A TOMM40 poly-T variant modulates gene expression and is associated with vocabulary ability and decline in nonpathologic aging

Payton, Antony; Sindrewicz, Paulina; Pessoa, Veridiana; Platt, Hazel; Horan, Michael A.; Ollier, William; Bubb, Vivien J.; Pendleton, Neil; Quinn, John P.

doi:10.1016/j.neurobiolaging.2015.11.017

Cited by 37 publications

(65 citation statements)

References 37 publications

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“…The TOMM40 effect was attributable to the VL poly-T length[44]. The VL isoform was also associated with increased rate of vocabulary decline in a study of healthy cognitive aging[45]. These genetics analysis show TOMM40 and APOE make separate and distinguishable contributions to cognitive aging, and TOMM40 , specifically the VL poly-T length, is involved at some early step in cognitive decline, and complement the conclusion of the cell biological analysis, that altered mitochondrial protein import contributes to AD pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

“…We[46] and others[45, 47, 48] investigated the effects of the ‘523’ poly-T length polymorphisms on TOMM40 and APOE transcription. Using brain samples from APOE ε3/3 homozygotes to distinguish TOMM40 effects from those due to APOE, we found both APOE and TOMM40 mRNA levels were dose-dependent on the numbers of VL strands in brain samples from cognitively normal individuals[46].…”

Section: Introductionmentioning

confidence: 99%

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The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease

Zeitlow

Charlambous

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease

Zeitlow

Charlambous

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…The only 2 studies of which we are aware had relatively few numbers of longitudinal assessments; one had biannual assessments with a mean of z6 years, 14 and the other had up to 4 assessments in 5-year intervals. 15 Here, we investigate the effect of the TOMM409523 variant on cognitive decline by leveraging genetic and longitudinal cognitive data from .1,000 community-based older persons who were APOE e3/3 homozygous and were followed annually for up to 21 years. We summarize the distribution of 9523 length variation and examine its association with decline in global cognition and 5 relatively dissociable cognitive domains.…”

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confidence: 99%

TOMM40 ′523 variant and cognitive decline in older persons with APOE ε3/3 genotype

Lutz

Wilson

et al. 2017

Neurology

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Objective: To interrogate a poly-T variant (rs10524523, 9523) in TOMM40, a gene adjacent to the APOE gene on chromosome 19, in older persons with APOE e3/3 homozygosity for association with cognitive decline, the clinical hallmark of Alzheimer disease (AD).Methods: Data came from participants in 2 cohort studies of aging and dementia who underwent annual clinical evaluations for up to 21 years. APOE and TOMM409523 genotypes were determined from DNA from blood or brain samples. Linear mixed models compared the rates of decline in cognition among APOE e3/3 carriers with different 9523 genotypes.Results: The 1,170 APOE e3/3 homozygotes were of European ancestry, were free of dementia at baseline, and had an average age of 78.5 years at baseline. Three major genotypes at the 9523 variant were linked to APOE e3/3; 26.5% had 2 short poly-Ts (S/S), 48.5% had 1 short and 1 very long poly-T (S/VL), and 24.0% had 2 very long poly-Ts (VL/VL). Participants with '523-S/S had faster decline in global cognition than participants with '523-S/VL or VL/VL (p 5 0.002). The same association was observed for episodic memory (p , 0.001) and semantic memory (p 5 0.003) but not for working memory, perceptual speed, or visuospatial ability. Conclusions:Our data reveal an association of APOE e3/3-TOMM409523 haplotypes with cognitive decline in community-based older persons such that the S/S poly-T genotype is related to faster cognitive decline, primarily in the domains of episodic and semantic memory.

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“…The mitochondrial protein encoded by TOMM40 is essential in transporting protein precursors into mitochondria[45, 46]. Alterations of TOMM40 expression have been reported in AD, but with conflicting results[47, 48]. Notably, several studies have shown a cis-eQTL where ‘523-S acts as a repressor to reduce the gene expression[48, 49].…”

Section: Discussionmentioning

confidence: 99%

“…Alterations of TOMM40 expression have been reported in AD, but with conflicting results[47, 48]. Notably, several studies have shown a cis-eQTL where ‘523-S acts as a repressor to reduce the gene expression[48, 49]. This regulatory function of the ‘523 variant has also been reported in human cell culture, where the study demonstrates that ‘523 is a putative regulatory element that influences the TOMM40 promoter activity in vitro[50].…”

Section: Discussionmentioning

confidence: 99%

Neuropathologic features of TOMM40 '523 variant on late‐life cognitive decline

Lutz

Farfel

et al. 2017

Alzheimer's & Dementia

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INTRODUCTION The study investigated the role of neuropathologies in the relationship between TOMM40 ‘523 genotype and late life cognitive decline. METHODS Participants were community-dwelling older persons who had annual cognitive assessments and brain autopsies after death. Genotyping used DNA from peripheral blood or postmortem brain tissue. Linear mixed models assessed the extent to which the association of ‘523 genotype with cognitive decline is attributable to neuropathologies. RESULTS Relative to ε3/3 homozygotes with ‘523-S/VL or -VL/VL genotype, both ‘523-L carriers and ε3/3 homozygotes with ‘523-S/S genotype had faster cognitive decline. The association of ‘523-L with cognitive decline was attenuated and no longer significant after controlling for Alzheimer’s and other neuropathologies. By contrast, the association of ‘523-S/S was unchanged. DISCUSSION There are two distinct TOMM40 ‘523 signals in relation to late life cognitive decline. One signal primarily acts through AD and other common neuropathologies, while the other operates through a different mechanism.

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A TOMM40 poly-T variant modulates gene expression and is associated with vocabulary ability and decline in nonpathologic aging

Cited by 37 publications

References 37 publications

The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease

The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease

TOMM40 ′523 variant and cognitive decline in older persons with APOE ε3/3 genotype

Neuropathologic features of TOMM40 '523 variant on late‐life cognitive decline

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