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Ornit Chiba-Falek, William K Gottschalk, Michael W Lutz
The TOMM40 poly-T is a polymorphism in intron 6 of the TOMM40 gene, which is adjacent to and in linkage disequilibrium with APOE. Roses et al identified the association between the length of TOMM40 poly-T with the risk and age of onset of late-onset Alzheimer's disease (LOAD). Following the original discovery, additional studies found associations between the TOMM40 poly-T and LOAD-related phenotypes independent of APOE genotypes, while others did not replicate these associations. Furthermore, the identity of the TOMM40 poly-T risk allele has been controversial between different LOAD-related phenotypes...
March 7, 2018: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Anna Zettergren, Silke Kern, Lina Rydén, Svante Östling, Kaj Blennow, Henrik Zetterberg, Hanna Falk, Ingmar Skoog
Self-rated health (SRH) strongly predicts mortality. Twin studies estimate that genetic factors account for a substantial part of the variability in SRH. Variations in the gene FOXO3 (forkhead box O3), and in genes located at the APOE (apoplipoprotein E) locus, are associated with longevity. This study explores the relationship between SRH and genetic variation related to longevity, in a population-based cohort of older individuals. SRH was assessed among 1520 individuals aged 75 to 87, and five single nucleotide polymorphisms (SNPs), in APOE, TOMM40 (translocase of outer mitochondrial membrane 40 homolog), and FOXO3 were genotyped...
February 5, 2018: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Kahli Zietlow, Lefko Charalambous, Isaac Ng, Sonal Gagrani, Mirta Mihovilovic, Shuhong Luo, Daniel L Rock, Ann Saunders, Allen D Roses, W Kirby Gottschalk
No abstract text is available yet for this article.
January 27, 2018: Biochimica et Biophysica Acta
Yvonne Shao, McKenzie Shaw, Kaitlin Todd, Maria Khrestian, Giana D'Aleo, P John Barnard, Jeff Zahratka, Jagan Pillai, Chang-En Yu, C Dirk Keene, James B Leverenz, Lynn M Bekris
The apolipoprotein E (APOE) ε4 allele is the major genetic risk factor for Alzheimer's disease (AD). Multiple regulatory elements, spanning the extended TOMM40-APOE-APOC2 region, regulate gene expression at this locus. Regulatory element DNA methylation changes occur under different environmental conditions, such as disease. Our group and others have described an APOE CpG island as hypomethylated in AD, compared to cognitively normal controls. However, little is known about methylation of the larger TOMM40-APOE-APOC2 region...
January 25, 2018: Journal of Human Genetics
Chieh-Hsin Lin, Eugene Lin, Hsien-Yuan Lane
With ever-increasing elder populations, age-related cognitive decline, which is characterized as a gradual decline in cognitive capacity in the aging process, has turned out to be a mammoth public health concern. Since genetic information has become increasingly important to explore the biological mechanisms of cognitive decline, the search for genetic biomarkers of cognitive aging has received much attention. There is growing evidence that single-nucleotide polymorphisms (SNPs) within the ADAMTS9, BDNF, CASS4, COMT, CR1, DNMT3A, DTNBP1, REST, SRR, TOMM40 , circadian clock, and Alzheimer's diseases-associated genes may contribute to susceptibility to cognitive aging...
2017: Frontiers in Psychiatry
Akira Nishimura, Hidenori Nonomura, Shingo Tanaka, Michihiro Yoshida, Yuka Maruyama, Yutaka Aritomi, Ann M Saunders, Daniel K Burns, Michael W Lutz, Grant Runyan, Eric Lai, Kumar Budur, Allen D Roses
Introduction: Dementia is one of the major health threats to our aging society, and Alzheimer's disease (AD) is the leading cause. In Japan, ∼15% of the elderly population has dementia. The apolipoprotein E ( APOE ) genotype and a polymorphism (rs10524523) in the translocase of outer mitochondrial membrane 40 ( TOMM40 ) gene have been associated with the age of onset of AD. However, differences in allele frequencies of these markers in different ethnic populations are not well known...
November 2017: Alzheimer's & Dementia: Translational Research & Clinical Interventions
Anatoliy I Yashin, Fang Fang, Mikhail Kovtun, Deqing Wu, Matt Duan, Konstantin Arbeev, Igor Akushevich, Alexander Kulminski, Irina Culminskaya, Ilya Zhbannikov, Arseniy Yashkin, Eric Stallard, Svetlana Ukraintseva
Despite evident success in clarifying many important features of Alzheimer's disease (AD) the efficient methods of its prevention and treatment are not yet available. The reasons are likely to be the fact that AD is a multifactorial and heterogeneous health disorder with multiple alternative pathways of disease development and progression. The availability of genetic data on individuals participated in longitudinal studies of aging health and longevity, as well as on participants of cross-sectional case-control studies allow for investigating genetic and non-genetic connections with AD and to link the results of these analyses with research findings obtained in clinical, experimental, and molecular biological studies of this health disorder...
October 26, 2017: Experimental Gerontology
Ji Seon Shim, Min-Young Song, Sung-Vin Yim, Seung-Eun Lee, Kang-Sik Park
BACKGROUND: A number of reports have described the protective effects of ginsenoside Rg1 (Rg1) in Alzheimer's disease (AD). However, the protective mechanisms of Rg1 in AD remain elusive. METHODS: To investigate the potential mechanisms of Rg1 in β-amyloid peptide-treated SH-SY5Y cells, a comparative proteomic analysis was performed using stable isotope labeling with amino acids in cell culture combined with nano-LC-MS/MS. RESULTS: We identified a total of 1,149 proteins in three independent experiments...
October 2017: Journal of Ginseng Research
Peter Petschner, Xenia Gonda, Daniel Baksa, Nora Eszlari, Michael Trivaks, Gabriella Juhasz, Gyorgy Bagdy
Mitochondria densely populate cells in central nervous system providing essential energy for neurons and influencing synaptic plasticity. Harm to these organelles can impair cognitive performance through damaged neurotransmission and altered Ca(2+) homeostasis. Impaired cognition could be one underlying factor which can characterize major depressive disorder, a huge burden for society marked by depressed mood and anhedonia. A growing body of evidence binds mitochondrial dysfunctions with the disease. Cognitive disturbances with different severity are also observable in several patients, suggesting that damage or inherited alterations of mitochondria may have an important role in depression...
October 5, 2017: Neuroscience
Ayano Mise, Yuta Yoshino, Kiyohiro Yamazaki, Yuki Ozaki, Tomoko Sao, Taku Yoshida, Takaaki Mori, Yoko Mori, Shinichiro Ochi, Jun-Ichi Iga, Shu-Ichi Ueno
BACKGROUND: TOMM40 is located on chromosome 19, is in linkage disequilibrium with apolipoprotein E (APOE), andis reported in several genome-wide association studies to be associated with Alzheimer's disease (AD). OBJECTIVE: Assess APOE and TOM40 and mitochondrial genes as blood biomarkers for AD. METHODS: We examined TOMM40, PTEN-induced putative kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (PARK2), and APOE mRNA expression in relation to the methylation rates of CpG sites in the upstream region of TOMM40exon 1 in peripheral leukocytes and TOMM40523 polyT genotypes in 60 AD and age- and sex-matched control subjects...
2017: Journal of Alzheimer's Disease: JAD
Ornit Chiba-Falek, Michael W Lutz
INTRODUCTION: Developing biomarker tools for identification of individuals at high-risk for late-onset Alzheimer's disease (LOAD) is important for prognosis and early treatment. This review focuses on genetic factors and their potential role for precision medicine in LOAD. AREAS COVERED: APOEe4 is the strongest genetic risk factor for non-Mendelian LOAD, and the APOE-linkage disequilibrium (LD) region has produced the most significant association signal in multi-center genome-wide-association-studies (GWAS)...
2017: Expert Review of Precision Medicine and Drug Development
Vladimir N Babenko, Dmitry A Smagin, Natalia N Kudryavtseva
ApoE expression status was proved to be a highly specific marker of energy metabolism rate in the brain. Along with its neighbor, Translocase of Outer Mitochondrial Membrane 40 kDa (TOMM40) which is involved in mitochondrial metabolism, the corresponding genomic region constitutes the neuroenergetic hotspot. Using RNA-Seq data from a murine model of chronic stress a significant positive expression coordination of seven neighboring genes in ApoE locus in five brain regions was observed. ApoE maintains one of the highest absolute expression values genome-wide, implying that ApoE can be the driver of the neighboring gene expression alteration observed under stressful loads...
September 13, 2017: Journal of Integrative Bioinformatics
Xia-Fang Wang, Xu Lin, Ding-You Li, Rou Zhou, Jonathan Greenbaum, Yuan-Cheng Chen, Chun-Ping Zeng, Lin-Ping Peng, Ke-Hao Wu, Zeng-Xin Ao, Jun-Min Lu, Yan-Fang Guo, Jie Shen, Hong-Wen Deng
BACKGROUND: Both type 2 diabetes (T2D) and Alzheimer's disease (AD) occur commonly in the aging populations and T2D has been considered as an important risk factor for AD. The heritability of both diseases is estimated to be over 50%. However, common pleiotropic single-nucleotide polymorphisms (SNPs)/loci have not been well-defined. The aim of this study is to analyze two large public accessible GWAS datasets to identify novel common genetic loci for T2D and/or AD. METHODS AND MATERIALS: The recently developed novel conditional false discovery rate (cFDR) approach was used to analyze the summary GWAS datasets from International Genomics of Alzheimer's Project (IGAP) and Diabetes Genetics Replication And Meta-analysis (DIAGRAM) to identify novel susceptibility genes for AD and T2D...
September 15, 2017: Journal of the Neurological Sciences
Thalida E Arpawong, Neil Pendleton, Krisztina Mekli, John J McArdle, Margaret Gatz, Chris Armoskus, James A Knowles, Carol A Prescott
Verbal memory is typically studied using immediate recall (IR) and delayed recall (DR) scores, although DR is dependent on IR capability. Separating these components may be useful for deciphering the genetic variation in age-related memory abilities. This study was conducted to (a) construct individual trajectories in IR and independent aspects of delayed recall, or residualized-DR (rDR), across older adulthood; and (b) identify genetic markers that contribute to four estimated phenotypes: IR and rDR levels and changes after age 60...
2017: PloS One
Kahli Zeitlow, Lefko Charlambous, Isaac Ng, Sonal Gagrani, Mirta Mihovilovic, Shuhong Luo, Daniel L Rock, Ann Saunders, Allen D Roses, W Kirby Gottschalk
A variable-length poly-T variant in intron 6 of the TOMM40 gene, rs10524523, is associated with risk and age-of-onset of sporadic (late-onset) Alzheimer's disease. In Caucasians, the three predominant alleles at this locus are Short (S), Long (L) or Very long (VL). On an APOE ε3/3 background, the S/VL and VL/VL genotypes are more protective than S/S. The '523 poly-T has regulatory properties, in that the VL poly-T results in higher expression than the S poly-T in luciferase expression systems. The aim of the current work was to identify effects on cellular bioenergetics of increased TOM40 protein expression...
November 2017: Biochimica et Biophysica Acta
Morten Krogh Christiansen, Sanne Bøjet Larsen, Mette Nyegaard, Søs Neergaard-Petersen, Ramzi Ajjan, Morten Würtz, Erik Lerkevang Grove, Anne-Mette Hvas, Henrik Kjærulf Jensen, Steen Dalby Kristensen
INTRODUCTION: Genetic constitution and inflammation both contribute to development of coronary artery disease (CAD). Several CAD-associated single-nucleotide polymorphisms (SNPs) have recently been identified, but their functions are largely unknown. We investigated the associations between CAD-associated SNPs and five CAD-related inflammatory biomarkers. METHODS: We genotyped 45 CAD-associated SNPs in 701 stable CAD patients in whom levels of high-sensitivity C-reactive protein (hsRCP), interleukin-6, calprotectin, fibrinogen and complement component 3 levels had previously been measured...
2017: PloS One
Lei Yu, Michael W Lutz, Robert S Wilson, Daniel K Burns, Allen D Roses, Ann M Saunders, Jingyun Yang, Chris Gaiteri, Philip L De Jager, Lisa L Barnes, David A Bennett
Patterns of linkage between the ε4 allele of Apolipoprotein E (APOE) and '523 poly-T alleles in the adjacent gene, TOMM40, differ between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer's disease (AD) is unclear. We compared the APOE ε4-TOMM40 '523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia. Data came from three community based cohort studies of diverse participants. APOE genotypes were determined by polymorphisms of rs429358 and rs7412...
2017: PloS One
Zengpeng Han, Han Huang, Yue Gao, Qingyang Huang
Genome-wide association studies (GWASs) discovered a number of SNPs and genes associated with Alzheimer's disease (AD). However, how these SNPs and genes influence the liability to AD is not fully understood. We deployed computational approaches to explore the function and action mechanisms of AD -related SNPs and genes identified by GWASs, including the effects of 195 GWAS lead SNPs and 338 proxy SNPs on miRNAs binding and protein phosphorylation, their RegulomeDB and 3DSNP scores, and gene ontology, pathway enrichment and protein-protein interaction network of 126 AD-associated genes...
2017: PloS One
Jin Li, Qiushi Zhang, Feng Chen, Xianglian Meng, Wenjie Liu, Dandan Chen, Jingwen Yan, Sungeun Kim, Lei Wang, Weixing Feng, Andrew J Saykin, Hong Liang, Li Shen
The pathogenic relevance in Alzheimer's disease (AD) presents a decrease of cerebrospinal fluid amyloid-ß42 (Aß42) burden and an increase in cerebrospinal fluid total tau (T-tau) levels. In this work, we performed genome-wide association study (GWAS) and genome-wide interaction study of T-tau/Aß42 ratio as an AD imaging quantitative trait on 843 subjects and 563,980 single-nucleotide polymorphisms (SNPs) in ADNI cohort. We aim to identify not only SNPs with significant main effects but also SNPs with interaction effects to help explain "missing heritability"...
September 2017: Neurobiology of Aging
Lei Yu, Michael W Lutz, Jose M Farfel, Robert S Wilson, Daniel K Burns, Ann M Saunders, Philip L De Jager, Lisa L Barnes, Julie A Schneider, David A Bennett
INTRODUCTION: The study investigated the role of neuropathologies in the relationship between TOMM40 '523 genotype and late-life cognitive decline. METHODS: Participants were community-dwelling older persons who had annual cognitive assessments and brain autopsies after death. Genotyping used DNA from peripheral blood or postmortem brain tissue. Linear mixed models assessed the extent to which the association of '523 genotype with cognitive decline is attributable to neuropathologies...
December 2017: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
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