Longitudinal modeling of cognitive aging and the TOMM40 effect

Richard J. Caselli, Amylou C. Dueck, Matthew J. Huentelman, Michael W. Lutz, Ann M. Saunders, Eric M. Reiman, Allen D. Roses

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


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. Conclusion: Both TOMM40 and APOE significantly influence age-related memory performance, but they appear to do so independently of each other.

Original languageEnglish (US)
Pages (from-to)490-495
Number of pages6
JournalAlzheimer's and Dementia
Issue number6
StatePublished - Nov 2012


  • APOE
  • Cognitive aging
  • Preclinical Alzheimer's disease
  • TOMM40

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health


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