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

Alzheimers Dement. 2011 Jul;7(4):456-65. doi: 10.1016/j.jalz.2010.11.012.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Alzheimer Disease / etiology
  • Alzheimer Disease / genetics
  • Analysis of Variance
  • Apolipoprotein E3 / genetics*
  • Brain / pathology*
  • Cognition Disorders / etiology
  • Cognition Disorders / genetics*
  • Female
  • Gene Frequency
  • Genotype
  • Humans
  • Image Processing, Computer-Assisted
  • Magnetic Resonance Imaging
  • Male
  • Membrane Transport Proteins / genetics*
  • Middle Aged
  • Neuropsychological Tests
  • Poly T / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors


  • Apolipoprotein E3
  • Membrane Transport Proteins
  • TOMM40 protein, human
  • Poly T