Understanding the genetics of APOE and TOMM40 and role of mitochondrial structure and function in clinical pharmacology of Alzheimer's disease
Open accessAbstract
The methodology of Genome‐Wide Association Screening (GWAS) has been applied for more than a decade. Translation to clinical utility has been limited, especially in Alzheimer's Disease (AD). It has become standard practice in the analyses of more than two dozen AD GWAS studies to exclude the apolipoprotein E (APOE) region because of its extraordinary statistical support, unique thus far in complex human diseases. New genes associated with AD are proposed frequently based on SNPs associated with odds ratio (OR) < 1.2. Most of these SNPs are not located within the associated gene exons or introns but are located variable distances away. Often pathologic hypotheses for these genes are presented, with little or no experimental support. By eliminating the analyses of the APOE‐TOMM40 linkage disequilibrium region, the relationship and data of several genes that are co‐located in that LD region have been largely ignored. Early negative interpretations limited the interest of understanding the genetic data derived from GWAS, particularly regarding the TOMM40 gene. This commentary describes the history and problem(s) in interpretation of the genetic interrogation of the “APOE” region and provides insight into a metabolic mitochondrial basis for the etiology of AD using both APOE and TOMM40 genetics.
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APOE and TOMM40 are both AD susceptibility genes and interact with each other in modulating AD risk.
“The APOE and TOMM40 genes are both AD susceptibility genes and interact with each other in modulating AD risk26.”
From Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice (2021) · cites this paper as [26]
In “TOMM40 and AD,” the paper describes APOE–TOMM40 haplotypes as informative for AD risk estimates, particularly age of onset. In “Precision versus accuracy,” it says evidence for functional interactions is emerging. These passages support a joint genetic association, but not the unqualified claim that the genes interact to modulate the risk of developing AD. (LLM, conf=0.84)
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- Authors
- Roses, A., Sundseth, S., Saunders, A., Gottschalk, W., Burns, D., & Lutz, M.
- Affiliations
- Duke University (US)
- Corresponding author
- Roses, Allen
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2016-05-03
- Volume
- 12
- Issue
- 6
- Pages
- 687-694
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- OpenAlex
- W2346777292
- Cited by
- 70
- References
- 47
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 7 · 2023: 2 · 2022: 8 · 2021: 7 · 2020: 8 · 2019: 9 · 2018: 5 · 2017: 7
- FWCI
- 0.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, apolipoprotein E
- MeSH terms
- Mitochondrial Precursor Protein Import Complex Proteins, Alzheimer Disease, Apolipoproteins E, Humans, Mitochondria, Linkage Disequilibrium, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Membrane Transport Proteins, Genome-Wide Association Study
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