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.