Apolipoprotein E and intronic polymorphism of presenilin 1 and alpha-1-antichymotrypsin in Alzheimer's disease and vascular dementia

Apolipoprotein E (ApoE) genotypes, presenilin 1 (PS-1) and alpha(1)-antichymotrypsin (ACT) polymorphism and the association of the genotypes were examined in patients with Alzheimer's disease (AD, n = 121) or vascular dementia (VD, n = 68) in comparison with elderly controls (n = 125). The frequency of the ApoE epsilon 4 allele was significantly increased both in late-onset AD (0.35) and in VD (0.17); the frequency of ApoE epsilon 2 was significantly reduced in AD, but it was similar in VD and controls. The presence of the allele 1 of PS-1 intronic polymorphism was not associated with AD or VD and was not influenced by the ApoE genotypes. Also, the frequency of allele A of the intronic polymorphism of ACT was similar in AD, VD and controls and it was not altered by ApoE or PS-1 genotypes. The results confirm the association between ApoE epsilon 4 and AD and indicate an increase in ApoE epsilon 4 in Vd, too. A potential protective role of ApoE epsilon 2 is also suggested for late-onset AD but not for VD. No association was shown between ACT allele A and PS-1 allele 1 in AD or VD.     

Presenilin-1 Polymorphism in Alzheimer''s Disease and Vascular Dementia

Recent reports suggest an association between an intronic polymorphism at the 3′ position of exon 8 of the presenilin-1 (PS-1) gene and late-onset Alzheimer's disease (AD), but little is known about its role in the pathogenesis of AD. By genotyping 193 Japanese patients with vascular dementia or AD, and 186 elderly control subjects, we have shown no association between vascular dementia and this PS-1 polymorphism, though PS-1 genotype 1/1 and allele 1 frequencies were both significantly higher among patients with AD than among controls. These results argue for a specific role of PS-1 allele 1 in the pathogenesis of AD, rather than suggesting a broader role for this allele as, for example, in vascular dementia.     

Estrogen receptor gene polymorphisms in patients with Alzheimer's disease, vascular dementia and alcohol-associated dementia

The association between the estrogen receptor (ER-alpha) gene and dementia was examined in 223 patients with Alzheimer's disease (AD), 66 with vascular dementia (VD), 17 with alcohol-associated dementia (ALD) and 134 healthy elderly control subjects. The PvuII and XbaI restriction fragment length polymorphisms of the ER-alpha gene were represented as Pp (PvuII) and Xx (XbaI), with capital letters signifying the absence of restriction sites and small letters the presence of restriction sites. We found that the frequency of the ER-alpha gene P allele and X allele in the late-onset AD (LOAD) group (P allele was 0.51, X allele was 0.30) was significantly higher than that in controls (P 0.38, p < 0.01; X 0.20, p < 0.01), and that the frequency of the ER-alpha gene P allele and PP genotype was significantly different between apolipoprotein E epsilon4 carriers and noncarriers in LOAD. These findings suggest that the genotype of the ER-alpha gene may be specific in LOAD, and that the ER-alpha gene was an additional risk for LOAD.     

Lack of association between apolipoprotein E polymorphism and vascular dementia in Koreans

To investigate an association of vascular dementia (VD) with the apolipoprotein E (APOE) polymorphism, the APOE polymorphism of 100 VD patients, 100 age- and gender-matched Alzheimer disease (AD) patients, and 200 age- and gender-matched nondemented control (NC) subjects was genotyped. The distribution of APOE polymorphism was compared. Neither the APOE epsilon4 allele nor the APOE epsilon2 allele was more prevalent in the VD patients compared with the NC subjects (P > .1 by the chi 2 test), which was the case when both men and women were analyzed separately (P > .1 by the chi2 test) and when young patients (75 years old or less) and old patients (more than 75 years old) were analyzed separately (P > .1 by the chi2 test). The estimated statistical power was over 0.80 when the odds ratios (OR) for VD conferred to the APOE epsilon4 are assumed to be higher than 2.2 and the type I error probability is set at 0.05, which is much higher than the power of the previous studies on the VD/APOE association. In conclusion, the results suggested that APOE epsilon4 allele does not confer the risk for VD, and even if it does, it does so very modestly.     

Genetic heterogeneity of Alzheimer's disease: complexity and advances

Most of what we know about the pathological process of Alzheimer's disease (AD) results from research on the amyloid cascade hypothesis. This hypothesis in turn is derived largely from the characterization of rare disease-causing mutations in three genes, which code for the amyloid precursor protein (APP), presenilin 1 (PS-1) and presenilin 2 (PS-2) and account for most cases of early-onset autosomal dominant familial AD. These genetic findings also suggested that better understanding of the genetic components of AD, even in the late-onset sporadic forms of the disease, might help to identify central pathways of the AD process and lead to the rapid development of active molecules. Twin studies have reinforced the rationale of this approach, for they indicate that more than 50% of the late-onset AD risk may be attributable to genetic factors. The 1993 discovery that the apolipoprotein E4 (ApoE4) allele is genetically associated with increased risk in both sporadic and familial late-onset Alzheimer's disease strongly supports the validity of this genetic approach. Further progress based on this major finding has nonetheless been disappointing and raises questions about it. First, despite intensive researches, the exact role of APOE in the pathophysiological process still remains unknown. Second, the APOE gene is the only gene so far recognized as a consistent genetic determinant of sporadic forms of AD, even though numerous studies have looked for such genes; these disappointing results suggest persistent methodological limitations. However, recent methodologies allowing new strategies may allow important breakthrough.     

白介素-1α基因多态与阿尔茨海默病及血管性痴呆的关系

目的 研究中国汉族人群中白介素-1α基因(IL-1α多态与阿尔茨海默病及血管性痴呆的关系。方法 随机选取125名阿尔茨海默病患者、70名血管性痴呆患者和93名对照人群，用PCR(聚合酶链式反应)和RFLP(限制性片段长度多态性1方法，分析受检者的IL-1α、载脂蛋白E(APOE)基因型。结果 IL-1α等位基因在三组中差异无显著性区别。占主导地位是IL-1α等位基因(约90％)。APOE4等位基因在AD患者组中过表达。APOE4等位基因不影响IL1-1αd基因型或等位基因的分布频率。IL-1α等位基因，特别是TT纯合子，低于白种人，或许可解释白介素-1α基因(IL-1α多态与汉族AD无关。结论 IL-1α等位基因的出现不能被用来作为区分AD、VD和健康对照人群的标识。     

Alzheimer病和血管性痴呆患者载脂蛋白E基因多态性分析

探讨ApoE多态性与Alzheimer病（AD）和血管性痴呆（VD）的关系。方法：应用PCR—RFLP技术分析25例AD,30例VD及40例对照组人群的ApoE基因型。结果：与对照组相比较,AD和VD患者ε3频率降低（P＜0．05）,ε4频率升高（P＜0．05）,两组患者间各等位基因频率差异无统计学意义（P＜0．05）。结论：ApoE多态性与AD和VD的发病机制相关,其在这两种疾病中的作用相似。     

No association between an intronic polymorphism in the presenilin-1 gene and Alzheimer disease in a German population.

A polymorphism in intron 8 of the presenilin-1 (PS-1) gene has been demonstrated to increase the risk for developing late-onset Alzheimer disease (AD). Conflicting results exist for the association between this intronic polymorphism and AD probably due to variations in the PS-1 gene among different ethnic groups. We investigated the genetic association between this intronic polymorphism in the PS-1 gene and AD in a homogenous group of German Caucasians. The control group consisted of healthy subjects and depressed patients. There were no significant differences in the distribution of the PS-1 genotypes and allele frequencies between AD patients and controls. Our data do not support an association between the intronic polymorphism of the PS-1 gene and AD and there was no interaction between the PS-1 genotype and apolipoprotein E epsilon4 allele.     

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     

脑啡肽酶基因多态性与阿尔茨海默病及血管性痴呆的相关性研究

目的 探讨陕西延安地区汉族人群中脑啡肽酶(NEP)基因多态性与阿尔兹海默(AD)和血管性痴呆(VD)的相关性。方法 选择2013年1月-2016年6月在本科治疗的138例AD患者作为AD组,57例VD患者作为VD组,同时随机选择同期在本院体检的老年体检健康者150例作为对照组,采用聚合酶链反应-限制性内切酶分析(PCR-RFLP)结合DNA直接测序法检测NEP基因rs989692位点和rs6776185位点基因型。结果 各组NEP基因rs989692位点基因型和等位基因分布频率无明显差异(P均>0.05)。对于rs6776185位点AD组和VD组与对照组比较,AA基因型和A等位基因分布频率均明显增多(P均<0.05)。AD组与VD组基因型和等位基因分布频率无明显差异(P均>0.05)。结论 NEP基因rs6776185位点A等位基因和AA基因型可能是陕西延安地区汉族人AD和VD发病的危险因素。     

Association of alpha-2-macroglobulin deletion polymorphism with sporadic Alzheimer's disease in Koreans

Alpha-2-macroglobulin (A2M) deletion polymorphism was recently reported to be associated with Alzheimer's disease (AD) in a way comparable to apolipoprotein E (APOE) polymorphism in a family-based study. However, the association of A2M deletion polymorphism with AD has not been consistently replicated in successive case-controlled studies. In order to evaluate whether this A2M polymorphism is associated with AD in Koreans, we examined the frequencies of the A2M deletion (D) allele and D-bearing genotypes in a group of Koreans composed of 100 sporadic AD patients and 203 control subjects. The frequency of the deletion (D) allele (P=0.046) was significantly different between the total group of AD patients and the controls, although the frequency of the D-bearing genotypes did not attain significance (P=0.078). When the subjects were stratified according to age at onset, there was significant difference in the frequencies of the D allele (P=0.044) and D-bearing genotypes (P=0.041) between late-onset AD patients (> or =65 years) and the controls. However, no significant difference was observed between early-onset AD patients (<65 years) and the control group. Additionally, when we divided the late-onset AD and control subjects by APOE epsilon4 status, the difference of the A2M D allelic frequency was significant only in the APOE epsilon4 negative subjects (P=0.015). In conclusion, our data suggests that the A2M D allele is a modest risk factor for late-onset sporadic AD in Koreans, and the AD risk conferred by the A2M D allele increases in APOE epsilon4 negative subjects.     

Apolipoprotein E genotypes in hospitalized elderly patients with vascular dementia

BACKGROUND: Polymorphism in the apolipoprotein E (APOE) gene is the major genetic risk factor associated with late-onset Alzheimer's Disease (AD). However, it is still unclear if a relationship exists between the APOE epsilon4 allele and vascular dementia (VaD) in elderly subjects. OBJECTIVES: To evaluate the prevalence of APOE alleles in elderly patients with VaD compared to AD patients and to control subjects with no cognitive impairment (NoCI). PATIENTS AND METHODS: We evaluated 396 consecutive patients aged > or =65 years with definite or suspected cognitive impairment with a clinical (Mini-Mental State Examination, Clinical Dementia Rating, Geriatric Depression Scale), functional (Activities of Daily Living, Instrumental Activities of Daily Living), comorbidity (Cumulative Illness Rating Scale) and instrumental (CT scan, NMR) assessment. Diagnosis of dementia was made according to NINCDS-ADRDA and NINDS-AIREN Work Group and the DSM-IV. APOE genotypes were analyzed by a recently described method resulting in positive/negative chain reaction products for each APOE genotype. Statistical analysis was carried out using the Pearson chi(2), the Kruskal-Wallis test and the ANOVA post hoc comparisons. RESULTS: A total of 287 elderly patients (males = 138, females = 149, mean age = 77.8 +/- 6.9 years, range = 65-98) with diagnoses of VaD (n = 97), AD (n = 82) or NoCI (n = 108) were included in the study. A significantly higher APOE epsilon4 allele frequency was observed in AD patients compared to VaD and/or NoCI subjects, while no differences were found between VaD patients and subjects with NoCI (AD = 24.3%, VaD = 10.3, NoCI = 8.7, p < 0.05). Furthermore, a significantly lower APOE epsilon3 allele frequency was observed in AD patients compared to VaD and/or NoCI subjects but not between VaD and NoCI patients (AD = 71.3%, VaD = 80.9, NoCI = 83.4, p < 0.05). No significant differences were observed in the APOE epsilon2 allele (VaD = 8.8%, AD = 4.4, NoCI = 7.9, p = n.s.) among the 3 groups. CONCLUSIONS: In this population, the frequency of the APOE epsilon4 allele is lower in VaD than in AD.     

Alzheimer's disease and apolipoprotein e-4 allele in an amish population

Alzheimer's Disease (AD) is a complex genetic disorder with four loci already identified. Mutations in three of these, the amyloid precursor protein, presenilin I, and preseuilin II, cause early-onset AD. The apolipoprotein E (APOE) gene contributes primarily to late-onset AD. The APOE-4 allele acts in a doserelated fashion to increase risk and decrease the age-of-onset distribution in AD. We examined the effect of APOE on AD in a previously unstudied Amish population that has a lower prevalence of dementia compared with other populations. We sampled a large inbred family with 6 latehyphen: onset AD members. We also genotyped 53 individuals from the general Amish population as controls for the APOE allele frequency estimates. The frequency of the APOE-4 allele in the Amish controls was 0.037 ± 0.02. This differed significantly compared with three independent sets of non-Amish white controls (p < 2 × 10?4, p < 6 × 10?5, and p < 2 × 10?6). In addition, all Amish AD-affected individuals had APOE 3/3 genotypes; no APOE X/4 or 4/4 individuals were observed. We suggest that the lower frequency of dementia in the Amish may be partially explained by the decreased frequency of the APOE?4 allele in this population, and that the inbred nature of this pedigree, with its strong clustering of cases contrasted against the lower frequency of dementia, indicates that additional genetic factors influence late-onset AD.     

Polymorphisms of APOE and LRP genes in Brazilian individuals with Alzheimer disease

Alzheimer disease (AD) is the most frequent cause of dementia in Western countries. Putative genetic risk factors for AD are polymorphisms in the apolipoprotein E (APOE) gene and in the low-density lipoprotein receptor-related protein (LRP) gene. Our objective was to investigate the role of the APOE coding region polymorphisms epsilon 2, epsilon 3, and epsilon 4 and APOE promoter variants A/T at position -491 and G/T at -219, as well as LRP polymorphism C/T, as risk factors for AD in Brazilian individuals. One hundred and twenty patients with probable AD, along with 120 controls were analyzed. A significant difference between patients and controls for epsilon 4 alleles was observed: frequency of this allele in AD was 0.31, and 0.10 in controls. Individuals with 2 epsilon 4 alleles had a higher risk for AD than subjects with only 1 such allele; presence of 1 epsilon 2 allele proved protective. The presence of the T allele of the -219 polymorphism was also associated with an increased risk of AD, but this polymorphism is in linkage disequilibrium with APOE epsilon polymorphisms. No significant differences between patients and controls were observed for -491 APOE or LRP polymorphisms. In this Brazilian population, both the epsilon 4 allele and T -219 polymorphism were associated with an increased risk for AD.     

Candidate gene association studies in sporadic Alzheimer's disease

The genetics of Alzheimer's disease (AD) is complex. Three genes (amyloid precursor protein, presenilin 1 and presenilin 2) have been described in the relatively rare, early-onset, autosomal dominant familial form of AD. In the common, non-familial (sporadic) late-onset AD, the major known genetic risk factor is the epsilon4 allele of the apolipoprotein E (APOE) gene. However, at least half of the people who develop AD do not carry this allele, and not all people who do carry this allele develop AD even if they live to an old age. Therefore, approximately 30 other candidate genes involving a protein in a critical pathway in the pathogenesis of disease (principally interaction with amyloid-beta, oxidative stress and inflammation/apoptosis) have been considered as risk factors for sporadic AD. Then these genes have been sequenced in search of genetic variability or polymorphisms, and each putative polymorphism has been reported to alter the risk of AD either directly or by an interaction with the APOE epsilon4 allele. However, positive-association studies with these candidate genes have not been consistently confirmed.     

APOE genotype and cholesterol levels in lewy body dementia and Alzheimer disease: investigating genotype-phenotype effect on disease risk.

BACKGROUND: APOE is the most recognized genetic risk factor for sporadic late-onset Alzheimer disease (AD). The role of APOE genotype in Lewy body dementia (LBD) is still unknown as well as the relationship between APOE genotype and cholesterol levels. OBJECTIVE: The objective of this study was to explore the association between APOE genotype and cholesterol levels in patients with LBD and those with AD. METHODS: Eighty-two patients with LBD were consecutively enrolled as well as a comparable number of patients with AD and comparison group. Each subject underwent a clinical and neuropsychologic evaluation and APOE genotyping. RESULTS: The distribution of APOE genotypes significantly differed between AD and LBD cases compared with the comparison group, with the APOE epsilon4+ (epsilon4+/epsilon4 + or epsilon4+/epsilon4-) genotype more frequent in patient subgroups. Different models have been fitted, and total APOE epsilon4-hypercholesterolemia complete interaction effect was claimed in predicting their relationship on disease outcome. Subjects with hypercholesterolemia and heterozygous for APOE epsilon4 allele had more than threefold risk to develop AD compared both with the comparison group and with those with LBD. The risk to develop AD in hypercholesterolemic and APOE epsilon4 homozygous subjects was 13-fold compared with the comparison group and those with LBD. Conversely, there was not evidence for APOE epsilon4-hypercholesterolemia complete interaction effect in LBD and in the comparison group. CONCLUSIONS: This study highlighted that APOE is a risk factor not only for AD, but also for LBD, and that the APOE-cholesterol pathway differently affects AD and LBD. This approach may aid the search for the identification of an interactive effect of APOE genotype and modifiable risk factors, i.e., hypercholesterolemia, eventually resulting in individualized and effective cholesterol-lowering therapy in at-risk subjects.     

No evidence of association between apolipoprotein E gene regulatory region polymorphism and Alzheimer's disease in Japanese

The reported association between -491 A/T polymorphism in the regulatory region of the apolipoprotein E gene (APOE) and increased risk for Alzheimer's disease (AD) is controversial: Studies of different racial and ethnic populations have found both positive and negative associations. Examination of -491 A/T polymorphism in 216 patients with sporadic AD and 157 age- and gender-matched controls from the Japanese population revealed that, in contrast to findings for Caucasian populations, the -491 T allele, but not the A allele, was significantly more prevalent in patients with AD than in controls. This difference disappeared when the subjects were stratified by the gene dose of the APOE epsilon4 allele. Moreover, logistic regression analysis, controlling for age, sex, and the presence of the APOE epsilon4 allele, showed no association between the -491 polymorphism and AD. These results suggest that -491 polymorphism does not independently confer susceptibility to AD, but that this polymorphism is in partial linkage disequilibrium with the APOE epsilon2/3/4 polymorphism.     

What is the relationship among atherosclerosis markers,apolipoprotein E polymorphism and dementia?

Evidence suggests the important role of vascular factors both in vascular dementia (VaD) and Alzheimer disease (AD) pathogenesis. However, the relationship between apolipoprotein E (APOE) polymorphism and markers of atherosclerosis is still controversial. The aim of the study was to investigate the interplay between APOE polymorphisms and atherosclerosis in patients with AD and VaD. In this cross-sectional study, 101 demented (68 AD and 33 VaD) patients underwent APOE genotyping and neck vessel ultrasound to evaluate carotid artery disease [intima-media thickness (IMT) and plaques]. Patients with AD carrying ɛ 4 allele presented increased IMT values with respect to non- ɛ 4 carriers and VaD patients, whereas no relation was found between APOE polymorphisms and the presence or grade of carotid plaques both in AD and VaD patients. The ɛ 4 APOE allele may promote intima-media thickening, interacting with other factors contributing to AD development.     

Apolipoprotein E epsilon4 allele frequency in vascular dementia

AIM: The aim of the study was to investigate whether possession of the epsilon4 allelic form of the apolipoprotein E (APOE) gene increases the risk of developing vascular dementia (VaD). METHODS: APOE allele and genotype frequencies were determined by PCR in 89 patients with possible and probable VaD and compared with those in 97 patients with possible and probable Alzheimer's disease (AD) of similar age of disease onset and ethnic background, and with 766 control subjects drawn from the same geographical region. RESULTS: The APOE epsilon4 allele frequency in all 97 patients with possible and probable AD was significantly higher (p < 0.001) than that in control subjects. However, the APOE epsilon4 allele frequency in all 89 patients with possible and probable VaD was also significantly higher (p < 0.001) than that in control subjects, but not significantly different from that in AD. The APOE epsilon4 allele frequency was similarly, and still significantly (p < 0.001), increased when only those patients with probable AD or probable VaD were considered. CONCLUSION: Possession of APOE epsilon4 allele increases the risk of VaD.