ORCID Profile
0000-0002-1095-6722
Current Organisation
University of Oxford
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Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.NEUROBIOLAGING.2010.07.018
Abstract: Iron overload may contribute to the risk of Alzheimer's 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 APOEε4 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.
Publisher: Springer Science and Business Media LLC
Date: 05-06-2013
Publisher: Springer Science and Business Media LLC
Date: 17-03-2015
DOI: 10.1038/MP.2015.23
Publisher: Springer Science and Business Media LLC
Date: 2009
Publisher: Wiley
Date: 02-08-2011
DOI: 10.1002/AJMG.B.31216
Abstract: We sought to investigate the contribution of extended runs of homozygosity in a genome-wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no in idual run of homozygosity showed association to Alzheimer's disease.
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.NEUROBIOLAGING.2012.08.010
Abstract: Despite recent discoveries in the genetics of sporadic Alzheimer's 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 Alzheimer's disease and 6294 control subjects of the Epistasis Project, ided 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 ε4 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 Alzheimer's 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 ε4 allele of apolipoprotein E genotype, and geographic region.
Publisher: Public Library of Science (PLoS)
Date: 19-01-2010
Publisher: Public Library of Science (PLoS)
Date: 05-12-2012
Publisher: Springer Science and Business Media LLC
Date: 06-09-2009
DOI: 10.1038/NG.440
Publisher: Springer Science and Business Media LLC
Date: 08-11-2011
DOI: 10.1007/S00702-011-0732-4
Abstract: Altered glucose metabolism has been described in Alzheimer's 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.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.NEUROBIOLAGING.2008.02.013
Abstract: Mutations in amyloid precursor protein (APP) and presenilin (PSEN) genes are known to cause familial early-onset Alzheimer's 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.
Publisher: Wiley
Date: 23-11-2009
DOI: 10.1002/JNR.22290
Abstract: Alzheimer's disease (AD) is characterized by a complex neurodegenerative process affecting multiple genes and proteins in the neocortex, many of which have not been well-studied. In this study, we investigated genome-wide gene alterations in the temporal cortex of a well-characterized cohort of AD patients using a recently developed microarray platform, and compared some of the transcript changes with immunoblotting. Of the 5485 genes found to be significantly altered in AD, there were consistent patterns of changes which show that the AD transcriptome in neocortex is characterized by changes indicative of synaptic dysfunction, perturbed neurotransmission and activation of neuroinflammation. We also highlighted several genes of potential pathogenic significance which have not been well studied in AD. The current study aims to add to the growing body of knowledge relating to gene changes in AD and provide further insights into pathogenic mechanisms and potential targets of pharmacotherapy.
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.NEUROBIOLAGING.2012.07.011
Abstract: Impaired visuospatial associative memory may be one of the earliest changes predicting cognitive impairment and Alzheimer's disease. We explored the relationship between performance on a visuospatial associative memory task (the Placing Test) and brain structure and function in cognitively healthy older adults. First, we performed a voxel-based morphometry correlational analysis on structural magnetic resonance imaging (MRI) data from 144 healthy older adults with their scores on the Placing Test. Second, we carried out a functional MRI study on another group of 28 healthy older adults who performed a similar task during functional MRI. Decreased performance on the Placing Test was associated with increased atrophy in medial-temporal regions. Functional activation of the same regions-controlling for the effect of atrophy-occurred during successful performance of the same task. The colocalization of structural and functional MRI correspondents of visuospatial associative test performance within medial-temporal regions validates multimodal imaging in describing behaviorally relevant variability in the aging brain and suggests that the Placing Test has the potential for detecting early cognitive changes occurring in preclinical phases of Alzheimer's disease.
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.NEUINT.2011.03.010
Abstract: Glutamatergic AMPA receptors are of clinical significance in dementia because of their roles in mediating fast excitatory neurotransmission and other synaptic events relevant to cognition. Reductions in the AMPA receptor GluR2 subunit are well-established in Alzheimer's disease (AD), but the status of GluR2 in subcortical ischemic vascular dementia (SIVD) and mixed AD/SIVD (MIX) has not been investigated. In this study we measured GluR2 immunoreactivity and mRNA levels in the postmortem neocortex of a longitudinally assessed cohort of SIVD and MIX, together with age-matched controls. We found that GluR2 immunoreactivity and mRNA were up-regulated in SIVD, but remained unchanged in MIX. Furthermore, higher GluR2 immunoreactivity was associated with milder cognitive impairment and lower concentrations of Aβ42 peptide and phosphorylated tau. Our study suggests that GluR2 up-regulation may be an adaptive process in SIVD, and that this process is repressed in the presence of concomitant AD in mixed dementia.
Publisher: Springer Science and Business Media LLC
Date: 29-05-2013
DOI: 10.1038/NG0613-712A
Publisher: Public Library of Science (PLoS)
Date: 15-11-2010
Publisher: Springer Science and Business Media LLC
Date: 11-11-2010
Publisher: Springer Science and Business Media LLC
Date: 03-07-2202
DOI: 10.1038/NG.803
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for David Smith.