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

Publication ,  Journal Article
Lyall, DM; Harris, SE; Bastin, ME; Muñoz Maniega, S; Murray, C; Lutz, MW; Saunders, AM; Roses, AD; Valdés Hernández, MDC; Royle, NA; Starr, JM ...
Published in: Neurobiol Aging
June 2014

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.

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Published In

Neurobiol Aging

DOI

EISSN

1558-1497

Publication Date

June 2014

Volume

35

Issue

6

Start / End Page

1513.e25 / 1513.e33

Location

United States

Related Subject Headings

  • Polymorphism, Genetic
  • Phenotype
  • Neurology & Neurosurgery
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Membrane Transport Proteins
  • Male
  • Humans
  • Genotype
  • Genetic Predisposition to Disease
  • Genetic Association Studies
 

Citation

APA
Chicago
ICMJE
MLA
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Lyall, D. M., Harris, S. E., Bastin, M. E., Muñoz Maniega, S., Murray, C., Lutz, M. W., … Deary, I. J. (2014). Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936. Neurobiol Aging, 35(6), 1513.e25-1513.e33. https://doi.org/10.1016/j.neurobiolaging.2014.01.006
Lyall, Donald M., Sarah E. Harris, Mark E. Bastin, Susana Muñoz Maniega, Catherine Murray, Michael W. Lutz, Ann M. Saunders, et al. “Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936.Neurobiol Aging 35, no. 6 (June 2014): 1513.e25-1513.e33. https://doi.org/10.1016/j.neurobiolaging.2014.01.006.
Lyall DM, Harris SE, Bastin ME, Muñoz Maniega S, Murray C, Lutz MW, et al. Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936. Neurobiol Aging. 2014 Jun;35(6):1513.e25-1513.e33.
Lyall, Donald M., et al. “Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936.Neurobiol Aging, vol. 35, no. 6, June 2014, pp. 1513.e25-1513.e33. Pubmed, doi:10.1016/j.neurobiolaging.2014.01.006.
Lyall DM, Harris SE, Bastin ME, Muñoz Maniega S, Murray C, Lutz MW, Saunders AM, Roses AD, Valdés Hernández MDC, Royle NA, Starr JM, Porteous DJ, Wardlaw JM, Deary IJ. Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936. Neurobiol Aging. 2014 Jun;35(6):1513.e25-1513.e33.
Journal cover image

Published In

Neurobiol Aging

DOI

EISSN

1558-1497

Publication Date

June 2014

Volume

35

Issue

6

Start / End Page

1513.e25 / 1513.e33

Location

United States

Related Subject Headings

  • Polymorphism, Genetic
  • Phenotype
  • Neurology & Neurosurgery
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Membrane Transport Proteins
  • Male
  • Humans
  • Genotype
  • Genetic Predisposition to Disease
  • Genetic Association Studies