We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We have now analyzed additional samples with a ...confirmed pathologic diagnosis of late-onset Alzheimer disease (LOAD; final n = 188 controls, 176 cases). Nine percent of the cortical transcripts that we analyzed had expression profiles correlated with their genotypes in the combined cohort, and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate-gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power for discovering risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease.
It is widely assumed that genetic differences in gene expression underpin much of the difference among individuals and many of the quantitative traits of interest to geneticists. Despite this, there ...has been little work on genetic variability in human gene expression and almost none in the human brain, because tools for assessing this genetic variability have not been available. Now, with whole-genome SNP genotyping arrays and whole-transcriptome expression arrays, such experiments have become feasible. We have carried out whole-genome genotyping and expression analysis on a series of 193 neuropathologically normal human brain samples using the Affymetrix GeneChip Human Mapping 500K Array Set and Illumina HumanRefseq-8 Expression BeadChip platforms. Here we present data showing that 58% of the transcriptome is cortically expressed in at least 5% of our samples and that of these cortically expressed transcripts, 21% have expression profiles that correlate with their genotype. These genetic-expression effects should be useful in determining the underlying biology of associations with common diseases of the human brain and in guiding the analysis of the genomic regions involved in the control of normal gene expression.
Abstract Previously we have shown that the H1c haplotype on the background of the H1 clade of haplotypes at the MAPT locus is associated with increased risk for progressive supranuclear palsy (PSP), ...corticobasal degeneration (CBD) and Alzheimer’s disease (AD). Here we replicated the association with AD in an additional autopsy confirmed series. We show that this haplotype increases both the expression of total MAPT transcript as well as specifically increasing the proportion of 4 microtubule binding repeat containing transcripts. We discuss these findings both in terms of the problems facing the dissection of the etiologies of complex traits and the pathogenesis of the tauopathies.
Background: In the United States alone, Type 2 Diabetes is the 7th leading cause of death, with Alzheimer’s Disease ahead as the 6th leading cause of mortality. While specific mechanisms have yet to ...be recognized by mainstream medicine, the term Type 3 Diabetes has been adopted to describe diabetes of the brain. Overarching commonalities amongst each disease include (a) oxidative stress, (b) inflammation, (c) mitochondrial dysfunction, and (d) neuroendocrine abnormalities. Collectively, these factors have been found to directly contribute to pro-death genes, impaired energy metabolism, and cerebral hypoperfusion. Yet, Type 2 Diabetes remains one of the most adjustable risk factors for the development of Alzheimer’s Disease. This dissertation explores the available literature on increasing the awareness of Type 3 Diabetes in terms of present and future implications.Methods: The review highlighted the following topics: (a) Alzheimer’s disease, (b) Types 1 and 2 diabetes, (c) insulin resistance and cognitive decline, (d) Type 3 diabetes (e) ApoE(4) genetic perturbations, (f) prevention and lifestyle support for Alzheimer’s disease, (g) prevention and lifestyle support for diabetes, (h) social and economic consequences of Alzheimer’s disease, (I) social and economic consequences of diabetes.Results: While AD is a complex disorder, there is a plethora of irrefutable research that supports viewing it as Type 3 Diabetes. Increasing patient education of Type 3 Diabetes and focusing on prevention strategies would decrease disease burden, increase quality of life and at the same time, save trillions of dollars in healthcare spending.Conclusions: Since there is no pharmaceutical cure for AD, increasing awareness of Type 3 Diabetes has the potential to provide patients with sustainable, integrative therapies, allowing them to become invested in their health choices. This will also promote individual accountability and a sense of conscientiousness in taking back one’s own health through lifestyle choices while reducing unnecessary suffering for patients, family members and society.
The apolipoprotein E (
APOE
) ε4 allele is the best established genetic risk factor for late-onset Alzheimer’s disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide ...polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In ε4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the
GRB
-associated binding protein 2 (
GAB2
) gene and a common haplotype encompassing the entire
GAB2
gene. SNP rs2373115 (p = 9 × 10
−11
) was associated with an odds ratio of 4.06 (confidence interval 2.81–14.69), which interacts with
APOE
ε4 to further modify risk.
GAB2
was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with
GAB2
gene expression increased tau phosphorylation. Our findings suggest that
GAB2
modifies LOAD risk in
APOE
ε4 carriers and influences Alzheimer’s neuropathology.
For late onset Alzheimer's disease (LOAD), the only confirmed, genetic association is with the apolipoprotein E (APOE) locus on chromosome 19. Meta-analysis is often employed to sort the true ...associations from the false positives. LOAD research has the advantage of a continuously updated meta-analysis of candidate gene association studies in the web-based AlzGene database. The top 30 AlzGene loci on May 1(st), 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathoiogicaiiy verified controls genotyped at 312,316 SNPs using the Affymetrix 500K Mapping Platform. Of the 30 "top AlzGenes", 32 SNPs in 24 genes had odds ratios (OR) whose 95% confidence intervals that did not include 1. Of these 32 SNPs, six were part of the Affymetrix 500K Mapping panel and another ten had proxies on the Affymetrix array that had >80% power to detect an association with α=0.001. Two of these 16 SNPs showed significant association with LOAD in our sample series. One was rs4420638 at the APOE locus (uncorrected p-value=4.58E-37) and the other was rs4293, located in the angiotensin converting enzyme (ACE) locus (uncorrected p-value=0.014). Since this result was nominally significant, but did not survive multiple testing correction for 16 independent tests, this association at rs4293 was verified in a geographically distinct German cohort (p-value=0.03). We present the results of our ACE replication aiongwith a discussion of the statistical limitations of multiple test corrections in whole genome studies.
The apolipoprotein E (APOE) ɛ4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide ...polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In ɛ4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 × 10−11) was associated with an odds ratio of 4.06 (confidence interval 2.81–14.69), which interacts with APOE ɛ4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE ɛ4 carriers and influences Alzheimer's neuropathology.
The apolipoprotein E (APOE) epsilon4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide ...polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In epsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer's neuropathology.
The apolipoprotein E (APOE) varepsilon4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide ...polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In varepsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from theGRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entireGAB2gene. SNP rs2373115 (p = 9 × 10-11) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts withAPOEvarepsilon4 to further modify risk.GAB2was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference withGAB2gene expression increased tau phosphorylation. Our findings suggest thatGAB2modifies LOAD risk inAPOEvarepsilon4 carriers and influences Alzheimer's neuropathology.
PDF
