Laczó J, Andel R, Vyhnalek M, Matoska V, Kaplan V, Nedelska Z, Lerch O, Gazova I, Moffat SD, Hort J. Neurobiology of Aging. 2015 Jun;36(6):2024–33. doi: 10.1016/j.neurobiolaging.2015.03.004. Epub 2015 Mar 16. IF: 5.013
doc. MUDr. Jan Laczó, Ph.D., Department of Neurology
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.
