Increased Risk Of Late-onset AD Research Articles

Genetic Ancestry and Susceptibility to Late-Onset Alzheimer Disease (LOAD) in the Admixed Colombian Population.

Differences in the prevalence of dementia among populations and in the effect of apolipoprotein E (APOE) on the emergence of Alzheimer disease (AD), which is the main type of dementia, have been reported. This study estimated the ancestry of a group of individuals with late-onset Alzheimer disease (LOAD) (N=280) and established whether there were any differences when compared with a control group (N=357) in a sample of the Colombian population. When the analyses were adjusted for known risk factors such as age, sex, presence of APOE[Latin Small Letter Open E]4, socioeconomic status, educational attainment, and place of birth, African ancestry was associated with an increased LOAD risk (odds ratio: 1.55; 95% confidence interval, 1.09-2.03; P=0.029), whereas Native American ancestry was associated with lower risk (odds ratio: 0.75; 95% confidence interval, 0.61-0.98; P=0.046), for every 10% increase in ancestry. In addition, there were significant differences in the proportion of Native American ancestry between carriers and noncarriers of the APOE[Latin Small Letter Open E]4 allele (Mann-Whitney U test, P=0.047), with noncarriers having higher mean Native American ancestry when compared with carriers. Our results are consistent with the presence of variants of African origin in the genome of the Colombian population and different from APOE[Latin Small Letter Open E]4 that represents a risk factor for the development of LOAD, whereas variants of Native American origin may be conferring protection. However, unknown environmental factors or epigenetic differences among continental groups could also explain the observed associations.

Relationship of polymorphisms and haplotype in interleukin-16 and adiponectin gene with late-onset Alzheimer's disease risk.

AimsTo investigate the impact of Interleukin-16 (IL- 16) and Adiponectin (ANP) gene single nucleotide polymorphisms (SNPs), gene- gene interactions and haplotype on late-onset Alzheimer’s disease (LOAD) risk.MethodsHardy-Weinberg equilibrium (HWE), haplotype and pairwise linkage disequilibrium (LD) analysis were investigated by using SNPstats (available online at http://bioinfo.iconcologia.net/SNPstats). Generalized multifactor dimensionality reduction (GMDR) was used to examine interaction among 4 SNPs, odds ratio (OR) and 95% confident interval (95%CI) were calculated by logistic regression model.ResultsLOAD risk was significantly higher in carriers of rs266729- G allele than those with CC genotype (CG+ GG versus CC), OR (95%CI) =1.61 (1.26-1.96), and higher in carriers of rs1501299- T allele, OR (95%CI) = 1.62 (1.32-2.12), lower in carriers of rs4072111- T allele, adjusted OR (95%CI) =0.65 (0.44-0.93). We also found a significant gene- gene interaction between rs266729 and rs4072111. Participants with CG or GG of rs266729 and CC of rs4072111 genotype have the highest LOAD risk, OR (95%CI) = 2.62 (1.64 -3.58). Haplotype containing the rs266729- G and rs1501299- T alleles were associated with increased LOAD risk, OR (95%CI)= 1.83 (1.32- 2.43), and haplotype containing the rs1131445- C and rs4072111- T alleles were associated with decreased LOAD risk, OR (95%CI)= 0.53 (0.18- 0.95).ConclusionsWe concluded that rs266729 and rs1501299 minor alleles were associated with increased LOAD risk, but rs4072111 minor allele was associated with decreased LOAD risk. We also found that interaction involving rs266729 and rs4072111, and haplotype combinations were associated with LOAD risk.

Interaction between PPAR γ and SORL1 gene with Late-Onset Alzheimer's disease in Chinese Han Population.

AimsTo investigate the impact of sortilin-related receptor 1 gene 1 (SORL1) and peroxisome proliferator activated receptor gamma (PPAR G) gene single nucleotide polymorphisms (SNPs), gene- gene and gene- environment interactions and haplotype on late-onset Alzheimer’s disease (LOAD) risk.MethodsHardy-Weinberg equilibrium (HWE), haplotype analysis and pairwise linkage disequilibrium (LD) analysis were investigated by using SNPStats (available online at http://bioinfo.iconcologia.net/SNPstats). Logistic regression was performed to investigate association between SNPs and LOAD. Generalized multifactor dimensionality reduction (GMDR) was used to investigate the interaction among gene- gene and gene- environment interaction.ResultsLogistic regression analysis showed that LOAD risk was significantly higher in carriers of the A allele of rs1784933 polymorphism than those with GG (GA+ AA versus GG), adjusted OR (95%CI) = 1.63(1.27-1.98), and higher in carriers of G allele of the rs1805192 polymorphism than those with CC (CG+ GG versus CC), adjusted OR (95%CI) = 1.70 (1.25-2.27). GMDR analysis suggested a significant two-locus model (p = 0.0010) involving rs1784933 and rs1805192, and a significant two-locus model (p = 0.0100) involving rs1784933 and alcohol drinking. Haplotype containing the rs1784933- A and rs689021- C alleles were associated with a statistically increased LOAD risk (OR = 1.86, 95%CI = 1.37– 2.52, p < 0.001).ConclusionsWe conclude that rs1784933 and rs1805192 minor alleles, gene- gene interaction between rs1784933 and rs1805192, gene- environment interaction between rs1784933 and alcohol drinking, and haplotype containing the rs1784933- A and rs689021- C alleles are all associated with increased LOAD risk.

The Methylenetetrahydrofolate Reductase C677T Polymorphism and Risk for Late-Onset Alzheimer's disease: Further Evidence in an Italian Multicenter Study.

A functional polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, namely C677T (rs1801133), results in increased Hcy levels and has been associated with risk of late-onset Alzheimer's disease (LOAD). Many investigators reported association between rs1801133 and LOAD risk in Asian populations and in carriers of the apolipoprotein E (APOE) ɛ4 allele, but recent meta-analyses suggest a contribution also in other populations, including Caucasians and/or northern Africans. To further address this issue, we performed a relatively large case-control study, including 581 LOAD patients and 468 matched controls of Italian origin. APOE data were available for a subgroup of almost 600 subjects. Genotyping for rs1801133 was performed with PCR-RFLP techniques. In the total population, the MTHFR 677T allele (OR = 1.20; 95% CI = 1.01-1.43) and carriers of the MTHFR 677T allele (CT+TT versus CC: OR = 1.34; 95% CI = 1.03-1.73) resulted in increased LOAD risk. Similarly, in APOEɛ4 carriers, we observed an increased frequency of MTHFR 677CT carriers (CT versus CC: OR = 2.82; 95% CI = 1.25-6.32). Very interestingly, also in non-APOEɛ4 carriers, both MTHFR 677T allele (OR = 1.38; 95% CI = 1.03-1.85) and MTHFR 677TT genotype (OR = 2.08; 95% CI = 1.11-3.90) were associated with LOAD. All these associations survived after corrections for age, gender, and multiple testing. The present results suggest that the MTHFR C677T polymorphism is likely a LOAD risk factor in our cohort, either in APOEɛ4 or in non-APOEɛ4 carriers.

Gene- Gene Interaction between PPARG and APOE Gene on Late-Onset Alzheimer's Disease: A Case- Control Study in Chinese Han Population.

The aim was to investigate the impact of PPARG and APOE gene single nucleotide polymorphisms (SNPs) and additional gene- gene interaction on late-onset Alzheimer's disease (LOAD) risk based on Chinese Han population. A total of 928 participants (466 males, 462 females), with a mean age of 81.3 ± 16.4 years old, were included in the study, including 460 LOAD patients and 468 normal controls participants. Logistic regression was performed to investigate association between SNP and LOAD risk and generalized multifactor dimensionality reduction (GMDR) was used to analysis the gene-gene interaction. Logistic regression analysis showed that LOAD risk was significantly higher in carriers of G allele of the rs405509 polymorphism than those with AA (AG+ GG versus AA, adjusted OR (95%CI) =1.54(1.20-1.89), and higher in carriers of G allele of the rs1805192 polymorphism than those with CC (CG+ GG versus CC, adjusted OR (95%CI) =1.32(1.16-2.43). We also found that there was a potential gene-gene interaction between rs405509 and rs1805192. Participants with AG or GG of rs405509 and CG or GG of rs1805192 genotype have the highest AD risk, compared to participants with AA of rs405509 and CC of rs1805192 genotype, OR (95%CI) was 2.62(1.64 -3.58), after covariates adjustment. G allele of the rs405509 of APOE and G allele of the rs1805192 of PPAR G polymorphism were associated with increased LOAD risk, and participants with AG or GG of rs405509 and CG or GG of rs1805192 genotype have the highest AD risk.

Association of Single-Nucleotide Polymorphism in ANK1 with Late-Onset Alzheimer's Disease in Han Chinese.

Recently, two CpG sites in ankyrin 1 (ANK1) gene were identified to be hypermethylated and associated with Alzheimer's disease (AD)-related neuropathology in two large independent studies. Genetic variations are indicated to be involved in DNA methylation, especially when the associated single-nucleotide polymorphisms (SNPs) are located adjacent to the CpG site. Accordingly, ANK1 polymorphisms might contribute to late-onset AD (LOAD) risk. One polymorphism rs515071 was identified to be a potential risk factor for type 2 diabetes (T2D). As shared genetic background was found underlying T2D and AD, we postulate that rs515071 polymorphism may be associated with late-onset AD (LOAD) risk and assessed the association in 982 LOAD patients and 1346 sex- and age-matched healthy controls. Our results showed that minor allele A of rs515071 significantly increased LOAD risk in the APOE ε4 (+) subgroup (genotype P = 0.015, allele P = 0.020). After adjusting for age and gender, the association remained significant under the dominant model (OR = 1.809, 95% confidence interval (CI) = 1.186-2.757, P = 0.006). In conclusion, our findings demonstrate that rs515071 in ANK1 is a novel genetic risk for LOAD susceptibility in Han Chinese.

Association between polymorphisms of the insulin-degrading enzyme gene and late-onset Alzheimer disease.

The insulin-degrading enzyme (IDE) gene is a strong positional and biological candidate for late-onset Alzheimer disease (LOAD) susceptibility, with recent studies independently demonstrating an association between IDE gene variants and LOAD. However, previous data have been controversial. To investigate the relationship between IDE gene polymorphisms and LOAD risk, a case-control association study of 406 Han Chinese participants in Xinjiang, China, was undertaken. The LOAD and control groups consisted of 202 and 204 participants, respectively. The single-nucleotide polymorphisms rs1887922 and rs1999764 of the IDE gene were linked to LOAD incidence. The presence of the CT+CC genotype of rs1999764 had a protective effect compared to the TT genotype (adjusted P=.0001; odds ratio [OR]=0.226; 95% confidence interval [CI]=0.116-0.441), while the CT+CC genotype of rs1887922 was associated with increased LOAD risk (adjusted P=.0001; OR=3.640; 95% CI=1.889-7.016). Moreover, the effects of rs1887922 and rs1999764 were associated with LOAD risk independent of the apolipoprotein E ∊4 polymorphism and were more significant in men and women, respectively. These results demonstrate that the polymorphisms rs1887922 and rs1999764 of the IDE gene are associated with LOAD susceptibility in the Xinjiang Han population.

Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease

Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972–1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983–1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.

Meta-analysis of the association between CR1 polymorphisms and risk of late-onset Alzheimer's disease

CR1 polymorphisms have been reported to be associated with late-onset Alzheimer's disease (LOAD) susceptibility. The findings of these studies, however, have been inconsistent. Therefore, we performed a meta-analysis to assess the association between CR1 variants and LOAD susceptibility. We retrieved all relevant studies of the associations between CR1 polymorphisms and the susceptibility to LOAD for the period up to March 30, 2014. The strength of the association between CR1 polymorphisms and LOAD risk was estimated by odds ratios (ORs) and their 95% confidence intervals (CIs). A total of 6 articles were eventually identified with 2752 LOAD cases and 2313 controls for the rs6656401 polymorphism, and 4 studies containing 2547 LOAD cases and 2338 controls were included for the rs3818361 polymorphism. Overall, the pooled data showed that the CR1 rs6656401 polymorphism was significantly associated with LOAD risk in the overall population (A vs. G: OR=1.32, 95%CI=1.17–1.50, P=0.000; AG+AA vs. GG: OR=1.39, 95%CI=1.20–1.61, P=0.000). With respect to the CR1 rs3818361 polymorphism, a statistically significant increased LOAD risk was observed in the overall population (T vs. C: OR=1.24, 95% CI=1.13–1.37, P=0.000; TT+TC vs. CC: OR=1.30, 95% CI=1.15–1.46, P=0.000; TT vs. TC+CC: OR=1.35, 95% CI=1.06–1.71, P=0.014). This meta-analysis demonstrated significant associations of both the CR1 rs6656401 and CR1 rs3818361 polymorphisms with LOAD susceptibility.

The Genetic Variation of ARRB2 is Associated with Late-onset Alzheimer's Disease in Han Chinese

Emerging evidence indicates that β-arrestin 2, an important regulator of G protein coupled receptors, is involved in the pathogenesis of Alzheimer's disease (AD). The aim of this study was to investigate the association between β-arrestin 2 gene (ARRB2) variation and the risk of late-onset AD (LOAD). A total of 1132 LOAD patients and 1158 healthy controls from the Han Chinese population were included in this study. Initially, four common single nucleotide polymorphisms (SNPs) (rs3786047, rs16954146, rs1045280 and rs2271167) were selected by consulting the Han Chinese from Beijing genotype data in HapMap database. Considering the fact that these four SNPs were located in one haplotype block and any two of them were in almost complete linkage disequilibrium (D'=1, r2≥0.897), we chose rs1045280 (a coding- synonymous variant) that covered all the common genetic variations in ARRB2 with r2≥0.8 as the tag SNP (tSNP) for the subsequent genotyping. Our results showed that the minor allele of rs1045280 was associated with an increased LOAD risk after adjusting for age, gender, educational level, and the apolipoprotein E (APOE) ε4 status under dominant (OR=1.291; 95% CI: 1.063-1.568; Bonferroni-corrected P=0.03) and additive (OR=1.269; 95% CI: 1.069-1.507; Bonferroni- corrected P=0.018) models. Meanwhile, when these data were stratified by APOE ε4 status, this association was evident only in APOE ε4 carriers (OR=1.617; 95% CI: 1.01-2.588; P=0.045). In summary, this study provide the first evidence that the tSNP of ARRB2 significantly increases LOAD risk in Han Chinese, suggesting ARRB2 may represent a susceptibility gene for LOAD.

Identification of a Late Onset Alzheimer's Disease Candidate Risk Variant at 9q21.33 in Polish Patients

Late onset Alzheimer's disease (LOAD) accounts for about 95% of all Alzheimer's disease cases. While the APOE ε4 variant seems to have unparalleled influence on increased LOAD risk, it does not explain all of the heritability of LOAD. In this study, we present the application of a cost-effective, pooled DNA genome-wide association study (GWAS) to uncover genetic risk variants associated with LOAD in Polish women diagnosed with either mild cognitive impairment (MCI) or well-defined LOAD. A group of 141 patients (94 LOAD and 47 MCI), as well as 141 controls, were assayed using Affymetrix Genome-Wide Human SNP 6.0 arrays. Allele frequency distributions were compared using χ(2)-tests, and significantly associated SNPs at p < 0.0001 with a proxy SNP were selected. GWAS marker selection was conducted using PLINK, and selected SNPs were validated on DNA samples from the same cohort using KASPar Assays. In addition, to determine the genotype of APOE variants (rs429358, rs7412), a multiplex tetra-primer amplification refractory mutation system was applied. The GWAS revealed nine SNPs associated with MCI and/or LOAD. Of these, the association of seven SNPs was confirmed by genotyping of individual patients. Furthermore, the APOE ε4 appeared to be a risk variant for LOAD, while the APOE ε3 showed a protective effect. Multivariate analysis showed association between rs7856774 and LOAD, independently from the effect of APOE variation. Pooled DNA GWAS enabled the identification of a novel LOAD candidate risk variant, rs7856774 (9q21.33), tagging a possible genomic enhancer affecting proximal transcribed elements including DAPK1 gene.

Association of polymorphism of DNA repair gene XRCC1 with sporadic late-onset Alzheimer's disease and age of onset in elderly Han Chinese

Alzheimer's disease (AD) is characterized by the presence of β-amyloid plaques, neurofibrillary tangles and extensive neuronal loss. There is evidence indicating that the increased DNA damages may contribute to neuronal loss in AD. Recently, it has been shown that the capacity of some types of DNA repair is impaired in the neurons of AD patients. A functional polymorphism (Arg194Trp) of X-ray repair cross-complementing group 1 ( XRCC1) gene may be associated with the repair efficiency of DNA damage which may have a role in AD. Therefore, XRCC1 Arg194Trp polymorphism may be a good candidate for genetic risk analysis in AD. A case–control study from Turkey found that XRCC1 194Trp was associated with late-onset AD (LOAD). In order to determine whether the XRCC1 gene Arg194Trp polymorphism contributes to the risk for LOAD in elderly Han Chinese, we have investigated it in 212 sporadic LOAD patients and 203 healthy controls from Chinese. No significantly increased risk of LOAD in the carriers of XRCC1 194Trp allele (OR = 1.04, 95% CI 0.70–1.52, P = 0.860) was observed. As expected, Apolipoprotein ( APOE) ε4 allele significantly increased the risk of LOAD (OR = 2.95, 95% CI 1.90–4.58, P < 0.001), while APOE ε2 allele significantly decreased the risk of LOAD (OR = 0.13, 95% CI 0.08–0.24, P < 0.001). After stratifying by APOE ε4 status, no increased LOAD risks associated with the XRCC1 194Trp allele carriers were observed. Our findings suggest that it is unlikely that the XRCC1 Arg194Trp polymorphism plays a major role in the pathogenesis of LOAD in elderly Han Chinese and does not support the previous findings that 194Trp allele confers an increased risk for LOAD.

Genetic analysis of tumor necrosis factor-α (TNF-α) G-308A and Saitohin Q7R polymorphisms with Alzheimer's disease

Neuroinflammation and abnormal phosphorylation of TAU proteins have been implicated in the etiology of Alzheimer's disease (AD). Several studies have suggested the G-308A promoter polymorphism in one of the proinflammatory cytokine genes tumor necrosis factor-alpha (TNF-alpha) encoding TNF-alpha may be associated with AD pathogenesis. Association between the Q7R polymorphism in saitohin (STH), a gene nested within the intron of the Tau gene, has also been reported. To determine whether these two polymorphisms contribute to the risk for late-onset AD (LOAD) in Chinese, we have investigated 207 sporadic LOAD patients and 222 healthy controls. The associations of the AA genotype and A-allele with LOAD (chi(2) = 8.74, df = 1, P = 0.0031, and chi(2) = 4.47, df = 1, P = 0.035) were found. After stratifying by apolipoprotein E allele 4 (APOE epsilon4) status, increased LOAD risks associated with the AA genotype and A-allele only in the APOE epsilon4 non-carriers (chi(2) = 9.21, df = 1, P = 0.002; chi(2) = 10.02, df = 1, P = 0.0015) were seen. These results suggested that the TNF-alpha gene G-308A polymorphism might be a risk factor for LOAD and dependent on APOE epsilon4 status in Chinese. Homozygous Q/Q of STH Q7R polymorphism was the only one genotype found in either LOAD group or controls. No R allele was detected in LOAD and control groups. The extremely rare frequency of the ancestral R allele differs sharply from that observed in studies in the Caucasian population, suggesting obvious ethnic differences.

The association of mitochondrial aldehyde dehydrogenase gene (ALDH2) polymorphism with susceptibility to late-onset Alzheimer's disease in Chinese

A functional polymorphism of mitochondrial aldehyde dehydrogenase gene (ALDH2 1/2 polymorphism) can influence the accumulation of acetaldehyde which may have a role in Alzheimer's disease (AD), and is widely prevalent among Mongoloids. Therefore ALDH2 1/2 polymorphism may represent a good candidate for genetic risk factors for AD, especially in East Asian. A case-control study from Japan found that ALDH2*2 was associated with late-onset AD (LOAD), interacting synergistically with the presence of the apolipoprotein E allele 4 (APOE epsilon4). But the subsequent studies in Koreans didn't find the similar result. To determine whether the ALDH2 gene 1/2 polymorphism contributes to the risk for LOAD in Chinese, we have investigated 188 sporadic LOAD patients and 223 healthy controls from Chinese. A significantly increased risk of AD in the carriers of ALDH2*2 allele (OR=3.11, 95% CI 2.06-4.69, P<0.001) was observed. After stratifying by APOE epsilon4 status, increased LOAD risks associated with the ALDH2 2 allele carriers only in the APOE epsilon4 non-carriers (chi2=31.79, df=1, P<0.001) and with the 2-allele in either groups (chi2=6.64 df=1, P=0.0099 and chi2=37.38, df=1, P<0.001) were seen. These results suggested that the ALDH2 gene 1/2 polymorphism might be a risk factor for LOAD and dependent on APOE epsilon4 status in Chinese.

Association Between Alzheimer’s Disease and the NOS3 gene Glu298Asp Polymorphism in Chinese

The oxidative stress caused by nitric oxide (NO) in the brain has been proposed as a pathogenic mechanism in Alzheimer's disease. Endothelial NO synthase (ecNOS) produces the majority of circulating NO. The biological functional and genetic association studies suggested that the Glu298Asp polymorphism of the ecNOS gene (NOS3) may be a genetic risk factor for late-onset Alzheimer's disease (LOAD). To investigate an association between the NOS31 Glu298Asp polymorphism and sporadic LOAD in Chinese, we examined 338 LOAD patients and 378 healthy controls. The associations of the Glu/Glu genotype and Glu allele with LOAD (chi2 = 9.12, df = 1, P = 0.003 by genotype; chi2 = 8.37, df = 1, P = 0.038 by allele) were found. After stratifying by apolipoprotein E allele 4 (APOE epsilon 4) status, increased LOAD risks associated with the Glu/Glu genotype and Glu allele only in the APOE epsilon 4 noncarriers (chi2 = 6.28, df = 1, P = 0.012 by genotype; chi2 = 5.62, df = 1, P = 0.018 by allele) were seen. These results suggest that the NOS3 gene Glu298Asp polymorphism might be a risk factor for LOAD and dependent on APOE epsilon 4 status in Chinese.

The Insertion Polymorphism in Angiotensin-Converting Enzyme Gene Associated With the APOE ε4 Allele Increases the Risk of Late-Onset Alzheimer Disease

Several studies have shown that a common insertion (I)/deletion (D) polymorphism of angiotensin-converting enzyme (ACE) gene may confer an increased risk of late-onset Alzheimer disease (LOAD). However, the result has not been replicated by all studies. In order to clarify the role of the polymorphism for the occurrence of LOAD in Chinese and the possibility of a synergistic effect with the apolipoprotein E allele 4 on the risk of Alzheimer disease, we examined the ACE and APOE genotypes in a Chinese sample consisting of 104 sporadic LOAD patients and 128 healthy controls. An obvious difference of allelic and genotypic distributions of ACE I/D polymorphism between cases and controls was observed (chi2 = 6.61, df = 2, p = 0.037 by genotype; chi2 = 4.67, df = 1, p = 0.031 by allele). And ACE I allele carriers showed an increased risk for LOAD developing (chi2 = 6.59, df = 1, p =0.01, OR = 2.91, 95% CI 1.25-6.77). After stratifying by APOE epsilon 4 status, the increased LOAD risks associated with I allele carriers only in the APOE epsilon 4 noncarriers was seen (chi2 = 4.12, df = 1, p = 0.042). Logistic regression analysis of total subjects demonstrated a more than sevenfold increase in the risk of developing LOAD in subjects carrying both the ACE I allele and the APOE epsilon 4 (OR = 7.39, 95% CI 2.50-21.89, p < 0.001). Our data revealed that ACE I/D polymorphism is considered to be an additional risk factor, which has strong synergistic interaction with APOE epsilon 4 on the risk of LOAD.

Association of &lt;I&gt;MTHFR&lt;/I&gt; Gene Polymorphism C677T With Susceptibility to Late-Onset Alzheimer's Disease

Increased total plasma homocysteine (t-Hcy) levels are found to be associated with Alzheimer's disease (AD). Because the methylenetetrahydrofolate reductase (MTHFR) gene encodes a key enzyme that influences the metabolism of homocysteine, it has been considered as a possible genetic risk factor for AD. Although the MTHFR gene C677T polymorphism has a significant impact on reducing enzyme activity and increasing t-Hcy concentrations, the association between the C677T polymorphism and AD remains inconclusive. To determine whether the MTHFR gene C677T polymorphism contributes to the risk for late-onset AD (LOAD) in Chinese, we have investigated 104 sporadic LOAD patients and 130 healthy controls. The strong associations of the TT genotype and T-allele with LOAD (p 0.001, OR 5.73 95% CI 1.85-17.72, and p 0.002, OR 1.89 95% CI 1.25-2.86) were found. After stratifying by apolipoprotein E allele 4 (APOE epsilon4) status, increased LOAD risks associated with the TT genotype only in the APOE epsilon4 noncarriers (chi2=8.92, df=1, p=0.003) and with the T-allele in either group (chi2=5.18, df=1, p=0.023 and chi2=5.53, df=1, p=0.019) were seen. These results suggest that as an APOE epsilon4 allele-dependent risk factor, the MTHFR gene C677T polymorphism is involved in developing LOAD in Chinese.