title: Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936.
abstract: Apolipoprotein E (APOE) ε genotype has previously been significantly associated with cognitive, brain imaging, and Alzheimer's disease-related phenotypes (e.g., age of onset). In the TOMM40 gene, the rs10524523 ("523") variable length poly-T repeat polymorphism has more recently been associated with similar ph/enotypes, although the allelic directions of these associations have varied between initial reports. Using diffusion magnetic resonance imaging tractography, the present study aimed to investigate whether there are independent effects of apolipoprotein E (APOE) and TOMM40 genotypes on human brain white matter integrity in a community-dwelling sample of older adults, the Lothian Birth Cohort 1936 (mean age = 72.70 years, standard deviation = 0.74, N approximately = 640-650; for most analyses). Some nominally significant effects were observed (i.e., covariate-adjusted differences between genotype groups at p < 0.05). For APOE, deleterious effects of ε4 "risk" allele presence (vs. absence) were found in the right ventral cingulum and left inferior longitudinal fasciculus. To test for biologically independent effects of the TOMM40 523 repeat, participants were stratified into APOE genotype subgroups, so that any significant effects could not be attributed to APOE variation. In participants with the APOE ε3/ε4 genotype, effects of TOMM40 523 status were found in the left uncinate fasciculus, left rostral cingulum, left ventral cingulum, and a general factor of white matter integrity. In all 4 of these tractography measures, carriers of the TOMM40 523 "short" allele showed lower white matter integrity when compared with carriers of the "long" and "very-long" alleles. Most of these effects survived correction for childhood intelligence test scores and vascular disease history, though only the effect of TOMM40 523 on the left ventral cingulum integrity survived correction for false discovery rate. The effects of APOE in this older population are more specific and restricted compared with those reported in previous studies, and the effects of TOMM40 on white matter integrity appear to be novel, although replication is required in large independent samples.
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Brain Research Imaging Centre, Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK; Department of Psychology, University of Edinburgh, Edinburgh, UK; Medical Genetics Section, University of Edinburgh Centre for Genomics and Experimental Medicine, Western General Hospital, Edinburgh, UK; MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors: Donald M
authors: DM
authors: Lyall
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Medical Genetics Section, University of Edinburgh Centre for Genomics and Experimental Medicine, Western General Hospital, Edinburgh, UK; MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors: Sarah E
authors: SE
authors: Harris
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Brain Research Imaging Centre, Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK; Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, The University of Edinburgh, Edinburgh, UK.
authors: Mark E
authors: ME
authors: Bastin
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Brain Research Imaging Centre, Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK; Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, The University of Edinburgh, Edinburgh, UK.
authors: Susana
authors: S
authors: Muñoz Maniega
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors: Catherine
authors: C
authors: Murray
authors: Department of Neurology, Joseph & Kathleen Bryan Alzheimer's Disease Research Center, Durham, NC, USA; Duke University Medical Center, Durham, NC, USA.
authors: Michael W
authors: MW
authors: Lutz
authors: Department of Neurology, Joseph & Kathleen Bryan Alzheimer's Disease Research Center, Durham, NC, USA.
authors: Ann M
authors: AM
authors: Saunders
authors: Department of Neurology, Joseph & Kathleen Bryan Alzheimer's Disease Research Center, Durham, NC, USA; Duke University Medical Center, Durham, NC, USA; Zinfandel Pharmaceuticals, Inc, Durham, NC, USA.
authors: Allen D
authors: AD
authors: Roses
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Brain Research Imaging Centre, Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK; Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, The University of Edinburgh, Edinburgh, UK.
authors: Maria del C
authors: Mdel C
authors: Valdés Hernández
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Brain Research Imaging Centre, Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK; Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, The University of Edinburgh, Edinburgh, UK.
authors: Natalie A
authors: NA
authors: Royle
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
authors: John M
authors: JM
authors: Starr
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Medical Genetics Section, University of Edinburgh Centre for Genomics and Experimental Medicine, Western General Hospital, Edinburgh, UK; MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors: David J
authors: DJ
authors: Porteous
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Brain Research Imaging Centre, Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK; Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, The University of Edinburgh, Edinburgh, UK.
authors: Joanna M
authors: JM
authors: Wardlaw
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Department of Psychology, University of Edinburgh, Edinburgh, UK. Electronic address: i.deary@ed.ac.uk.
authors: Ian J
authors: IJ
authors: Deary
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000235:genetics*; D001921:Brain / Q000473:pathology* / Q000502:physiology; D002648:Child; D003071:Cognition; D015331:Cohort Studies; D056324:Diffusion Tensor Imaging; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human
keywords: APOE; Alzheimer's disease; Cognitive ageing; Diffusion MRI; TOMM40; Tractography; White matter