Susceptibility Gene For Late-onset Alzheimer's Disease Research Articles

Genetic Variations in ABCA7 Can Increase Secreted Levels of Amyloid-β40 and Amyloid-β42 Peptides and ABCA7 Transcription in Cell Culture Models.

Alzheimer's disease (AD) is characterized by extracellular deposits of amyloid-β (Aβ) in the brain. ABCA7 is highly expressed in the brain and a susceptibility gene for late-onset AD (LOAD). The minor alleles at two ABCA7 single-nucleotide polymorphisms (SNPs), rs3764650 (T>G; intron13) and rs3752246 at a predicted myristoylation site (C>G; exon33; p.Gly1527Ala), are significantly associated with LOAD risk; however, the mechanism of this association is unknown. Functional consequences of both SNPs were examined in HEK293 and CHO cells stably expressing AβPPSwe. Luciferase reporter assays in HEK293 cells suggested that intron13 carrying rs3764650 major T-allele (int13-T) possessed promoter-enhancing capabilities. Co-transfection experiments with hABCA7 and int13-T resulted in significantly increased ABCA7 protein level relative to that with int13-G. Expression of hABCA7 carrying rs3752246 risk allele led to increases in secreted Aβ40 and Aβ42 and β-secretase activity in CHO- and HEK-AβPPSwe cells. Hydroxymyristic acid treatment of cells expressing hABCA7 carrying the rs3752246 major G allele resulted in increased β-secretase activity and levels of Aβ, suggesting that lack of myristoylation contributes to the observed cell-phenotypes. Molecular weight determination, by gel-electrophoresis and mass spectrometry, of hABCA7 peptides spanning position 1527 showed loss of post-translational modification in the risk-allele peptide. These results suggest that decreased expression, or impaired function, of ABCA7 may contribute to AD pathology.

Genetic Variations in ABCA7 Can Increase Secreted Levels of Amyloid-β40 and Amyloid-β42 Peptides and ABCA7 Transcription in Cell Culture Models.

Alzheimer's disease (AD) is characterized by extracellular deposits of amyloid-β (Aβ) in the brain. ABCA7 is highly expressed in the brain and a susceptibility gene for late-onset AD (LOAD). The minor alleles at two ABCA7 single-nucleotide polymorphisms (SNPs), rs3764650 (T>G; intron13) and rs3752246 at a predicted myristoylation site (C>G; exon33; p.Gly1527Ala), are significantly associated with LOAD risk; however, the mechanism of this association is unknown. Functional consequences of both SNPs were examined in HEK293 and CHO cells stably expressing AβPPSwe. Luciferase reporter assays in HEK293 cells suggested that intron13 carrying rs3764650 major T-allele (int13-T) possessed promoter-enhancing capabilities. Co-transfection experiments with hABCA7 and int13-T resulted in significantly increased ABCA7 protein level relative to that with int13-G. Expression of hABCA7 carrying rs3752246 risk allele led to increases in secreted Aβ40 and Aβ42 and β-secretase activity in CHO- and HEK-AβPPSwe cells. Hydroxymyristic acid treatment of cells expressing hABCA7 carrying the rs3752246 major G allele resulted in increased β-secretase activity and levels of Aβ, suggesting that lack of myristoylation contributes to the observed cell-phenotypes. Molecular weight determination, by gel-electrophoresis and mass spectrometry, of hABCA7 peptides spanning position 1527 showed loss of post-translational modification in the risk-allele peptide. These results suggest that decreased expression, or impaired function, of ABCA7 may contribute to AD pathology.

ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology.

Gene variants inABCA7encoding ATP-binding cassette transporter A7 are associated with the increased risk for late-onset Alzheimer's disease (AD). Importantly, we found the altered brain lipid profile and impaired memory in ABCA7 knock-out mice. The accumulation of amyloid-β (Aβ) peptides cleaved from amyloid precursor protein (APP) in the brain is a key event in AD pathogenesis and we also found that ABCA7 deficit exacerbated brain Aβ deposition in amyloid AD model APP/PS1 mice. Mechanistically, we found that ABCA7 deletion facilitated the processing of APP and Aβ production by increasing the levels of β-secretase 1 (BACE1) in primary neurons and mouse brains without affecting the Aβ clearance rate in APP/PS1 mice. Our study demonstrates a novel mechanism underlying how dysfunctions of ABCA7 contribute to the risk for AD.

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.

Genetic variation in Clusterin gene and Alzheimer's disease risk in Han Chinese

Clusterin gene (CLU), also known as apolipoprotein J (ApoJ), is a strong candidate gene for late-onset Alzheimer's disease (LOAD) according to the Alzgene database. To further characterize this association and to isolate the variants contributing to the pathogenesis of LOAD in Han Chinese, we first sequenced a small sample (n = 100) to discover variants in the promoter, exons, the 5′ and 3′ untranslated regions, and exon–intron boundaries of CLU. Follow-up genotyping of identified variants in a larger sample (n = 1592). Sequencing analysis identified 18 variants. Analysis in the larger population revealed that only the rs9331949 C allele was significantly associated with an increased risk of LOAD, even after adjusting for multiple testing (p = 0.026). Logistic analysis identified the rs9331949 polymorphism was still strongly associated with LOAD (additive model: p = 0.004, odds ratio = 1.274; dominant model: p = 0.039, odds ratio = 1.239; recessive model: p = 0.002, OR = 1.975) after adjusting for sex, age, and APOE ε4 status. Our findings implicate CLU as a susceptibility gene for LOAD in Han Chinese.

Exploration of deleterious single nucleotide polymorphisms in late-onset Alzheimer disease susceptibility genes

Non-synonymous single nucleotide polymorphisms (nsSNPs) are considered as biomarkers to disease susceptibility. In the present study, nsSNPs in CLU, PICALM and BIN1 genes were screened for their functional impact on concerned proteins and their plausible role in Alzheimer disease (AD) susceptibility. Initially, SNPs were retrieved from dbSNP database, followed by identification of potentially deleterious nsSNPs and prediction of their effect on proteins by PolyPhen and SIFT. Protein stability and the probability of mutation occurrence were predicted using I-Mutant and PANTHER respectively. SNPs3D and FASTSNP were used for the functional analysis of nsSNPs. The functional impact on the 3D structure of proteins was evaluated by SWISSPDB viewer and NOMAD-Ref server. On analysis, 3 nsSNPs with IDs rs12800974 (T158P) of PICALM and rs11554585 (R397C) and rs11554585 (N106D) of BIN1 were predicted to be functionally significant with higher scores of I-Mutant, SIFT, PolyPhen, PANTHER, FASTSNP and SNPs3D. The mutant models of these nsSNPs also showed very high energies and RMSD values compared to their native structures. Current study proposes that the three nsSNPs identified in this study constitute a unique resource of potential genetic factors for AD susceptibility.

Lack of association between two ACE gene polymorphisms (rs4291 and Alu I/D) and late onset Alzheimer’s disease

Alzheimer’s disease (AD) is a prevalent disorder and the most common cause of dementia in elderly populations. Genetic and environmental factors together play a role in developing late onset Alzheimer's disease (LOAD). According to the recent published papers, ACE is one of the candidate susceptibility genes for LOAD. In this study, allele and genotype frequencies for rs4291 and rs1799752 polymorphisms of ACE gene, for 100 Iranian patients, affected with AD and 100 healthy controls were compared using Chi-square test. No statistically significant differences were found in genotype and allele frequencies of rs4291 and rs1799752 polymorphisms between our LOAD patients and controls. The pair-wise haplotype analysis of rs4291 -240 A/T and rs1799752 Alu I/D polymorphisms were also performed, but no significant associations were identified. Key words : ACE, Alzheimer’s disease, Iranian, association, polymorphism.

Common variant in GAB2 is associated with late-onset Alzheimer's disease in Han Chinese

BackgroundGRB-associated binding protein 2 (GAB2) may function as a risk factor in the pathogenesis of Alzheimer disease (AD). A recent large genome-wide association study (GWAS) has identified a significant association of rs10793294 polymorphism within the GAB2 gene with AD in Caucasians. While there are no studies on the association of rs10793294 polymorphism with AD risk in the Chinese population. MethodsThe study investigated 358 sporadic late-onset AD (LOAD) and 366 healthy controls matched for sex and age in a Han Chinese population. The rs10793294 polymorphism within the GAB2 gene was genotyped using MALDI-TOF mass spectrometry. ResultsThe C allele of the rs10793294 polymorphism within GAB2 was significantly associated with an increased risk of LOAD (OR=1.33, 95% CI=1.04–1.72, P=0.029). Significance was observed in APOEε4 carriers (genotype P=0.039, allele P=0.016). While in APOE ε4 non-carriers, significant differences were observed in alleles (P=0.039) but not in genotypes (P=0.304). Logistic regression revealed that rs10793294 polymorphism was still strongly associated with LOAD in dominant model (OR=2.58, 95% CI=1.22–5.45, P=0.013) and additive model (OR=1.38, 95% CI=1.05–1.80, P=0.020) after adjusting for age, gender, and the APOE ε4 status. ConclusionsOur findings implicate GAB2 as a susceptibility gene for LOAD in Han Chinese.

Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

BackgroundLate Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.MethodologyWe applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.Principal FindingsWe found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.SignificanceProcesses related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

Implication of CLU gene polymorphisms in Chinese patients with Alzheimer's disease

Clusterin (also called apolipoprotein J) has a potential central role in the pathogenesis of Alzheimer's disease (AD). Recently, two genome-wide association studies have identified three variants in CLU gene encoding clusterin associated with AD risk in Caucasians, while there are no studies on the association of CLU with AD risk in Asians. The study investigated 324 sporadic late-onset AD (LOAD) and 388 healthy controls matched for sex and age in a Han Chinese population. Three common genetic variants (rs2279590, rs11136000 and rs9331888) in CLU gene were genotyped using MALDI-TOF mass spectrometry. The minor allele (G) of the rs9331888 polymorphism within CLU was significantly associated with an increased risk of LOAD (OR=1.39, 95% CI=1.13-1.72, P=0.002). Logistic regression analysis revealed that the rs9331888 polymorphism presented strong associations with LOAD in the dominant, recessive and additive models. No significant differences in genotype and allele frequencies of the rs2279590 and rs11136000 polymorphisms were found between LOAD patients and controls. Haplotype analysis identified a risk haplotype (CCG) (OR=1.66) and a protective haplotype (CCC)(OR=0.70). Our findings implicate CLU as a susceptibility gene for LOAD in Han Chinese.

Meta-analysis of linkage studies for Alzheimer's disease—A web resource

Familial late-onset Alzheimer's disease (LOAD) shows high heritability. However, with the exception of ApoE, no well-replicated susceptibility genes have been identified to date. Several genome-wide linkage studies have nominated potential susceptibility loci but results are inconsistent, with individual scans showing few significant LOD scores. We have pooled linkage results from five independent genome scans and used the genome search meta-analysis (GSMA) method to analyse these data. The combined sample results in 2206 affected individuals and 785 families from Caucasian and Caribbean Hispanic ethnicities. The Caucasian samples included subjects from the US, the Netherlands and Sweden. Genome-wide suggestive evidence for linkage was observed on chromosomes 1p13.3-q31.1, 7pter-p21.1 and 8p22-p21.1 in the weighted GSMA analysis. The chromosome 8p region achieved the lowest summed rank p-value of 0.001. We also identified seven loci with nominally significant evidence for linkage to 3q12.3-q22.1, 6p21.1-q15, 7p14.1-q21.11, 17q24.3-qter and 19p13.3-qter. The GSMA finding suggests that these loci may harbour susceptibility genes for LOAD. We have also developed a web resource ( http://alzres.iop.kcl.ac.uk/) to present additional GSMA analyses with different study selection criteria, facilitate the reanalysis of genome-wide linkage data and provide open access to the GSMA data.

200 Years After Darwin

ON FEBRUARY 12, 2009, WE CELEBRATE THE 200TH anniversary of the birth of Charles Darwin. He has earned the scientific reputation as being the most influential naturalist-biologist of his generation and perhaps of all time. Achievement of his esteemed status resulted initially from studying the geographical distribution of wildlife and fossils collected on his 5-year voyage on the Beagle and concluding that the “transmutation of species” was due to natural selection. In 1858, he was in the process of documenting his research when he received an essay from Alfred Russel Wallace putting forth the same concept of natural selection as the mechanism for generation of new species, resulting in a joint publication that same year. On the Origin of Species was published by Darwin in 1859, making it now the 150th anniversary of its publication. This book proposed evolution as the scientific basis of diversity and species generation produced through the effects of natural selection. Evolution has been proven to be the mechanism for species generation and the engine for change is natural selection, providing the evolved species, beginning from a common organism, adaptation and fitness to maximize reproduction and survival. Dobzhansky put it succinctly by saying that “nothing in biology makes sense except in the light of evolution.” Darwin expressed it eloquently in 1859: There is grandeur in this view of life, with its several powers, having been originally breathed into a few forms or into one; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being evolved. Two hundred years after Darwin’s birth, molecular genomic analyses of the human genome have been implemented, seeking the genetic basis for natural selection providing biological fitness and also risk of developing disease. Genome-wide association studies (GWASs) seeking gene variations, or single-nucleotide polymorphisms (SNPs), causal of several human diseases have been conducted in recent years. These diseases include autism, schizophrenia, obesity, diabetes, and heart disease. Several GWASs for risk association with neurological diseases,orneuromicstudies,havebeenreported. Increasedrisks foramyotrophic lateral sclerosis,Alzheimerdisease(AD), restless legssyndrome,andmultiplesclerosishavebeenassociated with polymorphisms in specific genes. It was hoped that these observationswouldadvanceanunderstandingof thecausation of inherited, complexpolygenetic,multifactorialneurological diseases. They have been made possible by the publication of thehumangenomeandhaplotypestudies (HapMapanalyses). Awhole-genomeanalysisofsporadicamyotrophiclateralsclerosis was published by Dunckley et al. They identified 10 genetic loci that were associated with sporadic amyotrophic lateral sclerosis in 3 independent series of patients and control subjects.Themostsignificantassociationwithdiseasewasfound foraSNPnearanuncharacterizedgeneknownasFLJ10986on chromosome1.Thus, theydescribedspecificSNPs that areassociated with onset of sporadic amyotrophic lateral sclerosis. Reiman et al conducted a genome-wide survey of 502 627 SNPs to characterize and confirm late-onset AD susceptibility genes. They found that late-onset AD was associated with 6 SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. The GAB2 gene was overexpressed in pathologically vulnerable neurons, and interference with GAB2 gene expression increased tau phosphorylation. They concluded that GAB2 modifies late-onset AD risk in apolipoprotein E (APOE) e4 allele carriers. Coon et al found a single SNP in linkage disequilibrium to the APOE e4 allele in a neurome-wide association study. Grupe et al described 3 additional SNPs on chromosome 19 in linkage disequilibrium to the APOE e4 locus also in a neurome-wide association study. Liu et al described significant linkage to 3q23 markers associated with AD in a genetically isolated Dutch population. In 2008, Li et al described SNPs associated with risk and ageatonsetofADinaGWASof469 438SNPs.They identified theAPOE linkagedisequilibriumregionasthestrongestgenetic risk factor for AD. They concluded that this event could be a consequence of the coevolution of more than 1 susceptibility allele, includingAPOC1, inthesameregion.Additionalpotential at-riskgenes forADwereof interestandrequire furtherstudies.

GAB2 is not associated with late-onset Alzheimer's disease in Japanese

The varepsilon4 allele of the apolipoprotein E gene (APOE) is unequivocally recognized as a genetic risk factor for late-onset Alzheimer's disease (LOAD). Recently, single-nucleotide polymorphisms (SNPs) of the GRB2-associated binding protein 2 gene (GAB2) were shown to be associated with LOAD in Caucasians carrying the APOE-varepsilon4 allele through a genome-wide association study. Here, we attempted to replicate the finding by genotyping these SNPs in a large clinical cohort of Japanese. We observed no association of any of the SNPs with LOAD. GAB2 may not be a disease susceptibility gene for LOAD in Japanese.

Dynamin 2 gene is a novel susceptibility gene for late-onset Alzheimer disease in non-APOE-ε4 carriers

Alzheimer disease (AD) is characterized by progressive cognitive decline caused by synaptic dysfunction and neurodegeneration in the brain, and late-onset AD (LOAD), genetically classified as a polygenetic disease, is the major form of dementia in the elderly. It has been shown that beta amyloid, deposited in the AD brain, interacts with dynamin 1 and that the dynamin 2 (DNM2) gene homologous to the dynamin 1 gene is encoded at chromosome 19p13.2 where a susceptibility locus has been detected by linkage analysis. To test the genetic association of LOAD with the DNM2 gene, we performed a case-control study of 429 patients with LOAD and 438 sex- and age-matched control subjects in a Japanese population. We found a significant association of LOAD with single nucleotide polymorphism markers of the DNM2 gene, especially in non-carriers of the apolipoprotein E-epsilon4 allele. Even though subjects with the genotype homozygous for the risk allele at rs892086 showed no mutation in exons of the DNM2 gene, expression of DNM2 mRNA in the hippocampus was decreased in the patients compared to non-demented controls. We propose that the DNM2 gene is a novel susceptibility gene for LOAD.

Evidence that common variation in NEDD9 is associated with susceptibility to late-onset Alzheimer's and Parkinson's disease.

Late-onset Alzheimer's disease (LOAD) and Parkinson's disease (PD) are the most common neurodegenerative disorders and in both diseases susceptibility is known to be influenced by genes. We set out to identify novel susceptibility genes for LOAD by performing a large scale, multi-tiered association study testing 4692 single nucleotide polymorphism (SNPs). We identified a SNP within a putative transcription factor binding site in the NEDD9 gene (neural precursor cell expressed, developmentally down-regulated), that shows good evidence of association with disease risk in four out of five LOAD samples [N = 3521, P = 5.38x10(-6), odds ratio (OR) = 1.38 (1.20-1.59)] and in addition, we observed a similar pattern of association in two PD sample sets [N = 1464, P = 0.0145, OR =1.31 (1.05-1.62)]. In exploring a potential mechanism for the association, we observed that expression of NEDD9 and APOE show a strong inverse correlation in the hippocampus of Alzheimer's cases. These data implicate NEDD9 as a novel susceptibility gene for LOAD and possibly PD.

Association studies of 23 positional/functional candidate genes on chromosome 10 in late‐onset Alzheimer's disease

Late-onset Alzheimer's disease (LOAD) is a common neurodegenerative disorder, with a complex etiology. APOE is the only confirmed susceptibility gene for LOAD. Others remain yet to be found. Evidence from linkage studies suggests that a gene (or genes) conferring susceptibility for LOAD resides on chromosome 10. We studied 23 positional/functional candidate genes from our linkage region on chromosome 10 (APBB1IP, ALOX5, AD037, SLC18A3, DKK1, ZWINT, ANK3, UBE2D1, CDC2, SIRT1, JDP1, NET7, SUPV3L1, NEN3, SAR1, SGPL1, SEC24C, CAMK2G, PP3CB, SNCG, CH25H, PLCE1, ANXV111) in the MRC genetic resource for LOAD. These candidates were screened for sequence polymorphisms in a sample of 14 LOAD subjects and detected polymorphisms tested for association with LOAD in a three-stage design involving two stages of genotyping pooled DNA samples followed by a third stage in which markers showing evidence for association in the first stages were subjected to individual genotyping. One hundred and twenty polymorphisms were identified and tested in stage 1 (4 case + 4 control pools totaling 366 case and 366 control individuals). Single nucleotide polymorphisms (SNPs) showing evidence of association with LOAD were then studied in stage 2 (8 case + 4 control pools totaling 1,001 case and 1,001 control individuals). Five SNPs, in four genes, showed evidence for association (P < 0.1) at stage 2 and were individually genotyped in the complete dataset, comprising 1,160 LOAD cases and 1,389 normal controls. Two SNPs in SGPL1 demonstrated marginal evidence of association, with uncorrected P values of 0.042 and 0.056, suggesting that variation in SGPL1 may confer susceptibility to LOAD.

GAB2 Alleles Modify Alzheimer's Risk in APOE ɛ4 Carriers

The apolipoprotein E (APOE) epsilon4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In epsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer's neuropathology.

A High-Density Whole-Genome Association Study Reveals That APOE Is the Major Susceptibility Gene for Sporadic Late-Onset Alzheimer's Disease

While the apolipoprotein E (APOE) epsilon allele is a well-established risk factor for late-onset Alzheimer's disease (AD), initial genome scans using microsatellite markers in late-onset AD failed to identify this locus on chromosome 19. Recently developed methods for the simultaneous assessment of hundreds of thousands of single nucleotide polymorphisms (SNPs) promise to help more precisely identify loci that contribute to the risk of AD and other common multigenic conditions. We sought here to demonstrate that more precise identification of loci that are associated with complex, multi-genic genetic disorders can be achieved using ultra-high-density whole-genome associations by demonstrating their ability to identify the APOE locus as a major susceptibility gene for late-onset AD, despite the absence of SNPs within the APOE locus itself, as well as to refine odds ratios (ORs) based on gold-standard phenotyping of the study population. An individualized genome-wide association study using 502,627 SNPs was performed in 1086 his-topathologically verified AD cases and controls to determine the OR associated with genes predisposing to Alzheimer's disease. As predicted, ultra-high-density SNP genotyping, in contrast to traditional microsatellite-based genome screening approaches, precisely identified the APOE locus as having a significant association with late-onset AD. SNP rs4420638 on chromosome 19, located 14 kilobase pairs distal to the APOE epsilon variant, significantly distinguished between AD cases and controls (Bonferroni corrected p value = 5.30 x 10(-34), OR = 4.01) and was far more strongly associated with the risk of AD than any other SNP of the 502,627 tested. This study provides empirical support for the suggestion that the APOE locus is the major susceptibility gene for late-onset AD in the human genome, with an OR significantly greater than any other locus in the human genome. It also supports the feasibility of the ultra-high-density whole-genome association approach to the study of AD and other heritable phenotypes. These whole-genome association studies show great promise to identify additional genes that contribute to the risk of AD.

Glutathione S-Transferase P1 *C Allelic Variant Increases Susceptibility for Late-Onset Alzheimer Disease: Association Study and Relationship with Apolipoprotein E ε4 Allele

Oxidative stress and neuronal cell death have been implicated in the pathogenesis of Alzheimer disease (AD). Considering that the glutathione transferase (GST) supergene family encodes isoenzymes that appear to be critical in protection against oxidative stress, we aimed at determining the various GSTP1, GSTM1, and GSTT1 polymorphisms and ApoE genotypes to investigate their role as susceptibility genes for late-onset AD (LOAD). We included 210 LOAD patients and 228 healthy controls matched for age, sex, and educational level in our case-control genetic association study. GSTM1 and GSTT1 genotypes were studied by conventional PCR, whereas GSTP1 and ApoE genotypes were determined by real-time PCR on the LightCycler. We found a significant association between LOAD and the GSTP1*C allelic variant [odds ratio (OR) = 1.9; P < 0.05], but no association between the GSTM1 and GSTT1 deleted genotypes and LOAD. In addition, a preliminary result suggested that carriers of both the GSTP1*C and ApoE epsilon4 allelic variants were at increased risk of LOAD (OR = 19.98; P < 0.0001). The GSTP1*C allelic variant should be considered a candidate for LOAD, particularly in persons having the ApoE epsilon4 allelic variant, because the GSTP1 and ApoE gene products are implicated in oxidative stress and apoptosis processes leading to beta-amyloid-mediated neurodegeneration.

An autosomal genomic screen for dementia in an extended Amish family

Apolipoprotein E (APOE) is the only universally confirmed susceptibility gene for late-onset Alzheimer disease (LOAD), although many loci are believed to modulate LOAD risk. The genetic homogeneity of isolated populations, such as the Amish, potentially provide increased power to identify LOAD susceptibility genes. Population homogeneity in these special populations may reduce the total number of susceptibility genes contributing to the complex disorder, thereby increasing the ability to identify any one susceptibility gene. Dementia in the Amish is clinically indistinguishable from LOAD in the general population. Previous studies in the Amish demonstrated a significantly decreased frequency of the APOE-4 susceptibility allele, but significant familial clustering of dementia [M.A. Pericak-Vance, C.C. Johnson, J.B. Rimmler, A.M. Saunders, L.C. Robinson, E.G. D’Hondt, C.E. Jackson, J.L. Haines, Alzheimer's disease and apolipoprotein E-4 allele in an Amish population, Ann. Neurol. 39 (1996) 700–704]. These data suggested that a genetic etiology independent of APOE may underlie the dementia observed in this population. In the present analysis, we focused on a large, multiplex, inbred Amish family (24 sampled individuals; 10 of whom are affected). We completed a genomic screen to identify novel LOAD loci ( n = 316 genetic markers), using both model-dependent “affecteds-only” analysis (dominant and recessive) and model-independent affected relative pair analysis. Interesting results (lod > 1.5 or p < 0.01) were obtained for markers on eight chromosomes (2q, 5q, 6q, 7p, 8p, 8q, 11p, 18p, 18q, and 19q). The highest overall score was a multipoint lod score of 3.1 on chromosome 11p. Most regions we identified were not previously detected by genomic screens of outbred populations and may represent population-specific susceptibilities to LOAD. These loci are currently under further investigation in a study of LOAD including additional Amish families.