The Effect of TOMM40 Poly-T length on Gray Matter Volume and Cognition in Middle-Aged Persons with APOE ε3/ε3 Genotype

Johnson SC, La Rue, A, Hermann BP, Xu G, Koscik R, Jonaitis EM, Bendlin BB, Hogan KJ, Roses AD, Saunders AM, Lutz MW, Asthana S, Green RC, Sager MA

Alzheimers and Dementia 7, 456-465


Objective: Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late onset Alzheimer’s disease (LOAD), with APOE ε4 having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the TOMM40 gene has been shown to influence age of onset in LOAD, with very long 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 N=117 healthy APOE ε3 homozygous adults (mean age 55), we compared those homozygous for very long (VL/VL; n=35) TOMM40 poly-T lengths (who are presumably at higher risk) to 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 exhibited 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 AD. 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 very long TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes.

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