A TOMM40/APOE allele encoding APOE‐E3 predicts high likelihood of late‐onset Alzheimer’s disease in autopsy cases

Abstract

Background The APOE ‐ε4 allele is an established risk factor for Alzheimer's disease (AD). TOMM40 located adjacent to APOE has also been implicated in AD but reports of TOMM40 associations with AD that are independent of APOE ‐ε4 are at variance. Methods We investigated associations of AD with haplotypes defined by three TOMM40 and two APOE single nucleotide polymorphisms in 73 and 71 autopsy cases with intermediate and high likelihood of AD (defined by BRAAK stages <V and V‐VI), respectively, and in 150 controls without major neurodegenerative diseases. Results We observed eight haplotypes with a frequency >0.02. The two haplotypes encoding APOE ‐E4 showed strong associations with AD that did not differ between intermediate and high likelihood AD. In contrast, a TOMM40 haplotype encoding APOE‐ E3 was identified as risk haplotype of high‐ ( p = .0186), but not intermediate likelihood AD ( p = .7530). Furthermore, the variant allele of rs2075650 located in intron 2 of TOMM40 , increased the risk of high‐, but not intermediate likelihood AD on the APOE ‐ε3/ε3 background ( p = .0230). Conclusion The striking association of TOMM40 only with high likelihood AD may explain some contrasting results for TOMM40 in clinical studies and may reflect an association with more advanced disease and/or suggest a role of TOMM40 in the pathogenesis of neurofibrillary tangles.

Reassessment of Pioglitazone for Alzheimer’s Disease

“…TOMM40 encodes the mitochondrial protein import channel, and is indispensable for maintaining mitochondrial homeostasis ( Baker et al, 1990 ; Taylor et al, 2003 ) and for life ( Zeh, 2013 ). Multiple SNPs in TOMM40 are associated with AD risk independently of the APOE gene., including rs7259620 ( Takei et al, 2009 ; Nazarian et al, 2019 ), rs760136 ( Marioni et al, 2018 ), rs2075650 ( He et al, 2016 ; Huang et al, 2016 ; Bussies et al, 2020 ; Soyal et al, 2020 ; Squillario et al, 2020 ), and rs10524523 ( Roses, 2010 ; Li et al, 2013 ; Yu et al, 2017a , b ). Both APOC1 and PVRL2 fit the pattern of being lipid- or immune-related.…”

Advances in Genetics and Epigenetic Alterations in Alzheimer’s Disease: A Notion for Therapeutic Treatment

“…However, more recent results based on gene haplotypes have shown a strong influence of the regulated expression of the gene in the brain [ 79 ]. Similarly, several association studies have shown mixed results regarding the association of TOMM40 (outer mitochondrial membrane translocase 40) with AD and the dysregulation of mitochondrial function independent of ApoE4 [ 80 , 81 ], but a recent haplotype study showed differences between TOMM40 haplotypes encoding ApoE4 and ApoE3 in the association probability for AD [ 82 ].…”

An increase in mitochondrial TOM activates apoptosis to drive retinal neurodegeneration

“…However, this does not explain why APOE and TOMM40 are independently linked to age of onset distributions for Alzheimer’s disease 15 , and why in individuals homozygous for APOE ε3 ( i.e. null for the ε4 allele), distinct TOMM40 variants differentially increase disease risk and age of onset 16 , 17 . There is a growing appreciation that upregulated TOMM40 gene expression due to TOMM40 polymorphisms is sufficient to predispose individuals to Alzheimer’s disease 16 , 18 – 21 , and an emerging school of thought endorses TOMM40 as an independent genetic determinant of Alzheimer’s pathology 22 , 23 .…”