Understanding the genetics of APOE and TOMM40 and role of mitochondrial structure and function in clinical pharmacology of Alzheimer's disease

Abstract

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.

Platelet cytochrome oxidase and citrate synthase activities in APOE ε4 carrier and non-carrier Alzheimer's disease patients

“…Caucasians show very frequent (98%) but not exclusive TOMM40 `523L and APOE ε4 allele linkage disequilibrium, while African Americans do not [21], [29]. Three of the 15 participants (20%) did not show APOE ε4-TOMM40 L linkage disequilibrium; two of these were African American.…”

“…Intron 6 of the TOMM40 gene contains a variable length poly-T region that defines the rs10524523 SNP (referred to herein as TOMM40 `523) [21]. To obtain the `523 poly-T length, we used a DNeasy kit (Qiagen) to prepare genomic DNA from 100 µl of whole blood and PCR-amplified the DNA with the following primers: 5′-6FAM-CTGACCTCAAGCTGTCCTC-3′ (forward) and 5′-GAGGCTGAGAAGGGAGGATT-3′ (reverse).…”

“…This interaction would presumably converge at the level of mitochondrial function. Also, the TOMM40 gene, which encodes a critical mitochondrial translocase, borders the APOE gene and as a result TOMM40 and APOE allele signatures show linkage disequilibrium [2], [19], [20], [21]. This raises the possibility that APOE alleles could relate indirectly to mitochondrial function through TOMM40 linkage disequilibrium.…”

Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE‐ε4/TOMM40 long poly‐T repeat allele variants

“…We also acknowledge that this study is smaller than currently available GWAS for PD or DLB [10,11,48]. However, even recent genome‐wide genotyping arrays do not directly genotype all variants investigated in our study (e.g., TOMM40 poly‐T repeats) [43], and GWAS are typically based on clinical data, thus diminishing their ability to evaluate genetic effects on accurate DLB and PDD clinicopathological phenotypes. Furthermore, our APOE ‐ε4 – DLB association findings were corroborated in independent data sets investigating the role of APOE specifically, which we combined in the hitherto largest meta‐analysis on the topic.…”

“…APOE is a key cholesterol transporter with known effects on lipid metabolism, mitochondrial function, and is possibly involved in immune‐modulating mechanisms [42]. TOMM40 Translocase, on the other hand, forms part of the outer mitochondrial membrane apparatus, with a key role in transmembrane transport mechanisms [43]. For AD, DLB, and other age‐related neurodegenerative diseases, we still have major gaps in understanding the composition and chronology of the etiological puzzle that leads to synaptic dysfunction and neuronal death.…”