α1—抗糜蛋白酶基因与Alzheimer病

α１－抗糜蛋白酶作为一种病理伴侣蛋白，通过影响β淀粉样沉积的生成而参与了ＡＤ的病理和发生过程，因此α１－抗糜蛋白酶基因也被认为是ＡＤ的又一候选基因，本就α１－抗糜蛋白酶及其基因与ＡＤ的关系进行阐述。     

Alzheimer病中载脂蛋白E基因与α1-抗糜蛋白酶基因的相互影响

目的探讨中国汉族Ａｌｚｈｅｉｍｅｒ病（Ａｌｚｈｅｉｍｅｒｄｉｓｅａｓｅ,ＡＤ）患者中载脂蛋白Ｅ基因多态性与α１抗糜蛋白酶基因多态性之间的关系。方法应用聚合酶链式反应（ＰＣＲ）－限制性片段长度多态性（ＲＦＬＰ）方法,在１２５例ＡＤ患者和１４０例正常人中观察了ＡＡＣＴ信号肽基因和ＡｐｏＥ基因多态性的分布,并对ＡＡＣＴ信号肽基因多态性与ＡｐｏＥ基因ε４等位基因进行关联分析。结果（１）ＡＡＣＴ信号肽基因多态性与ＡＤ之间不存在任何关联（Ｐ＞０．０５）;（２）无论是ＡｐｏＥε４型抑或非ＡｐｏＥε４型ＡＤ,均不出现与ＡＡＣＴ信号肽基因多态性的关联;（３）ＡＡＣＴ＊ＡＡ型ＡＤ患者与ＡｐｏＥ基因多态性无关,ＡＡＣＴ＊ＡＴ、ＡＡＣＴ＊ＴＴ型ＡＤ与ＡｐｏＥε４等位基因正关联。结论中国人群中ＡＡＣＴ信号肽基因多态性与ＡＤ之间不具关联,二者间的关系不受ＡｐｏＥε４等位基因的影响,但ＡＡＣＴ信号肽多态性可能对ＡｐｏＥε４等位基因与ＡＤ的关联产生影响。     

载脂蛋白E基因多态性与 Alzheimer病的关系探讨

目的 探讨Alzheimer病(Alzheimer disease,AD)患者的载脂蛋白E(apolipoproteinE,APOE)基因的分布,及其相关性.方法 利用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)技术对AD患者和相应健康对照的APOE基因进行分型,从而进行AD与APOE等位基因多态性的关联分析.结果 AD病人APOE等位基因.ε4占20.74%,明显高于正常人对照组的7.64%,而ε3则占64.63%,低于正常人对照组的84.12%.结论 APOE等位基因中,ε4可能为AD的易患因子,而ε3则为保护因子     

载脂蛋白E基因多态性与Alzheimer病的关系探讨

目的：探讨Alzheimer病（Alzheimer disease,AD)患者的载脂蛋白E(apolipoproteinE,APOE)基因的分布,及其相关性。方法：利用聚合酶链反应－限制性片段长度多态性（PCR－RFLP）技术对AD患者和相应健康对照的APOE基因进行分型,从而进行AD与APOE等位基因多态性的关联分析。结果：AD病人APOE等位基因。ε4占20．74％,明显高于正常人对照组的7．64％,而ε3则占64．63％,低于正常人对照组的84．12％。结论：APOE等位基因中,ε4可能为AD的易患因子,而ε则为保护因子。     

α1-抗糜蛋白酶基因与Alzheimer病

α１－抗糜蛋白酶作为一种病理伴侣蛋白，通过影响β淀粉样沉积的生成而参与了ＡＤ的病理和发生过程，因此α１－抗糜蛋白酶基因也被认为是ＡＤ的又一候选基因。本文就α１－抗糜蛋白酶及其基因与ＡＤ的关系进行阐述。     

Alzheimer病与性行为异常

Ａｌｚｈｅｉｍｅｒ（ＡＤ）病出现的异常性行为越来越引起精神病学家的重视，Ｂｕｒｎ［３］和Ｋｌｕｖｅｒ［４］曾有报道。本研究对天津市民政局所属五个单位收养系统的１８６例ＡＤ病例进行分析，试图对ＡＤ病人异常性行为的发生率、临床症状及有关因素作初步探讨。对...     

Presinilin1基因研究进展

Ａｌａｚｈｅｉｍｅｒ具有遗传异质性，已经证实４种ＡＤ疾病基因的存在，其中Ｐｒｅｓｉｎｉｌｉｎ１基因被认为是构成早发家族性ＡＤ的主要疾病基因，本就ＰＳ１基因的结构、功能及基基因突变在ＡＤ中的作用进行了综述。     

α3—巨球蛋白基因多态性与Alzheimer病的关联研究

目的：观察α2-巨球蛋白基因（α2-macroglobulin,A2M) 内含子17一种五核苷酸缺失突变在广州地区汉族老年人中的分布,探讨其与晚发Alzheimer病（AD）的相关性。方法：以97例晚发AD患者和111名健康老年人为对照进行病例－对照研究。用聚合酶链反应－限制性片段长度多态性方法分析A2M缺失／插入多态性和载脂蛋白E（apolipoproteinE,apoE)基因多态性。结果：（1）A2M基因缺失突变在晚发AD患者中的频率为2．6％,在正常老年人中的频率为2．7％,在所有受试者中未检测到A2M突变纯合体,晚发AD患者和健康老年人之间不存在A2M等位基因和基因型分布的差异,A2M基因多态性与晚发AD无关联。（2）晚发AD患者中apoE等位基因ε4频率显著升高（Z＝3．32,P＜0．01）。晚发AD与ε3／ε4基因型正关联（RR＝2．62,χ^2=6.89,P＜0．01）,和等位基因ε4正关联（RR＝2．67,χ^2=10.71,P＜0．01）。（3）晚发AD无论是否伴有apoE-ε4均与A2M不存在相关性。结论：广州汉族人群中A2M基因缺失突变多态性与晚发AD不具有关联。     

Alzheimer病的遗传学及基因与环境的相互作用

阿耳茨海默氏病的病因学问题至今尚未得到解决，虽然现在至少有五，六种有关阿耳茨海默氏病的病因学理论，但是它们之间都并不是互相排斥的，它们可能都是正确的，都是同一个问题的不同方面。从现在看来，几乎可以肯定地讲阿耳茨海默氏病是由不同原因导致的。在这里，遗传...     

c-fos过度表达与Alzheimer病

随着人类平均寿命的延长，世界人口日趋老龄化，老年期痴呆的发病率也随之增加。国外资料显示６５岁以上人群患病率为４％～６％，国内报告６０岁以上人群为３４６％～３９％。其中发达国家２／３是由阿尔兹海默病（Ａｌｚｈｅｉｍｅｒ’ｓｄｉｓｅａｓｅ，ＡＤ）所致...     

Genetic association study between alpha 1-antichymotrypsin polymorphism and Alzheimer disease in Chinese Han population

We investigated a common signal peptide polymorphism in the alpha 1-antichymotrypsin (ACT) gene in 125 sporadic Alzheimer disease (AD) patients and 141 healthy control subjects in Chinese Han population. We found no significant difference in the distribution of ACT polymorphism between AD cases and controls, and failed to detect any effects of ACT genotypes associated with AD. Thus, our data do not support the involvement of ACT polymorphism in the risk of AD in Chinese Han population. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:133-135, 2000.     

No synergistic effect between -850 tumor necrosis factor-alpha promoter polymorphism and apolipoprotein E epsilon 4 allele in Alzheimer's disease

The eukaryotic initiation factor-2B (eIF-2B) can regulate translation and protein synthesis. We used Western blot analysis to quantify the protein level of the catalytic epsilon (epsilon) subunit of eIF-2B in brains of rats fed lithium chloride (LiCl) for 6 weeks so as to produce a brain lithium concentration that is therapeutically effective in bipolar disorder. The ratio of eIF-2B (epsilon) to actin protein was significantly reduced (P<0.01) in LiCl-fed rats, 0.86+/-0.06 (SE) compared to 1.2+/-0.07 in control rats. These results suggest that a therapeutic level of lithium may downregulate the synthesis of proteins whose translation depends on eIF-2B.     

The association between delirium and the apolipoprotein E epsilon4 allele in the elderly

OBJECTIVE: As not all patients with similar risk factors and eliciting conditions develop delirium; it may be hypothesized that genetic variation may play a role in the risk of delirium. On the basis of the relationship between dementia, respectively reduced cholinergic activity, and the APOE epsilon4-allele, and the similarities between dementia and delirium in reduced cholinergic activity, the APOE epsilon4-allele is a rational candidate-gene for delirium. This study examined the association between APOE epsilon4-allele and delirium in elderly patients. METHODS: Acutely admitted patients to the Department of Medicine of 65 years and over were included during a 27-month time period. Delirium was scored by the confusion assessment method. Cognitive impairment was diagnosed by Mini Mental State Examination and informant questionnaire on cognitive decline. Genotyping was done with matrix-assisted laser-desorption/ionization time-of flight mass spectrometry. RESULTS: Of 415 included patients, a random sample of 264 patients was genotyped for APOE. The patients who met the criteria for delirium (35%) were significantly older and more frequently had preexisting functional and cognitive impairment. APOE genotype was borderline significantly associated with cognitive impairment in patients below 75 years (P=0.057). The odds ratio for carriers of an APOE epsilon4-allele compared with patients without an APOE epsilon4-allele for developing delirium was 1.17 (95% confidence interval (CI): 0.49-2.78) in the cognitively intact patients and 0.42 (95% CI: 0.14-1.30) in the cognitively impaired patients. No relation existed between the total number of APOE epsilon4-alleles and the different delirium subtypes (P=0.12). CONCLUSIONS: We found no convincing evidence that carriers of the APOE epsilon4-allele have a higher risk of delirium.     

载脂蛋白E基因多态性与疾病的相关性研究

载脂蛋白E（ApoE）是一种重要的血浆脂蛋白,由3种等位基因构成：E2、E3和E4。ApoE作为一种载脂蛋白,在脂质运输和代谢过程中发挥重要作用,而目前越来越多的研究表明：ApoE在免疫调节方面发挥重要作用,从而参与到多种疾病的发生发展中。近年来发现,ApoE及其基因多态性与高脂血症、动脉粥样硬化、Alzheimer病、神经系统病变及脓毒血症等人类疾患的发生发展有着密切关系。     

Association between apolipoprotein E polymorphism and Alzheimer disease in Tehran, Iran

Epsilon 4 allele of apolipoprotein E (APOE-epsilon4) is a major risk factor for Alzheimer's disease (AD). The association of APOE allele frequencies with AD remains unknown in developing countries. We examined the frequency of APOE alleles in 105 patients with AD and 129 cognitively normal subjects of similar age and sex (control group), in Tehran, Iran. The APOE-epsilon4 allele frequency was significantly higher in the AD subjects than in the control group (21% versus 6.2%, p < 0.001). In addition, the OR for APOE-epsilon4 heterozygous and homozygous subjects were 3.2 (p = 0.001) and 12.75 (p = 0.01), respectively. The OR was not uniform across age groups. The AD subjects carrying one or two APOE-epsilon4 allele showed earlier age-at-onset (p < 0.001). These data suggest that the APOE-epsilon4 allele increase the risk for AD in Tehran population in a dose and age-dependent manner. Although the APOE-epsilon2 allele frequency was lower in the AD subjects than in the control group (0.95% versus 2.7%, p = 0.15), APOE-epsilon2 was not associated with the onset of AD in Tehran's population. The OR for epsilon2 allele in AD subjects was 0.34 (p = 0.21). The genotype frequencies for epsilon3, epsilon4, and epsilon2 alleles in control subjects were 91.2, 6.1, and 2.7%, respectively. These values were similar to that reported for Turkish, Greece, Japanese, Spanish, and Moroccan populations, but they were significantly different from the reported values for the other ethnic populations. This observation emphasizes the importance of geographical location and ethnical background of the subjects in the study of APOE genotypes and their association with AD.     

载脂蛋白E基因多态性与散发性老年性痴呆病的关系

目的:探讨载脂蛋白E(apoE)外显子4和增强子元件基因多态性与散发性Alzheimer病(AD)的关系。方法:应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术分别检测apoE外显子4和内含子1内增强子元件(IE1)基因型。结果:(1)ApoE外显子4基因多态性:AD组ε3/4基因型频率(0.381)和ε4等位基因频率(0.226)显著高于对照组(P＜0.05)。(2)ApoEIE1基因多态性AD组G/G基因型频率(0.595)显著高于对照组(P＜0.05)。(3)有apoEε4个体患AD风险为无ε4个体的3倍,比值比为2.932,95%可信区间1.379~6.226;G/G基因型个体患AD风险为G/C、C/C个体的2倍,比值比为2.223,95%可信区间1.075~4.599;经统计分析发现apoEε4与IE1G/G呈非常显著性正相关(P＜0.01);排除apoEε4后发现IE1G/G与AD发病风险无关。结论:ApoEε4等位基因是个体发生AD的危险因素,IE1G/G增加AD发病风险是因其与ε4相关所致。     

Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) gene interactions with the apolipoprotein E epsilon4 allele as risk factors in Alzheimer's disease and in Parkinson's disease with coexisting Alzheimer pathology

Alzheimer's disease (AD) and Parkinson's disease (PD) are genetically heterogeneous. Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) genes may modify the risk of these disorders. We investigated whether common polymorphisms present in these genes operate as risk factors for AD and PD in Finnish subjects, independently or in concert with the apolipoprotein E ε4 allele (APOE ε4). Eighty late onset sporadic AD patients, 53 PD patients (34 of whom had concomitant AD pathology), and 67 control subjects were genotyped for the insertion (I)/deletion (D) polymorphism of DCP1 and the K variant of BCHE. In logistic regression analysis, the DCP1 *I allele in combination with APOE ε4 significantly increased the risk of AD (OR 30.0, 95% CI 7.3-123.7), compared to subjects carrying neither of the alleles. Similar analysis showed that the risk of AD was significantly increased in subjects carrying both the BCHE wild type (*WT/*WT) genotype and ε4 (OR 9.9, 95% CI 2.9-33.8), compared to those without this BCHE genotype and ε4. Further, the risk of PD with AD pathology was significantly increased for carriers of DCP1 *I and ε4 (OR 8.0, 95% CI 2.1-31.1). We thus conclude that, in Finns, interaction between DCP1 *I and ε4 increases the risk of AD as well as of PD with coexisting Alzheimer pathology, which underlines the importance of the DCP1 I/D polymorphism in the development of Alzheimer neuropathology, whereas the wild type BCHE genotype in combination with ε4 had a combined effect with regard to the risk of AD.


Keywords: Alzheimer's disease; Parkinson's disease; dipeptidyl carboxypeptidase 1; butyrylcholinesterase     

Influence of the apolipoprotein E epsilon4 allele on human embryonic development

Human apolipoprotein E (apoE) exists in three major isoforms encoded by distinct alleles (APOE epsilon2, epsilon3 and epsilon4) and has important functions in nerve development and repair. Inheritance of the 4 allele is a major risk factor for the development of Alzheimer's disease. To investigate the role of APOE polymorphisms in embryonic development, we analyzed the APOE genotypes of 81 spontaneously aborted embryos and 110 adult controls using a solid-phase minisequencing technique. The epsilon4 allele was significantly less frequent in the spontaneous abortion group than in the control group (P=0.009), while the frequency of epsilon3 was significantly increased (P=0.005), suggesting that epsilon4 may have protective effects during embryogenesis. These protective effects might counterbalance the deleterious age-related effects of the epsilon4 allele in natural selection.     

Interaction between matrix metalloproteinase 3 and the epsilon4 allele of apolipoprotein E increases the risk of Alzheimer's disease in Finns

Polymorphisms affecting the expression of matrix metalloproteinases (MMPs), i.e. proteolytic enzymes that degrade intercellular material, have been found at position -1607 (1G/2G) in MMP1 and at -1171 (5A/6A) in MMP3. Interestingly, elevated levels of MMP1 and MMP3 have been observed in the brains of Alzheimer's disease (AD) patients and those of tissue inhibitors of MMPs in the cerebrospinal fluid of AD and Parkinson's disease (PD) patients, suggesting a role for MMPs in these disorders. The aim was to investigate a possible association between the afore-mentioned MMP1 and MMP3 polymorphisms and the risk of developing AD or PD. The polymorphisms were genotyped in 97 AD, 52 PD and 101 control patients. We found an interaction between MMP3*5A and APOE 4 alleles (P < 0.0001) which increases the risk of AD (OR: 23.7, 95% CI: 5.8-144.9, P < 0.0001) compared to those who possess neither MMP3*5A nor APOE 4. In conclusion, our finding suggests that the MMP3 gene, especially together with APOE 4, may contribute to the development of AD.     

Apolipoprotein E and α-1-antichymotrypsin allele polymorphism in sporadic and familial Alzheimer's disease

Alzheimer disease (AD) patients with both sporadic and familial forms of AD and non-demented controls were genotyped for common polymorphisms in the signal peptide for α-1-antichymotrypsin (ACT) gene and in two different regions of apolipoprotein E (APOE) gene. The ACT TT genotype was over-represented (P=0.025) in patients with early onset of sporadic AD. In this patient's group ACT TT genotype conferred a significant crude odds ratio for the disease (OR=2.09; 95% CI=1.09–4.00, P=0.025). After adjustment for the APOE ε4 and APOE −491 genotypes, logistic regression analysis confirmed that the ACT TT genotype resulted independently associated with early onset AD (adjusted OR=2.56; 85% C.I.=1.3–5.2, P=0.009). The frequency of APOE ε4 allele was increased in AD, as expected (OR=5.92, 95% CI=3.60–9.70, P=0.0001). On the contrary, the APOE −491 A/T genotypes were not associated with AD. No preferential association of the APOE ε4 allele or APOE −491 A/T genotypes with ACT A/T alleles was observed in AD. Present findings indicated that subjects with ACT TT genotype had an increased risk of developing AD and suggested that this genotype influenced the risk of an early onset of the disease by affecting the production of ACT molecules.