The effect of TOMM40 poly‐T length on gray matter volume and cognition in middle‐aged persons with APOEɛ 3/ɛ 3 genotype
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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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The TOMM40 gene, and by extension its protein product, could potentially impact LOAD.
“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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Hayden, K. M., McEvoy, J. M., Linnertz, C., Attix, D., Kuchibhatla, M., Saunders, A. M., Lutz, M. W., Welsh‐Bohmer, K. A., Roses, A. D., & Chiba‐Falek, O. (2012) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.10.005 · Cited by 53 · see citing works
Self-citationTOMM40 rs10524523 polymorphism's role in late-onset Alzheimer's disease and in longevity
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Self-citationTOMM40 Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease
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Self-citationThe effect of TOMM40 on spatial navigation in amnestic mild cognitive impairment
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TOMM40 genetic variants associated with healthy aging and longevity: a systematic review
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The Role of Upregulated APOE in Alzheimer's Disease Etiology
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Opportunities in pharmacogenomics for the treatment of Alzheimer’s disease
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New Genetic Approaches to AD: Lessons from APOE-TOMM40 Phylogenetics
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Self-citationTOMM40 intron 6 poly‐T length, age at onset, and neuropathology of AD in individuals with APOE ɛ3/ɛ3
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A genetics-based biomarker risk algorithm for predicting risk of Alzheimer's disease
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Self-citationNeuropathologic features of TOMM40 '523 variant on late‐life cognitive decline
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Self-citationBurggren, A. C., Mahmood, Z., Harrison, T. M., Siddarth, P., Miller, K. J., Small, G. W., Merrill, D. A., & Bookheimer, S. Y. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.12.009 · Cited by 27 · see citing works
Serial position effects in the Logical Memory Test: Loss of primacy predicts amyloid positivity
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Self-citationTOMM40 rs2075650 May Represent a New Candidate Gene for Vulnerability to Major Depressive Disorder
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DNA methylation in genes associated with the evolution of ageing and disease: A critical review
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TOMM40‐APOE haplotypes are associated with cognitive decline in non‐demented Blacks
Deters, K., Mormino, E. C., Yu, L., Lutz, M. W., Bennett, D. A., & Barnes, L. L. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12295 · Cited by 18 · see citing works
Self-citationFecal short‐chain fatty acids vary by sex and amyloid status
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Self-citationBiochemical Studies of Poly-T Variants in the Alzheimer's Disease Associated TOMM40 Gene
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Self-citationAPOE-TOMM40 in the Pharmacogenomics of Dementia
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Alzheimer’s disease cortical morphological phenotypes are associated with TOMM40′523-APOE haplotypes
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An increase in mitochondrial TOM activates apoptosis to drive retinal neurodegeneration
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Biomarkers for the early diagnosis of Alzheimer’s disease: The challenge of XXI century
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Self-citationSanabria, F. C., Bonilla-Vargas, K. J., Estrada, K., Páez, O. M., Vega, E., Guerrero, E., Ortega-Rojas, J., María, F. M., Romero, A., Montañés, P., et al. (2020) · Neurología (English Edition) · doi:10.1016/j.nrleng.2018.07.012 · Cited by 12 · see citing works
TOMM40 ‘523 Associations with Baseline and Longitudinal Cognition in APOE ɛ 3 Homozygotes
Watts, A. S., Wilkins, H., Michaelis, E. K., & Swerdlow, R. H. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190293 · Cited by 11 · see citing works
The Combined Effect of APOE and BDNF Val66Met Polymorphisms on Spatial Navigation in Older Adults
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Self-citationTOMM40 gene polymorphisms association with lipid profile
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Self-citationUncovering the Localization and Function of a Novel Read-Through Transcript ‘TOMM40-APOE’
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The Role of TOMM40 in Cardiovascular Mortality and Conduction Disorders: An Observational Study
Stolfo, G. D., Mastroianno, S., Soldato, N., Massaro, R. S., Luca, G. D., Seripa, D., Urbano, M., Gravina, C., Greco, A., Siena, P., et al. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13113177 · Cited by 4 · see citing works
- 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
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › 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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