Longitudinal modeling of cognitive aging and the TOMM40 effect

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

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 2012

Fingerprint

Apolipoproteins E
Apolipoprotein E4
Genotype
Cognitive Aging
Apolipoprotein E3
Poly T
Verbal Learning
Long-Term Memory
Linkage Disequilibrium
Mitochondrial Membranes
Statistical Models
Introns
Alzheimer Disease

Keywords

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

ASJC Scopus subject areas

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

Cite this

Caselli, R. J., Dueck, A., 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

Longitudinal modeling of cognitive aging and the TOMM40 effect. / Caselli, Richard John; Dueck, Amylou; Huentelman, Matthew J.; Lutz, Michael W.; Saunders, Ann M.; Reiman, Eric M.; Roses, Allen D.

In: Alzheimer's and Dementia, Vol. 8, No. 6, 11.2012, p. 490-495.

Research output: Contribution to journalArticle

Caselli, RJ, Dueck, A, Huentelman, MJ, Lutz, MW, Saunders, AM, Reiman, EM & Roses, AD 2012, 'Longitudinal modeling of cognitive aging and the TOMM40 effect', Alzheimer's and Dementia, vol. 8, no. 6, pp. 490-495. https://doi.org/10.1016/j.jalz.2011.11.006
Caselli, Richard John ; Dueck, Amylou ; Huentelman, Matthew J. ; Lutz, Michael W. ; Saunders, Ann M. ; Reiman, Eric M. ; Roses, Allen D. / Longitudinal modeling of cognitive aging and the TOMM40 effect. In: Alzheimer's and Dementia. 2012 ; Vol. 8, No. 6. pp. 490-495.
@article{b3d7c3d9f5ea4f53bf8008d3f11e34a7,
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. Conclusion: Both TOMM40 and APOE significantly influence age-related memory performance, but they appear to do so independently of each other.",
keywords = "APOE, Cognitive aging, Preclinical Alzheimer's disease, TOMM40",
author = "Caselli, {Richard John} and Amylou Dueck and Huentelman, {Matthew J.} and Lutz, {Michael W.} and Saunders, {Ann M.} and Reiman, {Eric M.} and Roses, {Allen D.}",
year = "2012",
month = "11",
doi = "10.1016/j.jalz.2011.11.006",
language = "English (US)",
volume = "8",
pages = "490--495",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - Longitudinal modeling of cognitive aging and the TOMM40 effect

AU - Caselli, Richard John

AU - Dueck, Amylou

AU - Huentelman, Matthew J.

AU - Lutz, Michael W.

AU - Saunders, Ann M.

AU - Reiman, Eric M.

AU - Roses, Allen D.

PY - 2012/11

Y1 - 2012/11

N2 - 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.

AB - 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.

KW - APOE

KW - Cognitive aging

KW - Preclinical Alzheimer's disease

KW - TOMM40

UR - http://www.scopus.com/inward/record.url?scp=84867852032&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867852032&partnerID=8YFLogxK

U2 - 10.1016/j.jalz.2011.11.006

DO - 10.1016/j.jalz.2011.11.006

M3 - Article

C2 - 23102119

AN - SCOPUS:84867852032

VL - 8

SP - 490

EP - 495

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

SN - 1552-5260

IS - 6

ER -