title: Longitudinal modeling of cognitive aging and the TOMM40 effect.
abstract: BACKGROUND
  TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21-29 T residues) poly-T variants within intron 6 of TOMM40, whereas APOE e3 can be associated with either a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer's disease onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline.
  
  
  METHODS
  An APOE e4-enriched cohort of 639 cognitively normal individuals aged 21 to 97 years with known TOMM40 genotype underwent longitudinal neuropsychological testing every 2 years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross-sectional and longitudinal effects of age on the Auditory Verbal Learning Test Long-Term Memory score by APOE, TOMM40, and the interaction between the two.
  
  
  RESULTS
  There were significant effects overall for both TOMM40 (linear effect, P = .04; quadratic effect, P = .03) and APOE (linear effect, P = .06; quadratic effect, P = .008), with no significant interaction (P = .63). In a piecewise model, there was a significant TOMM40 effect before age 60 years (P = .009), characterized by flattened test-retest improvement (VL/VL subgroup only) but no significant APOE effect, and a significant APOE effect after age 60 years (P = .006), characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect.
  
  
  CONCLUSIONS
  Both TOMM40 and APOE significantly influence age-related memory performance, but they appear to do so independently of each other.
authors.affiliation: Department of Neurology, Mayo Clinic Arizona, Scottsdale, AZ, USA. Caselli.Richard@Mayo.edu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Caselli
authors.forename: Amylou C
authors.initials: AC
authors.lastname: Dueck
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lutz
authors.forename: Ann M
authors.initials: AM
authors.lastname: Saunders
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.forename: Allen D
authors.initials: AD
authors.lastname: Roses
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009483:Neuropsychological Tests; D055815:Young Adult
chemical_list: D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human