Definitive roles of TOMM40-APOE-APOC1 variants in the Alzheimer's risk

Kulminski, Alexander M.; Philipp, Ian; Shu, Leonardo; Culminskaya, Irina

doi:10.1016/j.neurobiolaging.2021.09.009

Cited by 19 publications

(24 citation statements)

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“…Our analyses show that carriers of the ɛ4 allele and minor alleles of rs2075650 and/or rs12721046 have substantially smaller chances of living to 85+ years (this work) and have strikingly higher risks of AD (Kulminski et al, 2022) compared with the ɛ4 carriers who do not carry the minor alleles of these two SNPs. A naive expectation is that AD would explain at least a fraction of the association of the identified compound genotypes with survival to 85+ years (i.e., that the magnitude of β would be smaller when AD subjects are excluded).…”

Section: Discussionmentioning

confidence: 52%

“…Compound genotypes were constructed using three SNPs, which contributed to the exceptionally high risk of AD (Kulminski et al, 2022 ), rs429358 ( APOE , T/c; upper/lower case denotes here major/minor allele; allele “c” encodes the ε4 allele), rs2075650 ( TOMM40 , A/g), and rs12721046 ( APOC1 , G/a). To increase the sample size, we imputed (Michigan Imputation Server, HRC panel) missing genotypes for some subjects in each study and retained genotypes with high imputation quality ( r 2 > 0.8).…”

Section: Methodsmentioning

confidence: 99%

“…The meta-analysis showed that the one individual ( 111 Given that the compound genotypes comprising rs429358, rs2075650, and rs12721046 contributed to an exceptionally high risk of AD (Kulminski et al, 2022), we examined whether the exclusion of AD-affected subjects impacted the estimates of β for ɛ4 carriers who have at least one minor allele of rs2075650 or rs12721046 compared with those with major alleles of both SNPs (Figure 1 and Table S4). The study-specific analysis and meta-analysis showed that the chances of living to 85+ years without AD were consistently and substantially smaller (i.e., the βs were uniformly more negative and their statistical significances were uniformly larger in each analysis) than the results in Table S3 which were computed without consideration of AD status.…”

Section: F I G U R Ementioning

confidence: 99%

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APOE ɛ4 allele and TOMM40‐APOC1 variants jointly contribute to survival to older ages

et al. 2022

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Age‐related diseases characteristic of post‐reproductive life, aging, and life span are the examples of polygenic non‐Mendelian traits with intricate genetic architectures. Polygenicity of these traits implies that multiple variants can impact their risks independently or jointly as combinations of specific variants. Here, we examined chances to live to older ages, 85 years and older, for carriers of compound genotypes comprised of combinations of genotypes of rs429358 (APOE ɛ4 encoding polymorphism), rs2075650 (TOMM40), and rs12721046 (APOC1) polymorphisms using data from four human studies. The choice of these polymorphisms was motivated by our prior results showing that the ɛ4 carriers having minor alleles of the other two polymorphisms were at exceptionally high risk of Alzheimer's disease (AD), compared with non‐carriers of the minor alleles. Consistent with our prior findings for AD, we show here that the adverse effect of the ɛ4 allele on survival to older ages is significantly higher in carriers of minor alleles of rs2075650 and/or rs12721046 polymorphisms compared with their non‐carriers. The exclusion of AD cases made this effect stronger. Our results provide compelling evidence that AD does not mediate the associations of the same compound genotypes with chances to survive until older ages, indicating the existence of genetically heterogeneous mechanisms. The survival chances can be mainly associated with lipid‐ and immunity‐related mechanisms, whereas the AD risk, can be driven by the AD‐biomarker‐related mechanism, among others. Targeting heterogeneous polygenic profiles of individuals at high risks of complex traits is promising for the translation of genetic discoveries to health care.

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Section: Discussionmentioning

confidence: 52%

Section: Methodsmentioning

confidence: 99%

Section: F I G U R Ementioning

confidence: 99%

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APOE ɛ4 allele and TOMM40‐APOC1 variants jointly contribute to survival to older ages

et al. 2022

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“…This result is consistence with other findings regarding TOMM40 increase in the N 2 a cells by proteomic profiling (Mise et al, 2017 ) and in both hippocampal homogenates and CA3 pyramidal cells from ApoE4 mice by immunoblot (Orr et al, 2019 ). Owing to the linkage disequilibrium with APOE (Simonovitch et al, 2019 ), TOMM40 expression is closely associated with APOE expression (Mise et al, 2017 ), and APOE - TOMM40 - APOC1 variants are strongly associated with a high instance of AD (Gottschalk et al, 2014 ; Kulminski et al, 2022 ). With increasing age, APOE ε4 has closely linked to various TOMM40 polymorphisms carried adverse impacts (Roses et al, 2013 ; Li et al, 2022 ), and alter the distribution and function of the TOMM40 haplotypes (Roses et al, 2010 ).…”

Section: Apoe4 and Mitophagy-specific Processes In Admentioning

confidence: 99%

A Review of ApoE4 Interference Targeting Mitophagy Molecular Pathways for Alzheimer's Disease

Chen

Jiang

et al. 2022

Front. Aging Neurosci.

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Alzheimer's disease (AD) is one of the major worldwide causes of dementia that is characterized by irreversible decline in learning, memory loss, and behavioral impairments. Mitophagy is selective autophagy through the clearance of aberrant mitochondria, specifically for degradation to maintain energy generation and neuronal and synaptic function in the brain. Accumulating evidence shows that defective mitophagy is believed to be as one of the early and prominent features in AD pathogenesis and has drawn attention in the recent few years. APOE ε4 allele is the greatest genetic determinant for AD and is widely reported to mediate detrimental effects on mitochondria function and mitophagic process. Given the continuity of the physiological process, this review takes the mitochondrial dynamic and mitophagic core events into consideration, which highlights the current knowledge about the molecular alterations from an APOE-genotype perspective, synthesizes ApoE4-associated regulations, and the cross-talk between these signaling, along with the focuses on general autophagic process and several pivotal processes of mitophagy, including mitochondrial dynamic (DRP1, MFN-1), mitophagic induction (PINK1, Parkin). These may shed new light on the link between ApoE4 and AD and provide novel insights for promising mitophagy-targeted therapeutic strategies for AD.

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“…The rs12721046 resides in the downstream gene to APOE, Apolipoprotein C1 (APOC1), and has also been shown to be associated with the AD phenotype 19,41,42 . A recent study 43 suggests that a haplotype across the APOE locus consisting of rs2075650 (TOMM40) -APOE ε4 -rs12721046 (APOC1), has a stronger association with AD than the ε4 allele alone. This would support the suggestion from this investigation that TOMM40 contributes to the AD phenotype, however the SNP Kulminski and colleagues 43 identified, although is not in the BDR analysis and so therefore is absent from our analysis, on exploration of the clump tagged IGAP_S1 dataset, it was found that rs2075650 resided in the linkage disequilibrium block "clump1" at all measures of r 2 (0.1-0.9) and suggests it may be part of the association block of rs429358.…”

Section: Discussionmentioning

confidence: 99%

Utilising Polygenic Risk Score Analysis for AD to Determine the “Sphere of Influence” of the APOE Isoform SNPs

Farrell¹,

Brookes²

2022

J Neurol Neuromedicine

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The APOE gene and particularly the ε4 allele have been a long-established risk factor for Alzheimer’s disease (AD), demonstrating the largest genetic effect size in this complex disease. In light of the odds ratios observed for the risk allele, many studies disregard neighbouring association signals as merely “tagging” this effect. Polygenic risk score (PRS) analyses in this field regularly use low linkage disequilibrium parameters (r2≥0.1) when selecting SNPs for analysis across the genome and remove kilobases of data surrounding the APOE locus, preventing confounding factors influencing their results. This study investigated a 500kb region surrounding the APOE locus, utilising PRS analysis to explore whether additional SNPs in this region could be providing contributory effects to AD predictability. The data presented here suggest that the “sphere of influence” of the APOE isoform SNPs covers a region of around 92kb; SNPs in Linkage Disequilibrium (LD) at r2<0.4 with rs429358 potentially contribute independently to the PRS predictability for AD, and that there are additional independent SNPs in this region that have increased effects in an APOE ε4 negative sample. This study concludes that further consideration is required when selecting LD parameters for PRS analysis and that additional investigation into the region surrounding APOE may yield polymorphisms that may play a pivotal role in the development of AD.

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Definitive roles of TOMM40-APOE-APOC1 variants in the Alzheimer's risk

Cited by 19 publications

References 50 publications

APOE ɛ4 allele and TOMM40‐APOC1 variants jointly contribute to survival to older ages

APOE ɛ4 allele and TOMM40‐APOC1 variants jointly contribute to survival to older ages

A Review of ApoE4 Interference Targeting Mitophagy Molecular Pathways for Alzheimer's Disease

Utilising Polygenic Risk Score Analysis for AD to Determine the “Sphere of Influence” of the APOE Isoform SNPs

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