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

NEUROBIOLOGY OF AGING

卷:35

Article

Lyall, Donald M.^1,2,3,4,5  Harris, Sarah E.^1,4,5  Bastin, Mark E.^1,2,6  Munoz Maniega, Susana^1,2,6  Murray, Catherine^1,3  Lutz, Michael W.^7,8  Saunders, Ann M.⁷  Roses, Allen D.^7,9  Hernandez, Maria del C. Valdes^1,2,6  Royle, Natalie A.^1,2,6  Starr, John M.^1,10  Porteous, David. J.^1,4,5  Wardlaw, Joanna M.^1,2,6  Deary, Ian J.^1,3 

[1] Univ Edinburgh, CCACE, Edinburgh EH8 9JZ, Midlothian, Scotland

[2] Univ Edinburgh, Div Neuroimaging Sci, Brain Res Imaging Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland

[3] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland

[4] Univ Edinburgh, Western Gen Hosp, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH8 9JZ, Midlothian, Scotland

[5] Western Gen Hosp, MRC Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland

[6] Univ Edinburgh, Dept Neuroimaging Sci, Platform Sci Excellence SINAPSE Collaborat, Scottish Imaging Network, Edinburgh EH8 9JZ, Midlothian, Scotland

[7] Joseph & Kathleen Bryan Alzheimers Dis Res Ctr, Dept Neurol, Durham, NC USA

[8] Duke Univ, Med Ctr, Durham, NC USA

[9] Zinfandel Pharmaceut Inc, Durham, NC USA

[10] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland

关键词: White matter;    Cognitive ageing;    Diffusion MRI;    Tractography;    APOE;    TOMM40;    Alzheimer's disease;   

DOI  :  10.1016/j.neurobiolaging.2014.01.006

来源: Elsevier

【 摘 要 】

Apolipoprotein E (APOE) e 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 epsilon 4 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 epsilon 3/epsilon 4 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. (c) 2014 The Authors. Published by Elsevier Inc. All rights reserved.

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