Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936

doi:10.1016/j.neurobiolaging.2014.01.006

. 2014 Jun;35(6):1513.e25-33.

doi: 10.1016/j.neurobiolaging.2014.01.006. Epub 2014 Jan 8.

Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Department of Psychology, University of Edinburgh, Edinburgh, UK.
⁵ Department of Neurology, Joseph & Kathleen Bryan Alzheimer's Disease Research Center, Durham, NC, USA; Duke University Medical Center, Durham, NC, USA.
⁶ Department of Neurology, Joseph & Kathleen Bryan Alzheimer's Disease Research Center, Durham, NC, USA.
⁷ 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.
⁸ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
⁹ 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.

PMID: 24508314
PMCID: PMC3969262
DOI: 10.1016/j.neurobiolaging.2014.01.006

Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936

Donald M Lyall et al. Neurobiol Aging. 2014 Jun.

. 2014 Jun;35(6):1513.e25-33.

doi: 10.1016/j.neurobiolaging.2014.01.006. Epub 2014 Jan 8.

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Department of Psychology, University of Edinburgh, Edinburgh, UK.
⁵ Department of Neurology, Joseph & Kathleen Bryan Alzheimer's Disease Research Center, Durham, NC, USA; Duke University Medical Center, Durham, NC, USA.
⁶ Department of Neurology, Joseph & Kathleen Bryan Alzheimer's Disease Research Center, Durham, NC, USA.
⁷ 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.
⁸ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
⁹ 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.

PMID: 24508314
PMCID: PMC3969262
DOI: 10.1016/j.neurobiolaging.2014.01.006

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.

Keywords: APOE; Alzheimer's disease; Cognitive ageing; Diffusion MRI; TOMM40; Tractography; White matter.

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References

1. Bastin M.E., Pettit L.D., Bak T.H., Gillingwater T.H., Smith C., Abrahams S. Quantitative tractography and tract shape modelling in amyotrophic lateral sclerosis. JMRI. 2013 - PubMed
1. Behrens T.E.J., Berg H.J., Jbabdi R., Rushworth M.F.S., Woolrich W.M. Probabilistic diffusion tractography with multiple fibre orientations: what can we gain? Neuroimage. 2007;34:144–155. - PMC - PubMed
1. Bekris L.M., Lutz F., Yu C.E. Functional analysis of APOE locus genetic variation implicates regional enhances in the regulation of both TOMM40 and APOE. Hum. Genet. 2012;57:18–25. - PMC - PubMed
1. Benjamini Y., Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. Roy Stat. Soc. 1995;57:289–300.
1. Biffi A., Anderson C.D., Desikan R.S., Sabuncu M., Cortellini L., Schmansky N., Salat D., Rosand J., Alzheimer's Disease Neuroimaging Initiative Genetic variation and neuroimaging measures in Alzheimer disease. Arch. Neurol. 2010;67:677–685. - PMC - PubMed

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[1] Bastin M.E., Pettit L.D., Bak T.H., Gillingwater T.H., Smith C., Abrahams S. Quantitative tractography and tract shape modelling in amyotrophic lateral sclerosis. JMRI. 2013 - PubMed

[2] Bastin M.E., Pettit L.D., Bak T.H., Gillingwater T.H., Smith C., Abrahams S. Quantitative tractography and tract shape modelling in amyotrophic lateral sclerosis. JMRI. 2013 - PubMed

[3] Behrens T.E.J., Berg H.J., Jbabdi R., Rushworth M.F.S., Woolrich W.M. Probabilistic diffusion tractography with multiple fibre orientations: what can we gain? Neuroimage. 2007;34:144–155. - PMC - PubMed

[4] Behrens T.E.J., Berg H.J., Jbabdi R., Rushworth M.F.S., Woolrich W.M. Probabilistic diffusion tractography with multiple fibre orientations: what can we gain? Neuroimage. 2007;34:144–155. - PMC - PubMed

[5] Bekris L.M., Lutz F., Yu C.E. Functional analysis of APOE locus genetic variation implicates regional enhances in the regulation of both TOMM40 and APOE. Hum. Genet. 2012;57:18–25. - PMC - PubMed

[6] Bekris L.M., Lutz F., Yu C.E. Functional analysis of APOE locus genetic variation implicates regional enhances in the regulation of both TOMM40 and APOE. Hum. Genet. 2012;57:18–25. - PMC - PubMed

[7] Benjamini Y., Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. Roy Stat. Soc. 1995;57:289–300.

[8] Benjamini Y., Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. Roy Stat. Soc. 1995;57:289–300.

[9] Biffi A., Anderson C.D., Desikan R.S., Sabuncu M., Cortellini L., Schmansky N., Salat D., Rosand J., Alzheimer's Disease Neuroimaging Initiative Genetic variation and neuroimaging measures in Alzheimer disease. Arch. Neurol. 2010;67:677–685. - PMC - PubMed

[10] Biffi A., Anderson C.D., Desikan R.S., Sabuncu M., Cortellini L., Schmansky N., Salat D., Rosand J., Alzheimer's Disease Neuroimaging Initiative Genetic variation and neuroimaging measures in Alzheimer disease. Arch. Neurol. 2010;67:677–685. - PMC - PubMed

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Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936

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Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936

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