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

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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. 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
Volume8
Issue number6
DOIs
StatePublished - Nov 1 2012

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Keywords

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

ASJC Scopus subject areas

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

Cite this

Caselli, R. J., Dueck, A. C., Huentelman, M. J., Lutz, M. W., Saunders, A. M., Reiman, E. M., & Roses, A. D. (2012). Longitudinal modeling of cognitive aging and the TOMM40 effect. Alzheimer's and Dementia, 8(6), 490-495. https://doi.org/10.1016/j.jalz.2011.11.006