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The effect of TOMM40 on spatial navigation in amnestic mild cognitive impairment.

Abstract
The very long (VL) poly-T variant at rs10524523 ("523") of the TOMM40 gene may hasten the onset of late-onset Alzheimer's disease (LOAD) and induce more profound cognitive impairment compared with the short (S) poly-T variant. We examined the influence of TOMM40 "523" polymorphism on spatial navigation and its brain structural correlates. Participants were apolipoprotein E (APOE) ε3/ε3 homozygotes with amnestic mild cognitive impairment (aMCI). The homozygotes were chosen because APOE ε3/ε3 variant is considered "neutral" with respect to LOAD risk. The participants were stratified according to poly-T length polymorphisms at "523" into homozygous for S (S/S; n = 16), homozygous for VL (VL/VL; n = 15) TOMM40 poly-T variant, and heterozygous (S/VL; n = 28) groups. Neuropsychological examination and testing in real-space human analog of the Morris Water Maze were administered. Both self-centered (egocentric) and world-centered (allocentric) spatial navigation was assessed. Brain magnetic resonance imaging scans were analyzed using FreeSurfer software. The S/S group, although similar to S/VL and VL/VL groups in demographic and neuropsychological profiles, performed better on allocentric navigation (p ≤ 0.004) and allocentric delayed recall (p ≤ 0.014), but not on egocentric navigation. Both S/VL and VL/VL groups had thinner right entorhinal cortex (p ≤ 0.043) than the S/S group, whereas only the VL/VL group had thinner left entorhinal cortex (p = 0.043) and left posterior cingulate cortex (p = 0.024) than the S/S group. In conclusion, TOMM40 "523" VL variants are related to impairment in allocentric spatial navigation and reduced cortical thickness of specific brain regions among aMCI individuals with (LOAD neutral) APOE ε3/ε3 genotype. This may reflect a specific role of TOMM40 "523" in the pathogenesis of LOAD.
AuthorsJan Laczó, Ross Andel, Martin Vyhnalek, Vaclav Matoska, Vojtech Kaplan, Zuzana Nedelska, Ondrej Lerch, Ivana Gazova, Scott D Moffat, Jakub Hort
JournalNeurobiology of aging (Neurobiol Aging) Vol. 36 Issue 6 Pg. 2024-33 (Jun 2015) ISSN: 1558-1497 [Electronic] United States
PMID25862420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Inc. All rights reserved.
Chemical References
  • Apolipoprotein E3
  • Membrane Transport Proteins
  • Mitochondrial Precursor Protein Import Complex Proteins
  • TOMM40 protein, human
Topics
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease (genetics, pathology, psychology)
  • Apolipoprotein E3 (genetics)
  • Cerebral Cortex (pathology)
  • Cognitive Dysfunction (genetics, pathology, psychology)
  • Female
  • Genotype
  • Homozygote
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Membrane Transport Proteins (genetics, physiology)
  • Middle Aged
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Neuropsychological Tests
  • Polymorphism, Genetic
  • Risk
  • Spatial Navigation (physiology)

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