Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39: 17-23

Harvard University, Cambridge, Massachusetts, United States
Nature Genetics (Impact Factor: 29.35). 02/2007; 39(1):17-23. DOI: 10.1038/ng1934
Source: PubMed


The past decade has witnessed hundreds of reports declaring or refuting genetic association with putative Alzheimer disease susceptibility genes. This wealth of information has become increasingly difficult to follow, much less interpret. We have created a publicly available, continuously updated database that comprehensively catalogs all genetic association studies in the field of Alzheimer disease ( We performed systematic meta-analyses for each polymorphism with available genotype data in at least three case-control samples. In addition to identifying the epsilon4 allele of APOE and related effects, we pinpointed over a dozen potential Alzheimer disease susceptibility genes (ACE, CHRNB2, CST3, ESR1, GAPDHS, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF) with statistically significant allelic summary odds ratios (ranging from 1.11-1.38 for risk alleles and 0.92-0.67 for protective alleles). Our database provides a powerful tool for deciphering the genetics of Alzheimer disease, and it serves as a potential model for tracking the most viable gene candidates in other genetically complex diseases.

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    • "However, accumulating evidence and a plethora of genome-wide association studies (GWAS) link LOAD to a fast growing number of genetic risk factors and it seems feasible that these genetic risk factors result in LOAD due to changes at the transcriptome and proteome level. Indeed, in our hippocampal aging study in mice, we found up-regulation of several homologs, interaction partners or other closely related genes to almost all genes that appear to be the top 10 single genetic risk factors for LOAD as designated by the AlzGene database (Bertram et al., 2007). Of particular interest in light of our data is the gene coding for complement receptor 1 (CR1), since this receptor binds processed C4 and C3 complement proteins including the products of the C4b gene, which we found to be most prominently up-regulated in the aging hippocampus. "
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    ABSTRACT: Aging is accompanied by gradually increasing impairment of cognitive abilities and constitutes the main risk factor of neurodegenerative conditions like Alzheimer's disease (AD). The underlying mechanisms are however not well understood. Here we analyze the hippocampal transcriptome of young adult mice and two groups of mice at advanced age using RNA sequencing. This approach enabled us to test differential expression of coding and non-coding transcripts, as well as differential splicing and RNA editing. We report a specific age-associated gene expression signature that is associated with major genetic risk factors for late-onset AD (LOAD). This signature is dominated by neuroinflammatory processes, specifically activation of the complement system at the level of increased gene expression, while de-regulation of neuronal plasticity appears to be mediated by compromised RNA splicing.
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    • "Several genetic association studies have identified common variants of genes including CLU (clusterin), BIN1 (bridging integrator 1), and PICALM (phosphatidylinositol binding clathrin assembly protein) as potential LOAD related risk genes [24]. Invertebrate orthologs of these genes (Table 1) have been associated with cellular cytoskeletal dynamics, clathrin-mediated endocytosis, and postsynaptic exocytosis [64] [65] [66] [67]. "

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    • "In addition, identification of such proteins has greatly facilitated studies at revealing the molecular events underlying neurodegenerative diseases. Research conducted in recent years has revealed the involvement of the oxidoreductase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in AD pathology [11] [12] [13]. Genetics and neuroproteomics have revealed high affinity interactions between GAPDH and neurodegenerative disease-associated proteins, including the b-amyloid (Ab) precursor protein (AbPP), Ab and neurofibrillary tangles. "
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    ABSTRACT: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a ubiquitous enzyme that catalyzes the sixth step of glycolysis and thus, serves to break down glucose for energy production. Beyond the traditional aerobic metabolism of glucose, recent studies have highlighted additional roles played by GAPDH in non-metabolic processes, such as control of gene expression and redox post-translational modifications. Neuroproteomics have revealed high affinity interactions between GAPDH and Alzheimer's disease-associated proteins, including the β-amyloid, β-amyloid precursor protein and tau. This neuronal protein interaction may lead to impairment of the GAPDH glycolytic function in Alzheimer's disease and may be a forerunner of its participation in apoptosis. The present review examines the crucial implication of GAPDH in neurodegenerative processes and clarifies its role in apoptotic cell death.
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