Late-onset Alzheimer's Disease Cases Research Articles

Novel presenilin mutations within Moroccan patients with Early-Onset Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive brain disorder that causes gradual and irreversible loss of higher brain functions and is the most common cause of dementia in the elderly, as assessed by autopsy and clinical series. Furthermore, it has an annual incidence of approximately 3% in the 65–74-year-old age group. This incidence rate doubles with every increment of 5years above the age of 65. In Morocco, AD affects almost 30,000 individuals and this number will possibly increase to 75,000 by 2020 (projections of the World Health Organization (WHO)). Genetically, AD is caused by a mutation in one of at least 3 genes: presenilin 1 (PS1), presenilin 2 (PS2) and the amyloid precursor protein (APP). Most cases are late onset and apparently sporadic, most likely as a result of a combination of environmental and non-dominant genetic factors. In Morocco, the genes predisposing individuals to AD and predicting disease incidence remain elusive. The purpose of the present study was to evaluate the genetic contribution of mutations in PS1 and PS2 genes to familial early-onset AD cases and sporadic late-onset AD cases. Seventeen sporadic late-onset AD cases and eight familial early-onset AD cases were seen at the memory clinic of the University of Casablanca Neurology Department. These patients underwent standard somatic neurological examination, cognitive function assessment, brain imaging and laboratory tests. Direct sequencing of each exon in PS1 and PS2 genes was performed on genomic DNA of AD patients. Further, we identified 1 novel frameshift mutation in the PS1 gene and 2 novel frameshift mutations in the PS2 gene. Our mutational analysis reports a correlation between clinical symptoms and genetic factors in our cases of Early-Onset Alzheimer’s Disease (EOAD). These putative mutations cosegregate with affected family members suggesting a direct mutagenic effect.

Investigation of an amyloid precursor protein protective mutation (A673T) in a North American case-control sample of late-onset Alzheimer's disease

A rare amyloid precursor protein gene variant, A673T (rs63750847) was recently reported to protect against Alzheimer's disease and age-related cognitive decline among Icelanders and the same rare variant was observed also in Finnish, Norwegian, and Swedish populations. We investigated this variant in 1674 late-onset Alzheimer's disease cases and 2644 elderly control subjects, all North American Whites (US Whites). We did not observe any example of the A673T variant in our large sample. Our findings suggest that this rare variant could be specific to the individuals of the origin from the Nordic countries.

The cis-regulatory effect of an Alzheimer’s disease-associated poly-T locus on expression of TOMM40 and apolipoprotein E genes

BackgroundWe investigated the genomic region spanning the Translocase of the Outer Mitochondrial Membrane 40-kD (TOMM40) and Apolipoprotein E (APOE) genes, that has been associated with the risk and age of onset of late-onset Alzheimer’s disease (LOAD) to determine whether a highly polymorphic, intronic poly-T within this region (rs10524523; hereafter, 523) affects expression of the APOE and TOMM40 genes. Alleles of this locus are classified as S, short; L, long; and VL, very long based on the number of T residues. MethodsWe evaluated differences in APOE messenger RNA (mRNA) and TOMM40 mRNA levels as a function of the 523 genotype in two brain regions from APOE ε3/ε3 white autopsy-confirmed LOAD cases and normal controls. We further investigated the effect of the 523 locus in its native genomic context using a luciferase expression system. ResultsThe expression of both genes was significantly increased with disease. Mean expression of APOE and TOMM40 mRNA levels were higher in VL homozygotes compared with S homozygotes in the temporal and occipital cortexes from normal and LOAD cases. Results of a luciferase reporter system were consistent with the human brain mRNA analysis; the 523 VL poly-T resulted in significantly higher expression than the S poly-T. Although the effect of poly-T length on reporter expression was the same in HepG2 hepatoma and SH-SY5Y neuroblastoma cells, the magnitude of the effect was greater in the neuroblastoma than in the hepatoma cells, which implies tissue-specific modulation of the 523 poly-T. ConclusionsThese results suggest that the 523 locus may contribute to LOAD susceptibility by modulating the expression of TOMM40 and/or APOE transcription.

A non-invasive, rapid method to genotype late-onset Alzheimer's disease-related apolipoprotein E gene polymorphisms.

The apolipoprotein E gene ε4 allele is considered a negative factor for neural regeneration in late-onset Alzheimer's disease cases. The aim of this study was to establish a non-invasive, rapid method to genotype apolipoprotein E gene polymorphisms. Genomic DNA from mouth swab specimens was extracted using magnetic nanoparticles, and genotyping was performed by real-time PCR using TaqMan-BHQ probes. Genotyping accuracy was validated by DNA sequencing. Our results demonstrate 100% correlation to DNA sequencing, indicating reliability of our protocol. Thus, the method we have developed for apolipoprotein E genotyping is accurate and reliable, and also suitable for genotyping large samples, which may help determine the role of the apolipoprotein E ε4 allele in neural regeneration in late-onset Alzheimer's disease cases.

SIRT2 polymorphism rs10410544 is associated with Alzheimer's disease in a Han Chinese population

Sirtuin 2 (SIRT2) is a strong protein deacetylase, which is highly expressed in central nervous system. Recently, an association between SIRT2 rs10410544 polymorphism and late-onset Alzheimer's disease (LOAD) was found in the APOEε4-negative Caucasian population. To investigate the potential association between the rs10410544 C/T polymorphism of SIRT2 and the risk of LOAD, we conducted an independent replication case–control study in a Northern Han Chinese population comprising 1133 cases and 1159 healthy controls being matched for age and gender. The results revealed that there were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P=0.008, allele P=0.009). When compared with the C allele, the T allele of rs10410544 demonstrated a 1.709-fold risk for developing LOAD. After stratification by apolipoprotein E (APOE) ε4-carrying status, only APOEε4 noncarriers (P=0.035, adjusted OR=1.656, 95% CI: 1.036–2.647) showed the relation between LOAD and SIRT2 rs10410544 T allele. This study provides the evidence that the rs10410544 C/T polymorphism of SIRT2 was associated with genetic susceptibility to LOAD in a Northern Han Chinese population.

Glucose metabolism in normal aging and Alzheimer’s disease: methodological and physiological considerations for PET studies

Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder associated with progressive loss of cognitive function. 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) has long been used to measure resting-state cerebral metabolic rates of glucose, a proxy for neuronal activity. Several FDG PET studies have shown that metabolic reductions occur decades before onset of AD symptoms, suggesting that metabolic deficits may be an upstream event in at least some late-onset AD cases. This review explores this possibility, initially discussing the link between AD pathology, neurodegeneration, oxidative stress and AD, and then discussing findings of FDG PET hypometabolism in AD patients as well as in at-risk individuals, especially those with a first-degree family history of late-onset AD. While the rare early-onset form of AD is due to autosomal dominant genetic mutations, the etiology and pathophysiology of age-dependent, late-onset AD is more complex. Recent FDG PET studies have shown that adult children of AD-affected mothers are more likely than those with AD-fathers to show AD-like brain changes. Given the connection between glucose metabolism and mitochondria, and the fact that mitochondrial DNA is maternally inherited in humans, it is here argued that altered bioenergetics may be an upstream event in those with a maternal history of late-onset AD. Biomarkers of AD have great potential for identifying AD endophenotypes in at-risk individuals, which may help direct investigation of potential susceptibility genes.

Genome-wide association analyses of onset age in late-onset Alzheimer disease (LOAD) demonstrate no strong effect outside of the APOE region

LOAD risk loci may also contribute to variation in age of onset (AAO) of LOAD, as do the allelic variants in APOE, however roles in AAO for the other newly identified risk loci (CLU, BIN1, and others) have not been explored. We examined variants at ten confirmed LOAD risk loci (APOE, CLU, PICALM, CR1, BIN1, CD2AP, EPHA1, the MS4A region, ABCA7, and CD33) to determine if they contribute to variation in AAO among 9,160 LOAD cases in the Alzheimer's disease Genetics Consortium (ADGC). We tested association with AAO for each locus using linear modeling with covariate adjustment for population substructure and performed a random-effects meta-analysis across datasets. We also examined genetic burden using genotype scores weighted by risk effect sizes to examine the aggregate contribution of these loci to variation in AAO. Analyses confirmed association of APOE regional variation with AAO (rs6857, P =3.30×10 -96), with statistically significant associations with AAO (P<0.005) demonstrated at several other LOAD risk loci, including rs6701713 in CR1 (P =0.00717), rs7561528 in BIN1 (P =0.00478), rs561655 in PICALM (P =0.00223). Associations remained largely unchanged after additional adjustment for dosage of APOE ε4 alleles. Burden analyses showed APOE contributes to 3.1% of variation in AAO (R 2 =0.078) whereas the other nine genes contribute to 1.1% of variation (R 2 =0.058) over baseline (R 2 =0.047). Secondary analyses of genome-wide association with AAO among non-risk loci identified several regions with multiple SNPs demonstrating suggestive associations (P<10 -6), including one nearing genome-wide statistical significance: MYO16 (47 SNPs; most significant: rs9521011, P =7.62×10 -8), CDH20 (4 SNPs; most significant: rs12956834, P =6.17×10 -6), and SGCZ (10 SNPs; most significant: rs7016159, P =7.70×10 -6). We confirmed the association of APOE variants with AAO among LOAD cases, and observe associations with AAO in CR1, BIN1, and PICALM. In contrast to earlier hypothetical modeling, we show that the combined effects of other loci do not exceed the effect of APOE on AAO, and if additional genetic contributions to AAO exist, they are likely very small individually or are hidden in gene-gene interactions.

The Genetic Variation of SORCS1 Is Associated with Late-Onset Alzheimer’s Disease in Chinese Han Population

The variations of SORCS1 gene may play potential key roles in late-onset Alzheimer’s disease (LOAD). To evaluate the relationship between the polymorphism of SORCS1 gene and LOAD in the ethnic Han Chinese, we conducted a case–control study to investigate the association between the single-nucleotide polymorphisms (SNPs) in intron 1 of SORCS1 and LOAD in Chinese Han population. Six reported SNPs in intron 1 of SORCS1 were analyzed by Snapshot, genotyping and haplotyping in 236 Chinese LOAD cases and 233 matched controls. The significant differences in frequencies of two SNPs (rs10884402, rs950809) were found between the two groups. In addition, haplotype analyses revealed that, in the LOAD group, the frequency of haplotypes C-C-G-T-C (alleles in order of rs17277986, rs6584777, rs10884402, rs7078098, rs950809 polymorphisms) were significantly higher (Psim<0.0001) while haplotype C-C-A-T-C, C-C-A-C-C, T-T-A-C-C were significantly lower (Psim<0.0001). Our data suggested that the genetic variation of the rs10884402 and rs950809 in intron 1 of SORCS1 was associated with the late-onset AD in the Chinese Han population.

Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer’s brains

PICALM, a clathrin adaptor protein, plays important roles in clathrin-mediated endocytosis in all cell types. Recently, genome-wide association studies identified single nucleotide polymorphisms in PICALM gene as genetic risk factors for late-onset Alzheimer disease (LOAD). We analysed by western blotting with several anti-PICALM antibodies the pattern of expression of PICALM in human brain extracts. We found that PICALM was abnormally cleaved in AD samples and that the level of the uncleaved 65-75 kDa full-length PICALM species was significantly decreased in AD brains. Cleavage of human PICALM after activation of endogenous calpain or caspase was demonstrated in vitro. Immunohistochemistry revealed that PICALM was associated in situ with neurofibrillary tangles, co-localising with conformationally abnormal and hyperphosphorylated tau in LOAD, familial AD and Down syndrome cases. PHF-tau proteins co-immunoprecipitated with PICALM. PICALM was highly expressed in microglia in LOAD. These observations suggest that PICALM is associated with the development of AD tau pathology. PICALM cleavage could contribute to endocytic dysfunction in AD.

Vascular Factors and Mitochondrial Dysfunction: a Central Role in the Pathogenesis of Alzheimer's Disease

The pathogenesis of Alzheimer's disease (AD) is complex, and only a minority of cases appears to be primarily genetic. A relationship between genetic and acquired vascular factors in AD has been hypothesized. Many vascular risk factors for AD, such as atherosclerosis, stroke and cardiac disease in the aging individual, could result in cerebrovascular dysfunction. A major vascular susceptibility factor gene is the apolipoprotein E gene, found to be associated with sporadic late-onset AD cases. Oxidative damage and mitochondrial dysfunction have been also implicated in the pathogenesis of AD, but the question as to whether they are involved in the onset and progression of the pathology or rather represent a consequence of neurodegeneration is still debated. Recent evidence suggests that chronic hypoperfusion may trigger mitochondrial dysfunction in vascular cells which, in turn, may enhance the production of reactive oxygen species. In this short review we revise the link between vascular factors and mitochondrial dysfunction in AD pathogenesis.

Vascular Factors and Mitochondrial Dysfunction: a Central Role in the Pathogenesis of Alzheimer’s Disease

The pathogenesis of Alzheimer’s disease (AD) is complex, and only a minority of cases appears to be primarily genetic. A relationship between genetic and acquired vascular factors in AD has been hypothesized. Many vascular risk factors for AD, such as atherosclerosis, stroke and cardiac disease in the aging individual, could result in cerebrovascular dysfunction. A major vascular susceptibility factor gene is the apolipoprotein E gene, found to be associated with sporadic late-onset AD cases. Oxidative damage and mitochondrial dysfunction have been also implicated in the pathogenesis of AD, but the question as to whether they are involved in the onset and progression of the pathology or rather represent a consequence of neurodegeneration is still debated. Recent evidence suggests that chronic hypoperfusion may trigger mitochondrial dysfunction in vascular cells which, in turn, may enhance the production of reactive oxygen species. In this short review we revise the link between vascular factors and mitochondrial dysfunction in AD pathogenesis. Keywords: Alzheimer disease, Ischemia, Mitochondria, mtDNA, Neurodegeneration, Oxidative stress, ROS

Association study of susceptibility genes for late-onset Alzheimer’s disease in the Japanese population

APOE is an established susceptibility gene for late-onset Alzheimer's disease (LOAD). Recent genome-wide association studies have identified many additional susceptibility genes for LOAD in populations of European descent. However, there is little information on whether or not genetic variants in these genes are associated with other ethnicities. To investigate the association of seven genes identified by genome-wide association studies, we carried out a case-control study using 825 LOAD cases and 2934 controls in the Japanese population. For the APOE gene, APOE-ε4 carriers had a 4.54-fold higher risk than APOE-ε4 noncarriers after adjusting for age and sex (P=4.6×10(-27)). For other genes, the single-nucleotide polymorphism in the PICALM gene was significantly associated with LOAD (P=0.02, odds ratio=1.23). There was no significant interaction between PICALM and APOE-ε4 carrier status (P for interaction=0.68). Our data indicate that PICALM is also a susceptibility gene for LOAD in the Japanese population.

Insulin-like growth factor 1 (IGF1) polymorphism is associated with Alzheimer's disease in Han Chinese

A review of pathogenic findings in Alzheimer's brains and the functional consequences of altered insulin-like growth factor 1 (IGF1) input to the brain suggest the association between Alzheimer's disease (AD) and the disrupted IGF1 signaling. Recently, the identification of polymorphism rs972936 that was associated with both an increased risk of AD and high circulating levels of IGF1 was reported in Southern European population. In order to evaluate the involvement of the IGF1 polymorphism in the risk of developing late-onset Alzheimer's disease (LOAD) in Chinese, we performed an independent case-control association study in a Han Chinese population (794 LOAD cases and 796 controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P=0.006, allele P=0.047). The T allele of rs972936 demonstrated a 1.16-fold risk for developing LOAD when compared with the C allele, which diverges to the report in the Caucasian population. After stratification by apolipoprotein E (APOE) ɛ4-carrying status, rs972936 polymorphism was only significantly associated with LOAD in non-ApoE ɛ4 allele carriers (genotype P=0.002, allele P=0.039). Multivariate logistic regression analysis also conferred this positive association between the SNP rs972936 and LOAD in the recessive and additive model after adjustment for age, gender, and the ApoE ɛ4 carrier status. These results suggest that IGF1 polymorphism has a possible role in changing the genetic susceptibility to LOAD in a Han Chinese population.

Genetic Association of SLC2A14 Polymorphism with Alzheimer’s Disease in a Han Chinese Population

Glucose uptake and metabolism are impaired in Alzheimer's disease (AD) brain, which appear to be a cause, rather than a consequence of neurodegeneration. Recently, the gene of the 14th isoform of subfamily A of solute carrier family 2 (SLC2A14), encoding glucose transporter 14 (GLUT14), was identified for the association in vivo with AD pathology of Tau, and rs10845990 within SLC2A14 showed association with AD in Caucasians. In order to evaluate the involvement of the SLC2A14 polymorphism in the risk of developing late-onset Alzheimer's disease (LOAD) in Chinese, we performed an independent case-control association study in a Han Chinese population (597 LOAD cases and 605 healthy controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P = 0.015, allele P = 0.039). The G-carrying genotype (GT + GG) individuals showed a 1.41-fold increased risk compared with the TT genotype carriers (odds ratio (OR) = 1.41, 95 % confidence interval (CI) = 1.11-1.79, P = 0.005, Power = 83.6 %). After stratification by ApoE ε4-carrying status, rs10845990 polymorphism was only significantly associated with LOAD in non-ApoE ε4 allele carriers (P < 0.001). Multivariate logistic regression analysis also conferred this positive association between the SNP rs10845990 and LOAD in the dominant and additive model after adjustment for age, gender, and the ApoE ε4 carrier status. These results suggested that SLC2A14 polymorphism has a possible role in changing the genetic susceptibility to LOAD in a Han Chinese population.

Lack of association between rs597668 polymorphism near EXOC3L2 and late-onset Alzheimer's disease in Han Chinese

Recently, an international genome-wide association study (GWAS) additionally found rs597668 near EXOC3L2/BLOC1S3/MARK4 was a new genome-wide significance locus associated with late-onset Alzheimer's disease (LOAD) in Caucasians. Follow-up replication studies were conducted almost exclusively in Caucasians, and the effects of the risk locus in other populations are as yet unknown. This study investigated the GWAS-associated locus near EXOC3L2 in 1205 unrelated Northern Han Chinese subjects comprising 598 LOAD patients and 607 healthy controls matched for gender and age. The results showed no significant differences in the genotypic or allelic distributions of rs597668 polymorphism between LOAD cases and healthy controls (genotype: P=0.653; allele: P=0.603), even after stratification for apolipoprotein E (APOE) ɛ4 status and statistical adjustment for age, gender and APOE ɛ4 status. This study suggests that the rs597668 polymorphism near EXOC3L2 may not play a major role in the susceptibility to LOAD in the Northern Han Chinese population.

Exploring the role of common regulatory variants in the etiology of late-onset Alzheimer’s disease

Background Late-onset Alzheimer’s disease (LOAD) is a complex disorder with a significant genetic component (heritability ~ 0.8). It is distressingly common: in the United States, approximately 13% of individuals over the age of 65 and 43% of individuals over the age of 85 are estimated to have AD [2011 Alzheimer’s Disease Facts and Figures, Alzheimer’s Association]. Although specific mutations have been linked to familial forms of AD, mutations in AD candidate genes among LOAD cases are rare. For this reason there is currently great interest in identifying common genetic variants that contribute to this disorder. The goal of the current study is to quantify allele-specific differences in the expression of mRNAs encoding candidate LOAD susceptibility genes in human brain and elucidate the genetic basis for this differential expression. Haplotypes or combinations of genotypes that correlate with mRNA should be useful as markers in future genetic association studies aimed at identifying genes that contribute to AD risk and protection.

Vitamin D receptor and Alzheimer's disease: a genetic and functional study

Genetic studies on late-onset Alzheimer's disease (AD) have repeatedly mapped susceptibility loci onto chromosome 12q13, encompassing the vitamin D receptor (VDR) gene. Epidemiology studies have indicated vitamin D insufficiency as a risk factor for AD. Given that VDR is the major mediator for vitamin D's actions, we sought to clarify the role of VDR in late-onset AD. We conducted an association study in 492 late-onset AD cases and 496 controls with 80 tagging single nucleotide polymorphisms (SNPs). The strongest association was found at a promoter SNP rs11568820 (P = 9.1×10−6, odds ratio (OR) = 1.69), which resides within the transcription factor Cdx-2 binding site and the SNP has been also known as CDX2. The risk-allele at rs11568820 is associated with lower VDR promoter activity (p < 10−11). The overexpression of VDR or vitamin D treatment suppressed amyloid precursor protein (APP) transcription in neuroblastoma cells (p < 0.001). We provide both statistical evidence and functional data suggesting VDR confers genetic risk for AD. Our findings are consistent with epidemiology studies suggesting that vitamin D insufficiency increases the risk of developing AD.

A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease

Studying rare extreme forms of Alzheimer disease (AD) may prove to be a useful strategy in identifying new genes involved in monogenic determinism of AD. Amyloid precursor protein (APP), PSEN1, and PSEN2 mutations account for only 85% of autosomal dominant early-onset AD (ADEOAD) families. We hypothesised that rare copy number variants (CNVs) could be involved in ADEOAD families without mutations in known genes, as well as in rare sporadic young-onset AD cases. Using high-resolution array comparative genomic hybridisation, we assessed the presence of rare CNVs in 21 unrelated ADEOAD cases, having no alteration on known genes, and 12 sporadic AD cases, with an age of onset younger than 55 years. The analysis revealed the presence of 7 singleton CNVs (4 in ADEOAD and 3 in sporadic cases) absent in 1078 controls and 912 late-onset AD cases. Strikingly, 4 out of 7 rearrangements target genes (KLK6, SLC30A3, MEOX2, and FPR2) encoding proteins that are tightly related to amyloid-β peptide metabolism or signalling. Although these variants are individually rare and restricted to particular subgroups of patients, these findings support the causal role, in human pathology, of a set of genes coding for molecules suspected for a long time to modify Aβ metabolism or signalling, and for which animal or cellular models have already been developed.

Relationship of Amyloid-Beta Burden With Age-At-Onset in Alzheimer Disease

To investigate the relationship between in vivo brain amyloid-beta (Aβ) burden, measured by C-labeled Pittsburgh Compound B (C-PiB) retention, and age-at-onset in patients with Alzheimer disease (AD). Cross-sectional study. University Dementia Clinic. Twenty-two AD patients including 11 early-onset AD (EOAD: onset <65 years) and 11 late-onset AD (LOAD: onset ≥65years) cases with matched dementia severity, duration of illness, and apolipoprotein E ε4 allele number. C-PiB positron emission tomography scans. Both region of interest and voxel-based analyses were performed to compare C-PiB retention between EOAD and LOAD groups, and to test linear relationship between age-at-onset and C-PiB retention. Both region of interest (ROI) and voxel-based analyses revealed that EOAD patients had significantly higher C-PIB retentions than LOAD patients in diffuse brain regions including frontal, lateral parietal, lateral temporal, and occipital cortex, and basal ganglia. Subgroup analyses showed that negative correlation between age-at-onset and C-PiB retention was significant in LOAD but not in EOAD. Our finding of a heavier Aβ burden in the brain of living EOAD patients than LOAD patients is in agreement with those from postmortem studies. The inverse relationship between age-at-onset and Aβ burden is possibly associated with aging-related decrease of brain or cognitive reserve and with aging-related increase of brain vulnerability.

Alzheimer's disease genetics consortium: new Alzheimer's disease genes and gene interactions

Late-onset Alzheimer Disease (LOAD) is a highly heritable neurological disorder, with susceptibility influenced by known genetic risk factors at CLU, PICALM, and BIN1. The Alzheimer's Disease Genetics Consortium (ADGC) examined gnome-wide genotyping data from 11,840 LOAD cases and 10,931 cognitive controls to identify novel genetic variants and gene-gene interactions associated with LOAD. The ADGC dataset consists of fifteen datasets genotyped using genome-wide genotyping platforms (Illumina or Affymetrix). All cases met standard clinical LOAD definitions (or were confirmed through autopsy); controls were age-matched to cases and were cognitively intact at exam. To create a common set of SNPs across all datasets, genotype imputation was performed using IMPUTE software and the October 2010 release of the 1,000 Genomes Project data as a reference. Association analysis was performed within each dataset using logistic regression for case-control datasets and generalized estimating equations (GEE) for datasets that include family members. For both family and case-control datasets genotype was modeled using an additive model on the dosage of the minor allele. Age at onset/exam, gender, and variables for population substructure were included as covariates. Data were then analyzed across the datasets using a meta-analysis approach. For the gene-gene interaction analysis, SNPs will be pruned based on LD to reduce redundancy and then filtered using Biofilter to identify potential interactions/effects using known biological connections. Association analysis of the interactions will be performed using logistic regression and an additive model. Ten distinct genomic regions showed SNP associations in the combined meta-analysis, including previously associated regions CLU, CR1, PICALM, BIN1, and APOE10−8. Additional associated regions include MS4A, EPHA1, CD33, and ABCA7. Analysis of the gene-gene interaction is ongoing and will be presented. We have confirmed the association of several putative LOAD risk loci (APOE, CR1, CLU, PICALM and BIN1) and identified new risk loci as well (MS4A, EPHA1, CD33 and ABCA7). These associations confirm that common variations influence the etiology of LOAD. More importantly, they provide novel targets for functional assessment and further association studies.