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

Lyall, D. M. et al. (2014) Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936. Neurobiology of Aging, 35(6), 1513.e25-1513.e33. (doi: 10.1016/j.neurobiolaging.2014.01.006)

[img]
Preview
Text
98429.pdf - Published Version
Available under License Creative Commons Attribution.

449kB

Publisher's URL: http://dx.doi.org/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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lyall, Dr Donald
Authors: Lyall, D. M., Harris, S. E., Bastin, M. E., Muñoz Maniega, S., Murray, C., Lutz, M. W., Saunders, A. M., Roses, A. D., Valdés Hernández, M. d. C., Royle, N. A., Starr, J. M., Porteous, D. J., Wardlaw, J. M., and Deary, I. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Public Health
Journal Name:Neurobiology of Aging
Publisher:Elsevier
ISSN:0197-4580
ISSN (Online):1558-1497
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Neurobiology of Aging 35(6):1513.e25-1513.e33
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record