JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
Acetylcholinesterase modulates presenilin-1 levels and ?-secretase activity.
J. Alzheimers Dis.
PUBLISHED: 04-05-2014
Show Abstract
Hide Abstract
The cholinergic enzyme acetylcholinesterase (AChE) and the catalytic component of the ?-secretase complex, presenilin-1 (PS1), are known to interact. In this study, we investigate the consequences of AChE-PS1 interactions, particularly the influence of AChE in PS1 levels and ?-secretase activity. PS1 is able to co-immunoprecipitate all AChE variants (AChE-R and AChE-T) and molecular forms (tetramers and light subunits) present in the human brain. Overexpression of AChE-R or AChE-T, or their respective inactive mutants, all trigger an increase in PS1 protein levels. The AChE species capable of triggering the biggest increase in PS1 levels is a complex of AChE with the membrane anchoring subunit proline-rich membrane anchor (PRiMA), which restricts the localization of the resulting AChE tetramer to the outer plasma membrane. Incubation of cultured cells with soluble AChE demonstrates that AChE is able to increase PS1 at both the protein and transcript levels. However, the increase of PS1 caused by soluble AChE is accompanied by a decrease in ?-secretase activity as shown by the reduction of the processing of the amyloid-? protein precursor. This inhibitory effect of AChE on ?-secretase activity was also demonstrated by directly assessing accumulation of CTF-A?PP in cell-free membrane preparations incubated with AChE. Our data suggest that AChE may function as an inhibitor of ?-secretase activity.
Related JoVE Video
Presenilin-1 influences processing of the acetylcholinesterase membrane anchor PRiMA.
Neurobiol. Aging
PUBLISHED: 01-26-2014
Show Abstract
Hide Abstract
Presenilin-1 (PS1) is the catalytic component of the ?-secretase complex. In this study, we explore if PS1 participates in the processing of the cholinergic acetylcholinesterase (AChE). The major AChE variant expressed in the brain is a tetramer (G(4)) bound to a proline-rich membrane anchor (PRiMA). Overexpression of the transmembrane PRiMA protein in Chinese hamster ovary cells expressing AChE and treated with the ?-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester have enabled us to study whether, through its ?-secretase activity, PS1 participates in the processing of PRiMA-linked AChE. ?-Secretase inhibition led to a notable increase in the level of PRiMA-linked AChE, suggesting that ?-secretase is involved in the cleavage of PRiMA. We demonstrate that cleavage of PRiMA by ?-secretase results in a C-terminal PRiMA fragment. Immunofluorescence labeling allowed us to identify this PRiMA fragment in the nucleus. Moreover, we have determined changes in the proportion of the raft-residing AChE-PRiMA in a PS1 conditional knockout mouse. Our results are of interest as both enzymes have therapeutic relevance for Alzheimer's disease.
Related JoVE Video
Confluence of ?-Synuclein, Tau, and ?-Amyloid Pathologies in Dementia With Lewy Bodies.
J. Neuropathol. Exp. Neurol.
PUBLISHED: 11-15-2013
Show Abstract
Hide Abstract
Dementia with Lewy bodies (DLB) is pathologically characterized by ?-synuclein aggregates in the brain. Most patients with DLB also show cerebral Alzheimer disease-type pathology (i.e. ?-amyloid plaques and hyperphosphorylated tau deposits). It is unclear whether this overlap is coincidental or driven by specific regional or cellular interactions. The aims of this study were to investigate the regional convergence of ?-synuclein, tau, and ?-amyloid and to identify patterns of cellular co-occurrence of tau and ?-synuclein in DLB. The study group consisted of 22 patients who met clinical and neuropathologic criteria for DLB. Protein aggregates were assessed semiquantitatively in 17 brain areas. APOE and MAPT genotypes were determined. Cellular co-occurrence of tau and ?-synuclein was evaluated by double immunofluorescence. We found that total ?-amyloid pathology scores correlated positively with total ?-synuclein pathology scores (? = 0.692, p = 0.001). The factors that correlated best with the amount of ?-synuclein pathology were the severity of ?-amyloid pathology and presence of the MAPT H1 haplotype. Tau and ?-synuclein frequently colocalized in limbic areas, but no correlation between total pathology scores was observed. This study confirms and extends the role of ?-amyloid deposition and the MAPT H1 haplotype as contributing factors in DLB pathogenesis and demonstrates the confluence of multiple agents in neurodegenerative diseases.
Related JoVE Video
Autosomal-dominant Alzheimers disease mutations at the same codon of Amyloid Precursor Protein differentially alter A? production.
J. Neurochem.
PUBLISHED: 02-23-2013
Show Abstract
Hide Abstract
Autosomal-dominant Alzheimers disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studying the mechanisms underlying these mutations can provide insight into the pathways that lead to AD pathology. The majority of biochemical studies on APP mutations to-date have focused on comparing mechanisms between mutations at different codons. It has been assumed that amino acid position is a major determinant of protein dysfunction and clinical phenotype. However, the differential effect of mutations at the same codon has not been sufficiently addressed. In the present study we compared the effects of the aggressive ADAD-associated APP I716F mutation with I716V and I716T on APP processing in human neuroglioma and CHO-K1 cells. All APP I716 mutations increased the ratio of A?42/40 and changed the product line preference of ?-secretase towards A?38 production. In addition, the APP I716F mutation impaired the ?-cleavage and the fourth cleavage of ?-secretase and led to abnormal APP ?-CTF accumulation at the plasma membrane. Taken together, these data indicate that APP mutations at the same codon can induce diverse abnormalities in APP processing, some resembling PSEN1 mutations. These differential effects could explain the clinical differences observed among ADAD patients bearing different APP mutations at the same position. This article is protected by copyright. All rights reserved.
Related JoVE Video
The sex-specific associations of the aromatase gene with Alzheimers disease and its interaction with IL10 in the Epistasis Project.
Eur. J. Hum. Genet.
PUBLISHED: 01-21-2013
Show Abstract
Hide Abstract
Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimers disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG=1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor=1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions ,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD.European Journal of Human Genetics advance online publication, 5 June 2013; doi:10.1038/ejhg.2013.116.
Related JoVE Video
Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset Alzheimers disease patients alter calcium homeostasis.
PLoS ONE
PUBLISHED: 01-01-2013
Show Abstract
Hide Abstract
Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimers disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca(2+)-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca(2+) permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca(2+) influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca(2+) influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca(2+) dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.
Related JoVE Video
Linking protective GAB2 variants, increased cortical GAB2 expression and decreased Alzheimers disease pathology.
PLoS ONE
PUBLISHED: 01-01-2013
Show Abstract
Hide Abstract
GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimers disease (LOAD) with reported odds ratios (ORs) ranging from 0.75-0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61-1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p<0.02) due to a potentially inflated effect size (OR?=?0.61-0.66) only observed in the smallest series (702 LOAD, 209 controls). Despite the lack of association in our series, the previously reported protective association for GAB2 remained after meta-analyses of our data with all available previously published series (11,952-22,253 samples; OR?=?0.82-0.88; all p<0.04). Using a freely available database of lymphoblastoid cell lines we found that protective GAB2 variants were associated with increased GAB2 expression (p?=?9.5×10(-7)-9.3×10(-6)). We next measured GAB2 mRNA levels in 249 brains and found that decreased neurofibrillary tangle (r?=?-0.34, p?=?0.0006) and senile plaque counts (r?=?-0.32, p?=?0.001) were both good predictors of increased GAB2 mRNA levels albeit that sex (r?=?-0.28, p?=?0.005) may have been a contributing factor. In summary, we hypothesise that GAB2 variants that are protective against LOAD in some populations may act functionally to increase GAB2 mRNA levels (in lymphoblastoid cells) and that increased GAB2 mRNA levels are associated with significantly decreased LOAD pathology. These findings support the hypothesis that Gab2 may protect neurons against LOAD but due to significant population heterogeneity, it is still unclear whether this protection is detectable at the genetic level.
Related JoVE Video
Interaction of insulin and PPAR-? genes in Alzheimers disease: the Epistasis Project.
J Neural Transm
PUBLISHED: 07-06-2011
Show Abstract
Hide Abstract
Altered glucose metabolism has been described in Alzheimers disease (AD). We re-investigated the interaction of the insulin (INS) and the peroxisome proliferator-activated receptor alpha (PPARA) genes in AD risk in the Epistasis Project, including 1,757 AD cases and 6,294 controls. Allele frequencies of both SNPs (PPARA L162V, INS intron 0 A/T) differed between Northern Europeans and Northern Spanish. The PPARA 162LL genotype increased AD risk in Northern Europeans (p = 0.04), but not in Northern Spanish (p = 0.2). There was no association of the INS intron 0 TT genotype with AD. We observed an interaction on AD risk between PPARA 162LL and INS intron 0 TT genotypes in Northern Europeans (Synergy factor 2.5, p = 0.016), but not in Northern Spanish. We suggest that dysregulation of glucose metabolism contributes to the development of AD and might be due in part to genetic variations in INS and PPARA and their interaction especially in Northern Europeans.
Related JoVE Video
Replication of EPHA1 and CD33 associations with late-onset Alzheimers disease: a multi-centre case-control study.
Mol Neurodegener
PUBLISHED: 05-26-2011
Show Abstract
Hide Abstract
A recently published genome-wide association study (GWAS) of late-onset Alzheimers disease (LOAD) revealed genome-wide significant association of variants in or near MS4A4A, CD2AP, EPHA1 and CD33. Meta-analyses of this and a previously published GWAS revealed significant association at ABCA7 and MS4A, independent evidence for association of CD2AP, CD33 and EPHA1 and an opposing yet significant association of a variant near ARID5B. In this study, we genotyped five variants (in or near CD2AP, EPHA1, ARID5B, and CD33) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ?4 dosage.
Related JoVE Video
Multiple insulin degrading enzyme variants alter in vitro reporter gene expression.
PLoS ONE
PUBLISHED: 02-10-2011
Show Abstract
Hide Abstract
The insulin degrading enzyme (IDE) variant, v311 (rs6583817), is associated with increased post-mortem cerebellar IDE mRNA, decreased plasma ?-amyloid (A?), decreased risk for Alzheimers disease (AD) and increased reporter gene expression, suggesting that it is a functional variant driving increased IDE expression. To identify other functional IDE variants, we have tested v685, rs11187061 (associated with decreased cerebellar IDE mRNA) and variants on H6, the haplotype tagged by v311 (v10; rs4646958, v315; rs7895832, v687; rs17107734 and v154; rs4646957), for altered in vitro reporter gene expression. The reporter gene expression levels associated with the second most common haplotype (H2) successfully replicated the post-mortem findings in hepatocytoma (0.89 fold-change, p?=?0.04) but not neuroblastoma cells. Successful in vitro replication was achieved for H6 in neuroblastoma cells when the sequence was cloned 5 to the promoter (1.18 fold-change, p?=?0.006) and 3 to the reporter gene (1.29 fold change, p?=?0.003), an effect contributed to by four variants (v10, v315, v154 and v311). Since IDE mediates A? degradation, variants that regulate IDE expression could represent good therapeutic targets for AD.
Related JoVE Video
Investigation of 15 of the top candidate genes for late-onset Alzheimers disease.
Hum. Genet.
PUBLISHED: 08-24-2010
Show Abstract
Hide Abstract
The 12 genome-wide association studies (GWAS) published to-date for late-onset Alzheimers disease (LOAD) have identified over 40 candidate LOAD risk modifiers, in addition to apolipoprotein (APOE) ?4. A few of these novel LOAD candidate genes, namely BIN1, CLU, CR1, EXOC3L2 and PICALM, have shown consistent replication, and are thus credible LOAD susceptibility genes. To evaluate other promising LOAD candidate genes, we have added data from our large, case-control series (n=5,043) to meta-analyses of all published follow-up case-control association studies for six LOAD candidate genes that have shown significant association across multiple studies (TNK1, GAB2, LOC651924, GWA_14q32.13, PGBD1 and GALP) and for an additional nine previously suggested candidate genes. Meta-analyses remained significant at three loci after addition of our data: GAB2 (OR=0.78, p=0.007), LOC651924 (OR=0.91, p=0.01) and TNK1 (OR=0.92, p=0.02). Breslow-Day tests revealed significant heterogeneity between studies for GAB2 (p<0.0001) and GWA_14q32.13 (p=0.006). We have also provided suggestive evidence that PGBD1 (p=0.04) and EBF3 (p=0.03) are associated with age-at-onset of LOAD. Finally, we tested for interactions between these 15 genes, APOE ?4 and the five novel LOAD genes BIN1, CLU, CR1, EXOC3L2 and PICALM but none were significant after correction for multiple testing. Overall, this large, independent follow-up study for 15 of the top LOAD candidate genes provides support for GAB2 and LOC651924 (6q24.1) as risk modifiers of LOAD and novel associations between PGBD1 and EBF3 with age-at-onset.
Related JoVE Video
Replication of CLU, CR1, and PICALM associations with alzheimer disease.
Arch. Neurol.
PUBLISHED: 06-14-2010
Show Abstract
Hide Abstract
To test for replication of the association between variants in the CLU, CR1, and PICALM genes with Alzheimer disease.
Related JoVE Video
The dopamine ?-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimers disease in the Epistasis Project.
BMC Med. Genet.
PUBLISHED: 06-04-2010
Show Abstract
Hide Abstract
The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimers disease (AD). Dopamine ?-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the pro-inflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls.
Related JoVE Video
Association and heterogeneity at the GAPDH locus in Alzheimers disease.
Neurobiol. Aging
PUBLISHED: 04-19-2010
Show Abstract
Hide Abstract
Glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) and its paralogs were implicated in late-onset Alzheimers disease (LOAD), although the strength and direction of association have not been consistent. We genotyped 3 previously reported single nucleotide polymorphisms (SNPs; rs3741916-GAPDH 5 UTR, rs2029721-pGAPD, and rs4806173-GAPDHS) in 3 case-control series (2112 cases and 3808 controls). Rs3741916 showed the strongest LOAD association (p = 0.003). The minor allele of rs3741916 showed a protective effect in our combined series (odds ratio [OR] = 0.87%, 95% confidence interval [CI] = 0.79-0.96). This is consistent with results from the 2 published follow-up studies and in opposite direction of the original report. Meta-analysis of the published series with ours suggests presence of heterogeneity (Breslow-Day p < 0.0001). Meta-analysis of only the follow-up series including ours revealed a significant protective effect for the minor allele of rs3741916 (OR = 0.85%, 95% CI = 0.76-0.96, p = 0.009). Our results support the presence of LOAD variants and heterogeneity at the GAPDH locus. The most promising rs3741916 variant is unlikely to be functional given opposing effects in different series. Identification of functional variant(s) in this region likely awaits deep sequencing.
Related JoVE Video
Transferrin and HFE genes interact in Alzheimers disease risk: the Epistasis Project.
Neurobiol. Aging
PUBLISHED: 01-31-2010
Show Abstract
Hide Abstract
Iron overload may contribute to the risk of Alzheimers disease (AD). In the Epistasis Project, with 1757 cases of AD and 6295 controls, we studied 4 variants in 2 genes of iron metabolism: hemochromatosis (HFE) C282Y and H63D, and transferrin (TF) C2 and -2G/A. We replicated the reported interaction between HFE 282Y and TF C2 in the risk of AD: synergy factor, 1.75 (95% confidence interval, 1.1-2.8, p = 0.02) in Northern Europeans. The synergy factor was 3.1 (1.4-6.9; 0.007) in subjects with the APOE?4 allele. We found another interaction, between HFE 63HH and TF -2AA, markedly modified by age. Both interactions were found mainly or only in Northern Europeans. The interaction between HFE 282Y and TF C2 has now been replicated twice, in altogether 2313 cases of AD and 7065 controls, and has also been associated with increased iron load. We therefore suggest that iron overload may be a causative factor in the development of AD. Treatment for iron overload might thus be protective in some cases.
Related JoVE Video
Replication by the Epistasis Project of the interaction between the genes for IL-6 and IL-10 in the risk of Alzheimers disease.
J Neuroinflammation
PUBLISHED: 07-09-2009
Show Abstract
Hide Abstract
Chronic inflammation is a characteristic of Alzheimers disease (AD). An interaction associated with the risk of AD has been reported between polymorphisms in the regulatory regions of the genes for the pro-inflammatory cytokine, interleukin-6 (IL-6, gene: IL6), and the anti-inflammatory cytokine, interleukin-10 (IL-10, gene: IL10).
Related JoVE Video
PSEN1 polymorphisms alter the rate of cognitive decline in sporadic Alzheimers disease patients.
Neurobiol. Aging
PUBLISHED: 04-02-2009
Show Abstract
Hide Abstract
Mutations in amyloid precursor protein (APP) and presenilin (PSEN) genes are known to cause familial early-onset Alzheimers disease (AD), which account for around 5% of AD cases. Genetic associations for the remaining "sporadic" cases, other than the risks associated with the apolipoprotein (APOE) epsilon4 allele are currently not fully established. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in PSEN1 are associated with a modified risk for sporadic AD or a modified disease phenotype. Eight tag SNPs were identified using linkage disequilibrium (LD) data from the International HapMap project providing coverage of the entire PSEN1 gene. These SNPs were investigated for AD susceptibility in a case-control haplotype association study (N=714) and for genotype-specific effects on cognitive performance in AD patients (N=169) using non-linear mixed effects modelling. Replication of a mild associated-risk of an intronic PSEN1 polymorphism with AD was achieved (P=0.03). No other single SNPs or haplotypes were associated with AD risk. However, 3 SNPs were associated with an altered rate of cognitive decline underlining their role as genetic modifiers of disease.
Related JoVE Video
Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimers disease.
Neurobiol. Aging
Show Abstract
Hide Abstract
Despite recent discoveries in the genetics of sporadic Alzheimers disease, there remains substantial "hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110 candidate polymorphisms in 1757 cases of Alzheimers disease and 6294 control subjects of the Epistasis Project, divided between a discovery and a replication dataset. We found an epistatic interaction, between rs7483 in GSTM3 and rs1111875 in the HHEX/IDE/KIF11 gene cluster, with a closely similar, significant result in both datasets. The synergy factor (SF) in the combined dataset was 1.79, 95% confidence interval [CI], 1.35-2.36; p = 0.00004. Consistent interaction was also found in 7 out of the 8 additional subsets that we examined post hoc: i.e., it was shown in both North Europe and North Spain, in both men and women, in both those with and without the ?4 allele of apolipoprotein E, and in people older than 75 years (SF, 2.27; 95% CI, 1.60-3.20; p < 0.00001), but not in those younger than 75 years (SF, 1.06; 95% CI, 0.59-1.91; p = 0.84). The association with Alzheimers disease was purely epistatic with neither polymorphism showing an independent effect: odds ratio, 1.0; p ? 0.7. Indeed, each factor was associated with protection in the absence of the other factor, but with risk in its presence. In conclusion, this epistatic interaction showed a high degree of consistency when stratifying by sex, the ?4 allele of apolipoprotein E genotype, and geographic region.
Related JoVE Video
Interactions between PPAR-? and inflammation-related cytokine genes on the development of Alzheimers disease, observed by the Epistasis Project.
Int J Mol Epidemiol Genet
Show Abstract
Hide Abstract
Neuroinflammation contributes to the pathogenesis of sporadic Alzheimers disease (AD). Variations in genes relevant to inflammation may be candidate genes for AD risk. Whole-genome association studies have identified relevant new and known genes. Their combined effects do not explain 100% of the risk, genetic interactions may contribute. We investigated whether genes involved in inflammation, i.e. PPAR-?, interleukins (IL) IL- 1?, IL-1?, IL-6, and IL-10 may interact to increase AD risk.
Related JoVE Video
Genetic variants influencing human aging from late-onset Alzheimers disease (LOAD) genome-wide association studies (GWAS).
Neurobiol. Aging
Show Abstract
Hide Abstract
Genetics plays a crucial role in human aging with up to 30% of those living to the mid-80s being determined by genetic variation. Survival to older ages likely entails an even greater genetic contribution. There is increasing evidence that genes implicated in age-related diseases, such as cancer and neuronal disease, play a role in affecting human life span. We have selected the 10 most promising late-onset Alzheimers disease (LOAD) susceptibility genes identified through several recent large genome-wide association studies (GWAS). These 10 LOAD genes (APOE, CLU, PICALM, CR1, BIN1, ABCA7, MS4A6A, CD33, CD2AP, and EPHA1) have been tested for association with human aging in our dataset (1385 samples with documented age at death [AAD], age range: 58-108 years; mean age at death: 80.2) using the most significant single nucleotide polymorphisms (SNPs) found in the previous studies. Apart from the APOE locus (rs2075650) which showed compelling evidence of association with risk on human life span (p = 5.27 × 10(-4)), none of the other LOAD gene loci demonstrated significant evidence of association. In addition to examining the known LOAD genes, we carried out analyses using age at death as a quantitative trait. No genome-wide significant SNPs were discovered. Increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in the future. In this report, we also discuss issues relating to the analysis of genome-wide association studies data from different centers and the bioinformatic approach required to distinguish spurious genome-wide significant signals from real SNP associations.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.