c4 allele was minimal or absent in the two intermediate age categories. The relative risk of AD conferred by the inheritance of at least one £4 allele showed no consistent age-related pattern. The overall risk expressed as an odds ratio was 5.0 (95% CI 2.4–10.5). With respect to the limitations of the study, we tentatively conclude (1) that the effect of the apoE 4 allele on the age at onset is not restricted to AD patients of a particular age, in accordance with current hypotheses on the role of apoE gene products in the biology of AD; (2) that the relative risk of AD associated with the 4 allele is not significantly modulated by age. Although the apoE 4 allele is an important susceptibility factor for AD occurring in middle age as well as in later life, it is of limited value in routine clinical diagnosis and should not be used for predictive testing in asymptomatic individuals.     

Association of interleukin-I beta and receptor antagonist gene polymorphisms with late onset Alzheimer''s disease in Taiwan Chinese

Interleukin (IL)-1 is markedly overexpressed in the brains of patients with Alzheimer's disease (AD). We aimed to evaluate the relationship between three polymorphisms of the IL1 gene (IL-1beta promoter -511T/C, IL-1beta exon 5 E1/E2 and IL-1-RA) and late onset AD in Taiwan Chinese. Forty-six late onset AD patients and 103 unrelated, age-matched, healthy controls living in the same area were included. PCR was used to resolve the two IL-1beta polymorphisms and the IL-1Ra intron 2 polymorphism. The -511T/T type of the IL-1beta promoter (unlike IL-1beta exon 5 and IL-1-RA) was more frequently found in AD than in healthy patients (-511C/C type versus T/T type, OR = 0.944, CI = 0.393, 2.269, P = 0.898; -511C/T type versus T/T type, OR = 0.375, CI = 0.156, 0.902, P = 0.028). The -511T/T genotype (unlike the other two polymorphisms) is a marker demonstrating that late onset AD in Chinese patients in Taiwan is genetically determined.     

中国人载脂蛋白E基因多态性与脑梗死的Meta分析

目的探讨我国人群中载脂蛋白E基因多态性与脑梗死之间的相关性。方法使用Review Manager 5.2统计分析软件对已发表的载脂蛋白E基因多态性与脑梗死关系的相关研究进行分析。结果 ApoEε3/3、ApoEε2/3、ApoEε4/4、ApoEε3/4及ApoEε2/4基因型的OR值分别是0.55(95%CI为0.43~0.72)、0.81(95%CI为0.66~0.98)、2.72(95%CI为1.63~4.57)、2.25(95%CI为1.66~3.04)、1.70(95%CI为1.12~2.60);携带ε4等位基因、携带ε3等位基因发生脑梗死的风险是对照组的2.44倍(95%CI为1.84~3.22)、0.59倍(95%CI为0.46~0.75)。结论 ApoEε3/3、ApoEε2/3基因型及ε3等位基因可能是脑梗死的保护因素;ApoEε4/4、ApoEε3/4及ApoEε2/4基因型和ε4等位基因可能是脑梗死的危险及遗传易感因素。