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Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study.

Publication ,  Journal Article
Zou, H; Luo, S; Liu, H; Lutz, MW; Bennett, DA; Plassman, BL; Welsh-Bohmer, KA
Published in: J Prev Alzheimers Dis
2023

BACKGROUND: The 523 poly-T length polymorphism (rs10524523) in TOMM40 has been reported to influence longitudinal cognitive test performance within APOE ε3/3 carriers. The results from prior studies are inconsistent. It is also unclear whether specific APOE and TOMM40 genotypes contribute to heterogeneity in longitudinal cognitive performance during the preclinical stages of AD. OBJECTIVES: To determine the effects of these genes on longitudinal cognitive change in early preclinical stages of AD, we used the clinical trial data from the recently concluded TOMMORROW study to examine the effects of APOE and TOMM40 genotypes on neuropsychological test performance. DESIGN: A phase 3, double-blind, placebo-controlled, randomized clinical trial. SETTING: Academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. PARTICIPANTS: Cognitively normal older adults aged 65 to 83. INTERVENTION: Pioglitazone tablet. MEASUREMENTS: Participants from the TOMMORROW trial were stratified based on APOE genotype (APOE ε3/3, APOE ε3/4, APOE ε4/4). APOE ε3/3 carriers were further stratified by TOMM40'523 genotype. The final analysis dataset consists of 1,330 APOE ε3/3 carriers and 7,001 visits. Linear mixed models were used to compare the rates of decline in cognition across APOE groups and the APOE ε3/3 carriers with different TOMM40'523 genotypes. RESULTS: APOE ε3/4 and APOE ε4/4 genotypes compared with the APOE ε3/3 genotype were associated with worse performance on measures of global cognition, episodic memory, and expressive language. Further, over the four years of observation, the APOE ε3/3 carriers with the TOMM40'523-S/S genotype showed better global cognition and accelerated rates of cognitive decline on tests of global cognition, executive function, and attentional processing compared to APOE ε3/3 carriers with TOMM40'523-S/VL and VL/VL genotypes and compared to the APOE ε3/4 and APOE ε4/4 carriers. CONCLUSIONS: We suggest that both APOE and TOMM40 genotypes may independently contribute to cognitive heterogeneity in the pre-MCI stages of AD. Controlling for this genetic variability will be important in clinical trials designed to slow the rate of cognitive decline and/or prevent symptom onset in preclinical AD.

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Published In

J Prev Alzheimers Dis

DOI

EISSN

2426-0266

Publication Date

2023

Volume

10

Issue

4

Start / End Page

886 / 894

Location

Switzerland

Related Subject Headings

  • Mitochondrial Precursor Protein Import Complex Proteins
  • Humans
  • Genotype
  • Cognition
  • Apolipoproteins E
  • Apolipoprotein E4
  • Apolipoprotein E3
  • Aged
  • 5204 Cognitive and computational psychology
  • 5202 Biological psychology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Zou, H., Luo, S., Liu, H., Lutz, M. W., Bennett, D. A., Plassman, B. L., & Welsh-Bohmer, K. A. (2023). Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study. J Prev Alzheimers Dis, 10(4), 886–894. https://doi.org/10.14283/jpad.2023.115
Zou, H., S. Luo, H. Liu, M. W. Lutz, D. A. Bennett, B. L. Plassman, and K. A. Welsh-Bohmer. “Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study.J Prev Alzheimers Dis 10, no. 4 (2023): 886–94. https://doi.org/10.14283/jpad.2023.115.
Zou H, Luo S, Liu H, Lutz MW, Bennett DA, Plassman BL, et al. Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study. J Prev Alzheimers Dis. 2023;10(4):886–94.
Zou, H., et al. “Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study.J Prev Alzheimers Dis, vol. 10, no. 4, 2023, pp. 886–94. Pubmed, doi:10.14283/jpad.2023.115.
Zou H, Luo S, Liu H, Lutz MW, Bennett DA, Plassman BL, Welsh-Bohmer KA. Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study. J Prev Alzheimers Dis. 2023;10(4):886–894.

Published In

J Prev Alzheimers Dis

DOI

EISSN

2426-0266

Publication Date

2023

Volume

10

Issue

4

Start / End Page

886 / 894

Location

Switzerland

Related Subject Headings

  • Mitochondrial Precursor Protein Import Complex Proteins
  • Humans
  • Genotype
  • Cognition
  • Apolipoproteins E
  • Apolipoprotein E4
  • Apolipoprotein E3
  • Aged
  • 5204 Cognitive and computational psychology
  • 5202 Biological psychology