Association analysis of NAD(P)H:quinone oxidoreductase gene 609 C/T polymorphism with Alzheimer's disease

Alterations of the NAD(P)H:quinone oxidoreductase (NQO1) activity are associated with Alzheimer's disease (AD). A polymorphism consisting of a single nucleotide (C-->T) change at position 609 of NQO1 influences the NQO1 activity. Therefore the NQO1 C609T polymorphism may confer susceptibility for AD developing. To test the hypothesis, we have performed an association study between the NQO1 gene polymorphism C609T and late-onset Alzheimer's disease (LOAD) in Chinese population. Totally 104 LOAD patients and 128 controls were enrolled in our data set. All subjects were genotyped for NQO1 and Apolipoprotein E (APOE). There were no significant differences in NQO1 genotype or allele frequencies between cases and controls. Likewise, with the stratification of APOE psilon4 status, no statistical difference was observed between cases and controls. Our findings suggested that this polymorphism might not represent additional genetic risk factor for LOAD. However, the present study cannot exclude NQO1 as a possible candidate for LOAD. Further study in a larger population and biological functional analysis of NQO1 gene is required to verify the role of NQO1 in LOAD.     

Gender-specific association of ATP-binding cassette transporter 1 (ABCA1) polymorphisms with the risk of late-onset Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder caused by a complex interaction of genetic and environmental factors. Increasing evidence highlights a potential role for cholesterol in the pathophysiology of AD. The ABCA1 gene, located in close vicinity to the 9q linkage peaks identified by genome-wide AD linkage studies, plays an important role in cellular cholesterol efflux, and is likely a good candidate gene. However, results from published genetic association studies between ABCA1 and AD are ambiguous. In the present study, we examined the role of two ABCA1 polymorphisms, R219K (rs2230806) and G-17C (rs2740483) in modifying the risk of late-onset AD (LOAD) in a large American white cohort of 992 AD cases and 699 controls. We observed significant gender x R219K interaction (p=0.00008). Female carriers of the 219K allele showed a 1.75-fold increased risk of developing AD compared to non-219K carrier females (95% CI 1.34-2.29; p=0.00004). The overall two-site haplotype distribution was also significant between female AD cases and controls (p=0.017). The risk associated with the R219K polymorphism was independent of the recently reported significant association in the ubiquilin (UBQLN1) gene in this region on chromosome 9q. Our data suggest a gender-specific and APOE and UBQLN1 independent association between the ABCA1/R219K polymorphism and LOAD.     

Alpha-1 antichymotrypsin and alpha-2 macroglobulin gene polymorphisms are not associated with Korean late-onset Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial disorder with possible involvement of several genetic and environmental factors. For late-onset AD (LOAD), the epsilon4 allele of apolipoprotein E (APOE) has been identified as a major susceptible gene. However, the observation that APOE epsilon4 accounted for approximately one half of the genetic variance of LOAD prompted many researchers to undertake genome surveys to identify other susceptible genes. Recently, several candidate genes such as alpha-1 antichymotrypsin (ACT) and alpha-2 macroglobulin (A2M) were reported to be associated with LOAD. To evaluate the possible association between these genes and LOAD in Korean population, we genotyped ACT A/T and A2M 5-bp deletion (exon 18) polymorphisms in 89 LOAD cases and 50 age-matched healthy controls. The frequencies of ACT A and A2M 5-bp deletion alleles in LOAD and controls were 0.39 vs. 0.37, and 0.05 vs. 0.05, respectively. Although APOE epsilon4 clearly showed higher frequency in LOAD (0.34) than that in controls (0.09), giving an odds ratio of 5.14 (95% confidence interval, 2.31-11.76), neither ACT nor A2M showed statistically significant difference between LOAD and controls regardless of APOE carrier status. Our results do not support previously reported association of ACT and A2M with LOAD, at least in Korean population.     

Investigation of the effect of brain-derived neurotrophic factor (BDNF) polymorphisms on the risk of late-onset Alzheimer's disease (AD) and quantitative measures of AD progression

BDNF is a functional candidate gene for AD, owing to its role in neuronal development and survival. The Val66Met (G196A), along with another C270T polymorphism has been associated with AD, however, the effects seem to be inconsistent across studies. We examined the association of the G196A and C270T polymorphisms with sporadic late-onset AD (LOAD) in a large American White cohort of 995 AD cases and 671 controls and an American Black cohort of 64 AD cases and 45 controls. We also examined the association of these polymorphisms with quantitative measures of AD progression, including age at onset (AAO), disease duration and Mini-Mental State Examination (MMSE) scores. No significant difference in allele, genotype or estimated haplotype frequencies was observed between AD cases and controls within the American White and Black cohorts for the G196A and C270T polymorphisms. However, the frequency of the 196*A allele was significantly lower in American Black subjects compared to Whites. While MMSE scores were significantly lower in C270T/CT carriers compared to C270T/CC subjects only among American Blacks, no such effect was observed among American Whites. The BDNF polymorphisms did not affect AAO or disease duration measures in American Whites or Blacks. Our finding does not support any association between the BDNF/G196A or C270T polymorphism and the risk of sporadic LOAD among American Whites or Blacks. The significant effect of the C270T polymorphism observed on MMSE scores among American Blacks needs to be further explored in a larger cohort.     

Coupling phenomena during asynchronous submaximal two-hand,multi-finger force production tasks in humans

Since a deletion/insertion polymorphism in the promoter region of the apolipoprotein C-I (APOC1) gene has been reported to be associated with late-onset Alzheimer's disease (LOAD), we examined the hypothesis in a Korean population with 120 LOAD cases and 132 age-matched controls. The frequency of APOC1 insertion allele (H2) was significantly increased in LOAD than in controls, giving an odds ratio of 3.3 (95% CI 2.0-5.5, P<0.0001). Logistic regression analysis revealed that the interaction model between APOE epsilon4 and APOC1 H2 yielded larger odds ratio than other models including either APOE epsilon4 or APOC1 H2 alone. In addition, the association between APOC1 H2 and LOAD remained significant after adjustment of the effect of APOE epsilon4 (P=0.036). These results support previous observations that the APOC1 might be an additional susceptibility gene for LOAD.     

Association of the HTR6 polymorphism C267T with late-onset Alzheimer's disease in Chinese

Serotonergic neurotransmitter system has been implicated in the pathogenesis of Alzheimer's disease (AD). 5-Hydroxytryptamine (5-HT)(6) receptor is mainly expressed in the brain areas involved in cognitive processes. And 5-HT(6) receptor gene (HTR6) variants may be a genetic risk factor for late-onset Alzheimer's disease (LOAD). To assess whether HTR6 increases the risk for LOAD, we carried out an association study between the HTR6 polymorphism C267T and sporadic LOAD in Mainland Chinese. An association of C/T genotype with LOAD (OR = 2.10, P = 0.014) was observed. And no statistical difference was found between cases and controls after stratification for APOE epsilon4 status. These data suggest that the HTR6 polymorphism C267T possibly involved in the susceptibility to LOAD as an APOE epsilon4-allele independent risk factor of LOAD.     

Association of RFC1 A80G and MTHFR C677T polymorphisms with Alzheimer's disease

We examined polymorphisms in reduced folate carrier gene (RFC1) and methylenetetrahydrofolate reductase gene (MTHFR) for association with sporadic AD (SAD) in Chinese population. Significant associations of RFC1 A80G G allele and GG genotype with SAD (p=0.008, OR=1.312, 95%CI=1.072-1.605, and p=0.042, OR=1.383, 95%CI=1.012-1.890) were found. Further stratification of total samples by APOE epsilon4 carrier status, age/age at onset and gender revealed that RFC1 A80G G allele was an APOE epsilon4-independent risk factor for late-onset AD, and it might increase the risk of AD in females. No significant associations of MTHFR C677T allele and genotype with AD were observed in total samples, but significant associations of T allele and TT genotype with AD (p=0.031, OR=1.586, 95%CI=1.042-2.414, and p=0.028, OR=2.250, 95%CI=1.074-4.712) were identified in APOE epsilon4 carrier subgroup, suggesting that MTHFR 677 T allele and APOE epsilon4 allele may synergistically act to increase AD risk. No significant effect of RFC1 G80A and MTHFR C677T polymorphisms on plasma folate and homocysteine levels was detected.     

The CDC2 I-G-T haplotype associated with the APOE epsilon4 allele increases the risk of sporadic Alzheimer's disease in Sicily

The cell division cycle 2 (CDC2) gene is a candidate susceptibility gene for Alzheimer's disease (AD). We investigated the CDC2 genotype, and allele and haplotype frequencies in AD patients and matched controls, distinguishing between apolipoprotein E (APOE) epsilon4 allele carriers and non-carriers. APOE epsilon4 is an established predictor of AD risk. APOE and CDC2 genotypes were examined in 109 sporadic AD patients and in 110 healthy age- and sex-matched controls from Sicily. The epsilon4 allele of APOE was predictive of AD risk in our study group (odds ratio: 5.37, 95% CI 2.77-10.41; P<0.0001). Genotype and allele frequencies of the three tested CDC2 polymorphisms (Ex6+7I/D, Ex7-15 G>A, Ex7-14 T>A) were not significantly different between AD patients and controls. However, a significant different distribution of a specific CDC2 haplotype (I-G-T) was found between AD patients and controls when analyzing APOE epsilon4-positive subjects (P=0.0288). Moreover, the combined presence of the I-G-T haplotype and the epsilon4 allele almost doubled the risk of AD (odds ratio: 10.09, 95% CI 3.88-26.25; P<0.0001) compared to carriers of epsilon4 alone. This study suggests that the I-G-T haplotype of the CDC2 gene increases the risk of AD in APOE epsilon4 carriers.     

Different implication of NEDD9 genetic variant in early and late-onset Alzheimer's disease

Alzheimer's disease (AD) is a complex and multifactorial progressive neurodegenerative disease. Recently, two studies reported inconsistent results on a possible involvement of the NEDD9 (neural precursor cell expressed, developmentally down-regulated 9, 6p25-p24) as a candidate gene for the risk of developing AD and/or Parkinson's disease (PD). We analyzed the distribution of the rs760678 SNP polymorphism in 735 Italian subjects: 214 unrelated sporadic late-onset AD patients (LOAD, 64.5% females, mean age-at-onset 71.8 ± 5.2 years), 135 early-onset AD patients (EOAD, 57.3% females, mean age-at-onset 57.5 ± 5.5 years) and 386 healthy controls (68.9% females, mean age 83.4 ± 17.9 years; SD). We observed a statistically significant difference between LOAD patients and controls according to genotypes (P = 0.016) and allele frequency (P = 0.007); CC genotype was more frequent in LOAD cases (44.4%) than controls (36.0%). No difference after stratification of the data in terms of gender and status of the APOE ?4 allele was observed. In conclusion, our data do support an implication of the NEDD9 allelic variant in late-onset AD, with an independent effect of the apolipoprotein E (APOE) ?4 allele in the risk of developing 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.     

Genetic association between low-density lipoprotein receptor-related protein gene polymorphisms and Alzheimer's disease in Chinese Han population

Alzheimer's disease (AD) is the most common neurodegenerative disorders in the elderly. Low-density lipoprotein receptor-related protein (LRP), as a receptor of apolipoprotein E (APOE), APP, and alpha2 macroglobulin (alpha2-M), keeps the balance between degeneration and production of beta-amyloid protein (Abeta) clearance. Its gene had been defined as a candidate gene for AD, but the results were not universal. Total 496 AD patients and 478 controls were recruited in Chinese Han population and real-time PCR was used to detect the polymorphism of LRP C766T. Multiple logistic regression, Chi-square test and survival analysis were performed to explore the association. The distribution of LRP genotypes and alleles was significantly different between cases and controls, and T allele could reduce the risk for developing AD (OR of CT genotype: 0.57; 95% CI: 0.38-0.85, rho=0.003; OR of T allele: 0.57; 95% CI: 0.39-0.83, rho=0.003). TT genotype carriers had 5 years later for developing AD compared with CC genotype carriers, but survival analysis did not conform this (LRP TT vs. CT and CC log rank chi(2)=2.71, rho=0.26). The distribution of LRP C766T genotypes and alleles was different among different severity stratified by MMSE yet (rho=0.26). Our data suggested that the polymorphism of LRP C766T was strongly associated with AD and T allele might be a protective factor for AD in Chinese Han population.     

Association between a T/C polymorphism in intron 2 of cholesterol 24S-hydroxylase gene and Alzheimer's disease in Chinese

A polymorphism (T/C) in intron 2 of the cholesterol 24-hydroxylase (CYP46) gene has recently been reported to be associated with the risk for late-onset Alzheimer's disease (LOAD). To investigate possible involvement of the CYP46 gene and apolipoprotein E (APOE) gene polymorphisms in the manifestation of LOAD, we analyzed 99 sporadic LOAD patients and 113 healthy controls of China. We found an obvious association between CYP46 TT genotype and LOAD (OR = 2.98, 95% CI 1.64-5.44, P < 0.001). A clear increase of the risk to develop LOAD was also observed in subjects carrying both the CYP46 TT genotype and the APOE epsilon4-allele (OR = 12.94, 95% CI 4.26-39.32, P < 0.001). Our data reveal that the polymorphism of CYP46 intron 2 is implicated in the susceptibility to LOAD and a strong synergistic interaction between CYP46 TT homozoygots and APOE epsilon4 carrier status on the risk of LOAD.     

Evidence for apolipoprotein E ϵ4 association in early-onset Alzheimer's patients with late-onset relatives

Recently several reports have extended the apolipoprotein E (APOE) ?4 association found in late-onset Alzheimer's disease (LOAD) patients to early-onset (EO) AD patients. We have studied this question in a large population of 119 EOAD patients (onset ?60 years) in which family history was carefully assessed and in 109 controls. We show that the APOE ?4 allele frequency is increased only in the subset of patients who belong to families where LOAD secondary cases are present. Our sampling scheme permits us to demonstrate that, for an individual, bearing at least one ?4 allele increases both the risk of AD before age 60 and the probability of belonging to a family with late-onset affected subjects. Our results suggest that a subset of EOAD cases shares a common determinism with LOAD cases. © 1995 Wiley-Liss, Inc.     

Butyrylcholinesterase K variant is genetically associated with late onset Alzheimer's disease in Northern Ireland

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has been associated, sometimes controversially, with polymorphisms in a number of genes. Recently the butyrylcholinesterase K variant (BCHE K) allele has been shown to act in synergy with the apolipoprotein E epsilon4 (APOE epsilon4) allele to promote risk for AD. Most subsequent replicative studies have been unable to confirm these findings. We have conducted a case-control association study using a clinically well defined group of late onset AD patients (n=175) and age and sex matched control subjects (n=187) from the relatively genetically homogeneous Northern Ireland population to test this association. The BCHE genotypes of patients were found to be significantly different from controls (chi(2)=23.68, df=2, p<0.001). The frequency of the K variant allele was also found to differ significantly in cases compared to controls (chi(2)=16.39, df=1, p<0.001) leading to an increased risk of AD in subjects with this allele (OR=3.50, 95% CI 2. 20-6.07). This risk increased in subjects 75 years and older (OR=5. 50, 95% CI 2.56-11.87). At the same time the APOE epsilon4 associated risk was found to decrease from 6.70 (95% CI 2.40-19.04) in 65-74 year olds to 3.05 (95% CI 1.34-6.95) in those subjects 75 years and older. However, we detected no evidence of synergy between BCHE K and APOE epsilon4. The results from this study suggest that possession of the BCHE K allele constitutes a significant risk for AD in the Northern Ireland population and, furthermore, this risk increases with increasing age.     

Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations-the ECTIM study

Apolipoprotein E (APOE) is a major protein in lipid metabolism existing in three common isoforms: APOE2, -3 and -4. The varepsilon4 allele of the APOE gene ( APOE ) coding for the APOE4 isoform is associated with an increased risk of myocardial infarction (MI) and of Alzheimer's disease (AD). Recently, several polymorphisms in the APOE regulatory region have been reported. Some of these have been associated with AD and modified APOE allelic mRNA expression in AD brains. Here, we have investigated whether three of these promoter polymorphisms (-491AT, -427CT and -219GT) can also modify cardiovascular risk. The hypothesis was tested in a large multicentre case-control study of MI, the ECTIM Study, on 567 cases and 678 controls. Among the three APOE promoter polymorphisms tested, only the-219T allele was associated with a significantly increased risk of MI (OR = 1.29, 95% CI: 1.09-1.52, P < 0.003) and the effect was shown to be independent of the presence of the other mutations, including the APOE epsilon2/epsilon3/epsilon4 polymorphism. Moreover, the-219T allele greatly decreased the APOE plasma concentrations in a dose-dependent manner ( P < 0.008). These data indicate that the-219GT polymorphism of the APOE regulatory region emerges as a new genetic susceptibility risk factor for MI and constitutes another common risk factor for both neurodegenerative and cardiovascular diseases.     

Analysis of association between Alzheimer disease and the K variant of butyrylcholinesterase (BCHE-K).

Butyrylcholinesterase (BCHE) is an enzyme expressed in most human tissues. Recently, an increased odds of carrying the K variant of BCHE (BCHE-K) was reported among Alzheimer disease (AD) cases as compared with controls. We tested our data set of 245 sporadic AD cases and 241 controls for an association between BCHE-K, APOE4, and AD using logistic regression and chi-square analyses. The sib transmission disequilibrium test (S-TDT) was also used to test for differences in BCHE-K allele frequencies between 163 discordant sib-pairs selected from multiplex AD families. No statistically significant differences were noted between BCHE-K case and control allele frequencies even after stratifying by APOE4 status. S-TDT analysis between the BCHE-K variant and AD was also not significant (P = 0.52). We conclude that BCHE-K is not a major genetic risk factor for AD in our study population.     

Investigation of association of 13 polymorphisms in eight genes in southeastern African American Alzheimer disease patients as compared to age-matched controls

Alzheimer disease (AD) is an emotionally devastating and exceptionally costly disease. Apolipoprotein E (APOE) is a major risk factor gene for AD regardless of age of onset or family history. However, this association may not be as strong or consistent in ethnic groups such as African Americans, raising the possibility of other modifier gene(s). In a group of African American AD patients, a significantly increased risk of AD was associated with two E4 alleles (OR = 5.6; 95% CI = 1.5-21.0) or one E4 allele (OR = 2.5; 95% CI = 1.3-5.0) when compared to E3/E3 genotype, and there was a significant lowering of age of onset for affecteds with E4/E4 genotype as compared to one E2 allele (P = 0.02) or all others (P = 0.03). We also found a significant increase in age of onset with the -308 #2 (A) allele of TNF when compared to AD cases with no #2 allele. A significant increase in age was also demonstrated with the #2 allele (99 base pairs) of the microsatellite TNFa, located approximately 10.5 kb upstream of TNF. When these two alleles were combined with the TNF -238G (#1) allele to give a haplotype, the significant increase in age was still demonstrated. Polymorphisms in the APOE promoter and six other candidate genes did not appear to demonstrate any significant association with our African American AD patients. Our results confirm the established association of APOE4 to AD observed in several ethnic groups, including African Americans. In addition, TNF appears to have some modifying effect in AD, primarily on age of onset, or it could be in linkage disequilibrium with a modifier locus nearby.     

Screening of two mutations at exon 3 of the apolipoprotein E gene (sites 28 and 42) in a sample of patients with sporadic late-onset Alzheimer's disease

The search for further variation at the APOE gene in a sample of patients with sporadic late-onset Alzheimer's disease (AD) and related controls revealed two different mutations in the exon 3 of the gene. One, the Leu28-->Pro, always found on an APOE e(*)4 allele, was present in five of the 94 patients and in 1 of the 157 controls. The other, Thr42-->Ala, found on an e(*)3 allele, was observed in only one AD patient, who also carried the Leu28-->Pro, but in none of the controls.In the AD patient group the allele e(*)4(-), corresponding to Leu28-->Pro, showed a frequency of 0.027, compared with only 0.003 in the controls. Compared to E3/3 and E3/2 genotypes, the risk of developing AD associated with the genotypes carrying the e(*)4 allele, the well-established risk allele for AD onset, was observed to be high (OR=3.16; 95% CI=1.62-6.20; P=0.0009), but the risk associated with genotypes carrying the Leu28-->Pro mutation was higher still (OR=10.95; 95% CI=1.25-95.75; P=0.015). The higher risk associated with this mutation was assessed by meta-analysis carried out using the data of three patient groups from a previously published study Kamboh et al. and from our study. The results indicated that, compared with all the other APOE genotypes, those carrying the Leu28-->Pro mutation were at a substantially higher risk of developing AD (OR=4.25; 95% CI=1.21-14.97).     

Low density lipoprotein receptor-related protein gene polymorphisms and risk for late-onset Alzheimer's disease in a Japanese population

Low density lipoprotein (LDL) receptor-related protein (LRP) gene polymorphisms located in the 5' region and in exon 3, and the apolipoprotein E (APOE) genotype were determined in 100 Japanese patients affected by late-onset Alzheimer's disease (AD). We matched 246 controls for age and found no association between the polymorphism located in the 5' region of the LRP gene. The distribution of LRP exon 3 genotypes and alleles did not differ between AD and the control groups. However, the frequency of T allele in the Alzheimer's group having APOE-epsilon4 was lower than that in the control group having APOE-epsilon4, but it was only marginally significant (p = 0.022). Age of onset was significantly younger in the patients with CC genotype than those carrying the T allele (p = 0.03), and this trend was more evident among non-APOE-epsilon4 carriers (p = 0.008). These results support the possibility that ApoE and LRP may contribute to the development of AD.     

The --491 TT apolipoprotein E promoter polymorphism is associated with reduced risk for sporadic Alzheimer's disease

Homozygosity for the A allele of the -491 A/T apolipoprotein E (APOE) promoter polymorphism has recently been reported to be associated with sporadic Alzheimer's disease (AD). Two hundred and fifty one patients with AD and an equal number of controls derived from the same region in a Spanish population, were genotyped for -491 A/T and epsilon2/epsilon3/epsilon4 APOE polymorphisms. We did not detect an elevated -491 AA genotype frequency when comparing AD cases to controls. In contrast, persons homozygous for the T allele were at a significantly reduced risk of AD (odds ratio of 0.10, P=0.006). Multiple logistic regression analysis indicated that the -491 TT polymorphism added information on the risk of AD which was independent of that of the APOE epsilon4 allele.