title: The effect of TOMM40 poly-T length on gray matter volume and cognition in middle-aged persons with APOE ε3/ε3 genotype.
abstract: 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.
authors.affiliation: Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. scjohnson@wisc.edu
authors.forename: Sterling C
authors.initials: SC
authors.lastname: Johnson
authors.forename: Asenath
authors.initials: A
authors.lastname: La Rue
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Hermann
authors.forename: Guofan
authors.initials: G
authors.lastname: Xu
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Koscik
authors.forename: Erin M
authors.initials: EM
authors.lastname: Jonaitis
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Bendlin
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Hogan
authors.forename: Allen D
authors.initials: AD
authors.lastname: Roses
authors.forename: Ann M
authors.initials: AM
authors.lastname: Saunders
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lutz
authors.forename: Sanjay
authors.initials: S
authors.lastname: Asthana
authors.forename: Robert C
authors.initials: RC
authors.lastname: Green
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sager
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics; D000704:Analysis of Variance; D053318:Apolipoprotein E3 / Q000235:genetics*; D001921:Brain / Q000473:pathology*; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009483:Neuropsychological Tests; D011071:Poly T / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
chemical_list: D053318:Apolipoprotein E3; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human; D011071:Poly T