Superior Frontal Gyrus TOMM40-APOE Locus DNA Methylation in Alzheimer’s Disease

Abstract

Background: The APOE ɛ4 allele is the strongest known genetic risk factor for sporadic Alzheimer’s disease (AD). The neighboring TOMM40 gene has also been implicated in AD due to its close proximity to APOE. Objective: Here we tested whether methylation of the TOMM40-APOE locus may influence ApoE protein levels and AD pathology. Methods: DNA methylation levels across the TOMM40-APOE locus and ApoE levels were measured in superior frontal gyrus tissues of 62 human brains genotyped for APOE and scored for AD neuropathology. Results: Methylation levels within the TOMM40 CpG island in the promoter or APOE CpG island in Exon 4 did not differ between APOE ɛ4 carriers versus non-carriers. However, APOE ɛ4 carriers had significantly higher methylation the APOE promoter compared with non-carriers. Although DNA methylation at TOMM40, APOE promoter region, or APOE did not differ between AD pathological groups, there was a negative association between TOMM40 methylation and CERAD scores. ApoE protein concentrations did not significantly different between APOE ɛ4 carriers and non-carriers, or between AD pathological groups. Finally, there was no correlation between ApoE protein concentrations and DNA methylation levels. Conclusion: APOE gene methylation may not be affected by genotype, relate to AD pathology or ApoE protein levels in the superior frontal gyrus, though, DNA methylation at the ApoE promoter differed between genotype. DNA methylation at TOMM40 associated with amyloid-β plaques and longitudinal fluid intelligence. In sum, these results suggest a complicated regulation of the TOMM40-APOE locus in the brain in controlling ApoE protein levels and AD neuropathology.

Association of ApoE gene polymorphisms with serum lipid levels and the risk of type 2 diabetes mellitus in the Chinese Han population of central China

“…These discrepancies may be due to racial and geographical differences. The two ApoE polymorphisms, rs429358 and rs7412 , are located in the coding region of exon 4, which overlaps with a clearly defined CpG island, distinguishing the three prevalent ApoE alleles, ɛ 2, ɛ 3, and ɛ 4 ( Bezuch et al, 2021 ). Both SNPs alter the number of CpG dinucleotides, which are the main locations for DNA methylation, in addition to the protein codon.…”

TOMM40 Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease

“…A high-density whole-genome association study showed strong associations between SNPs neighboring the APOE loci and AD risk [ 11 ]. Although APOE is a strong risk factor for AD, it is believed that additional factors with the APOE locus contribute to the pathogenesis of AD [ 18 , 45 , 46 ]. The TOMM40 gene is within APOE -surrounding regions and is located in proximity to the APOE gene [ 18 , 46 ].…”

“…Although APOE is a strong risk factor for AD, it is believed that additional factors with the APOE locus contribute to the pathogenesis of AD [ 18 , 45 , 46 ]. The TOMM40 gene is within APOE -surrounding regions and is located in proximity to the APOE gene [ 18 , 46 ]. DNA samples from 80 Taiwanese AD patients were examined using a targeted panel of whole-genome sequencing.…”

“…Other genetic modifiers are likely to contribute to the pathogenesis of AD in Asian patients [ 46 , 53 ]. Genetic variants in the TOMM40 - APOE locus could increase the susceptibility of AD [ 18 , 46 , 54 , 55 , 56 ]. The TOMM40 gene adjacent to the APOE gene is in strong linkage disequilibrium with APOE [ 57 ].…”

“…TOMM40 is a channel-forming subunit of the mitochondrial TOMM complex that is required for protein import into mitochondria [ 16 ]. Many studies suggest that the TOMM40 gene may contribute to AD risk [ 17 , 18 ]. Single-nucleotide polymorphisms (SNPs) within the TOMM40 gene are associated with amyloid deposition and influence the metabolism of amyloid beta peptide (Aβ) [ 19 , 20 , 21 ].…”