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The effect of TOMM40 poly‐T length on gray matter volume and cognition in middle‐aged persons with APOEɛ 3/ɛ 3 genotype
Open accessAbstract
OBJECTIVE: Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late-onset Alzheimer's disease (LOAD), with APOE epsilon 4 (APOE ε4) having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the translocase of the outer mitochondrial membrane (TOMM40) gene, has been shown to influence age of onset in LOAD, with very long (VL) poly-T length associated with earlier disease onset, and short poly-T length associated with later onset. In this study, we tested the hypothesis that brain and cognitive changes suggestive of presymptomatic LOAD may be associated with this TOMM40 polymorphism. METHODS: Among healthy APOE ε3 homozygous adults (N = 117; mean age, 55 years), we compared those who were homozygous for VL/VL (n = 35) TOMM40 poly-T lengths (who were presumably at higher risk) with those homozygous for short (S/S; n = 38) poly-T lengths, as well as those with heterozygous (S/VL; n = 44) poly-T length polymorphisms, on measures of learning and memory and on structural brain imaging. RESULTS: The VL/VL group showed lower performance than the S/S TOMM40 group on primacy retrieval from a verbal list learning task, a finding which is also seen in early Alzheimer's disease. A dose-dependent increase in the VL TOMM40 polymorphism (from no VL alleles, to S/VL heterozygous, to VL/VL homozygous) was associated with decreasing gray matter volume in the ventral posterior cingulate and medial ventral precuneus, a region of the brain affected early in LOAD. CONCLUSIONS: These findings among APOE ε3/ε3 late middle-aged adults suggest that a subgroup with VL TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes.
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“from a strict association perspective it does appear that the TOMM40 gene, and by extension its protein product, could potentially impact LOAD.”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [147]
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Metadata
- Authors
- Johnson, S. C., La Rue, A., Hermann, B. P., Xu, G., Koscik, R. L., Jonaitis, E. M., Bendlin, B. B., Hogan, K. J., Roses, A. D., Saunders, A. M., Lutz, M. W., Asthana, S., Green, R. C., & Sager, M. A.
- Affiliations
- University of Wisconsin–Madison (US)
- Wisconsin Alzheimer's Institute University of Wisconsin School of Medicine and Public Health Madison WI USA
- Duke University (US)
- Boston University (US)
- Corresponding author
- Johnson, Sterling C.
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2011-07
- Volume
- 7
- Issue
- 4
- Pages
- 456-465
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC3143375
- OpenAlex
- W2085579734
- Cited by
- 112
- References
- 41
- Citations by year
- 2025: 4 · 2024: 4 · 2023: 7 · 2022: 3 · 2021: 6 · 2020: 9 · 2019: 6 · 2018: 7 · 2017: 16 · 2016: 7 · 2015: 7 · 2014: 12 · 2013: 9 · 2012: 14
- FWCI
- 7.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Helen Bader Foundation
- Northwestern Mutual Foundation
- Extendicare Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- TOMM40
- MeSH terms
- Mitochondrial Precursor Protein Import Complex Proteins, Age Factors, Alzheimer Disease, Analysis of Variance, Brain, Cognition Disorders, Female, Gene Frequency, Genotype, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, Poly T, Risk Factors, Polymorphism, Single Nucleotide, Membrane Transport Proteins, Apolipoprotein E3
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