Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Jul;7(4):456-65.
doi: 10.1016/j.jalz.2010.11.012.

The effect of TOMM40 poly-T length on gray matter volume and cognition in middle-aged persons with APOE ε3/ε3 genotype

Sterling C Johnson  1 , Asenath La Rue, Bruce P Hermann, Guofan Xu, Rebecca L Koscik, Erin M Jonaitis, Barbara B Bendlin, Kirk J Hogan, Allen D Roses, Ann M Saunders, Michael W Lutz, Sanjay Asthana, Robert C Green, Mark A Sager
Affiliations

The effect of TOMM40 poly-T length on gray matter volume and cognition in middle-aged persons with APOE ε3/ε3 genotype

Sterling C Johnson et al. Alzheimers Dement. 2011 Jul.

Abstract

Objective: Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late-onset Alzheimer's disease (LOAD), with APOE epsilon 4 (APOE ε4) having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the translocase of the outer mitochondrial membrane (TOMM40) gene, has been shown to influence age of onset in LOAD, with very long (VL) poly-T length associated with earlier disease onset, and short poly-T length associated with later onset. In this study, we tested the hypothesis that brain and cognitive changes suggestive of presymptomatic LOAD may be associated with this TOMM40 polymorphism.

Methods: Among healthy APOE ε3 homozygous adults (N = 117; mean age, 55 years), we compared those who were homozygous for VL/VL (n = 35) TOMM40 poly-T lengths (who were presumably at higher risk) with those homozygous for short (S/S; n = 38) poly-T lengths, as well as those with heterozygous (S/VL; n = 44) poly-T length polymorphisms, on measures of learning and memory and on structural brain imaging.

Results: The VL/VL group showed lower performance than the S/S TOMM40 group on primacy retrieval from a verbal list learning task, a finding which is also seen in early Alzheimer's disease. A dose-dependent increase in the VL TOMM40 polymorphism (from no VL alleles, to S/VL heterozygous, to VL/VL homozygous) was associated with decreasing gray matter volume in the ventral posterior cingulate and medial ventral precuneus, a region of the brain affected early in LOAD.

Conclusions: These findings among APOE ε3/ε3 late middle-aged adults suggest that a subgroup with VL TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes.

PubMed Disclaimer

Figures

Figure 1
Figure 1
TOMM40 allele Frequency Distributions. Frequency distributions of the TOMM40 poly-T repeat length for 120 APOE3/3 subjects. The histogram clearly shows a bimodal distribution with most (98%) occurring at <= 20 repeats (short), or >= 30 repeats (very long). Each individual provides two poly-T lengths, representing each chromosome. Three individuals with poly-T repeat lengths >20 and <30 were classified by definition as an L allele, and excluded from further analysis.
Figure 2
Figure 2
Gray Matter Group Differences. Voxel-wise gray matter volume comparison between the S/S, S/VL and VL/VL TOMM40 groups depicting a “dose effect”. The boxplots depict the mean effect graphically, showing the first principle component scaled in arbitrary units extracted from the cluster in the posterior cingulate. The S/S group had the greatest volume, followed by the S/VL group, and the VL/VL group had the lowest volume.
Figure 3
Figure 3
Gray Matter by Age Slope Differences. (A) voxel-wise group by age interaction was found in a small cluster in the retrosplenial aspect of the posterior cingulate, indicating that the effect of age on gray matter atrophy differs as a function of group. (B) Plot of the effect indicating a greater negative slope with age in the VL/VL group. Note the y-axis is statistically adjusted GM, and thus should not be interpreted strictly as absolute gray matter.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. Jama. 1997;278:1349–1356. - PubMed
    1. Strittmatter WJ, Roses AD. Apolipoprotein E and Alzheimer’s disease. Annu Rev Neurosci. 1996;19:53–77. - PubMed
    1. Sleegers K, Lambert JC, Bertram L, Cruts M, Amouyel P, Van Broeckhoven C. The pursuit of susceptibility genes for Alzheimer’s disease: progress and prospects. Trends Genet. 2010;26:84–93. - PubMed
    1. Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90:1977–1981. - PMC - PubMed
    1. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology. 1993;43:1467–1472. - PubMed

Publication types

MeSH terms

Substances