Key result
TOMM40 very long allele linked to lower baseline cognition but greater executive function gains.
Why the study?
TOMM40 '523 is linked to cognitive performance and Alzheimer disease risk independently of APOE, but few studies have evaluated its longitudinal effect on cognitive change over time.
Does TOMM40 '523 genotype status affect change in cognitive performance over time in APOE ɛ3 homozygotes?
Cohort
Does TOMM40 '523 genotype status affect change in cognitive performance over time in APOE ɛ3 homozygotes?
Effect estimate: B = -0.088
p-value: p=0.034
TOMM40 very long allele carriers (in the absence of APOE ɛ4) show lower baseline executive function but greater improvement over time, suggesting mitochondrial function contributes to cognitive changes.
TOMM40 VL carriers show distinct cognitive trajectories; hypothesis-generating for independent effects beyond APOE in pre-MCI risk stratification.
BACKGROUND: TOMM40 '523 has been associated with cognitive performance and risk for developing Alzheimer's disease independent of the effect of APOE genotype. Few studies have considered the longitudinal effect of this genotype on change in cognition over time. OBJECTIVE: Our objective was to evaluate the relationship between TOMM40 genotype status and change in cognitive performance in the TOMMORROW study, which was designed to prospectively evaluate an algorithm that includes TOMM40 '523 for genetic risk for conversion to mild cognitive impairment. METHODS: We used latent growth curve models to estimate the effect of TOMM40 allele carrier (short, very long) status on the intercept and slope of change in cognitive performance in four broad cognitive domains (attention, memory, executive function, and language) and a combined overall cognitive score over 30 months. RESULTS: TOMM40 very long allele carriers had significantly lower baseline performance for the combined overall cognitive function score (B = -0.088, p = 0.034) and for the executive function domain score (B = -0.143, p = 0.013). Slopes for TOMM40 very long carriers had significantly greater increases over time for the executive function domain score only. In sensitivity analyses, the results for executive function were observed in participants who remained clinically stable, but not in those who progressed clinically over the study duration. CONCLUSIONS: Our results add to the growing body of evidence that TOMM40, in the absence of APOEɛ4, may contribute to cognitive changes with aging and dementia and support the view that mitochondrial function is an important contributor to Alzheimer's disease risk.
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Watts et al. (2023) conducted a cohort in Cognitive decline / Alzheimer's disease risk. TOMM40 '523 very long allele vs. TOMM40 short allele was evaluated on Combined overall cognitive function score (B = -0.088, p=0.034). TOMM40 very long allele carriers had significantly lower baseline overall cognitive function (B = -0.088, p = 0.034) but showed greater increases in executive function over 30 months.
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