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Clinical Trial
. 2023;10(4):886-894.
doi: 10.14283/jpad.2023.115.

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

H Zou  1 , S Luo, H Liu, M W Lutz, D A Bennett, B L Plassman, K A Welsh-Bohmer
Affiliations
Clinical Trial

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

H Zou et al. J Prev Alzheimers Dis. 2023.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01931566.

Keywords: APOE; Alzheimer’s disease; TOMM40; TOMMORROW; cognitive change.

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Conflict of interest statement

Dr. Zou has nothing to disclose. Dr. Luo has nothing to disclose. Hongliang Liu has nothing to disclose. Dr. Lutz has nothing to disclose. Dr. Bennett reports grants from NIH, during the conduct of the study; personal fees from Takeda Inc, outside the submitted work. Dr. Plassman reports grants from Alzheimer’s Disease Data Enablement Fund from the National Philanthropic Trust sponsor of the Alzheimer’s Drug Discovery Initiative , grants from NIH, during the conduct of the study. Dr. Welsh-Bohmer reports grants from Alzheimer’s Disease Data Enablement Fund from the National Philanthropic Trust sponsor of the Alzheimer’s Drug Discovery Initiative , grants from NIH, during the conduct of the study.

Figures

Figure 1.
Figure 1.
LOWESS curves of cognitive progression for different TOMM40’523 genotypes among APOE ε3/3 carriers A: global cognition; B: episodic memory; C: working memory; D: semantic memory; E: perceptual speed; F: visuospatial ability.
See this image and copyright information in PMC

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