Converging on 9 Areas of Focus

Whole Genome Sequencing and Epigenetics

Whole Genome Sequencing constitutes Phase III of the Alzheimer’s Genome Project™. While Phases I and II informed us which genes are implicated in risk for Alzheimer’s disease, this study will allow us to assess the entire human genome, including the 96 percent that is not made up of “genes,” per se, but instead includes the DNA that regulates the activity of the genes. Having attempted to identify all of the genes involved in Alzheimer’s disease susceptibility, we now will determine all of the DNA variants in the Alzheimer’s genes that directly influence risk for the disease, and determine all of the DNA variants in the intergenic portions of the genome that regulate the activities of the Alzheimer’s genes.

While much of Alzheimer’s risk and susceptibility is likely to be determined by changes in genes and DNA that are inherited, it also is possible that some of the risk may be a result of epigenetic changes, which modify the activation and pattern of expression of specific genes but do not modify the DNA sequence itself.

By studying Alzheimer’s genes, intergenic DNA and epigenetics, we will determine exactly how each Alzheimer’s gene functionally affects risk for the disease at the biological level. These findings then will be used not only to better understand the causes of Alzheimer’s disease, but also to guide drug discovery efforts to slow down, stop, or perhaps even reverse the disease process. 

 
 

  

Project Description Researchers
CIRCUITS: Production Center for Reference and Variation Gene-Regulatory Maps

Alzheimer’s disease is a devastating neurodegenerative disorder, afflicting 1 in 3 dying seniors and costing $236 billion annually in the United States alone. Its prevalence is increasing rapidly in an aging population, and currently there is no cure. Recent genetic studies provide new hope for therapeutic avenues, but translating genetic results into therapeutics has been remarkably difficult, due primarily to the fact that most genetic mutations do not alter protein function directly, but instead affect the expression of nearby genes in subtle ways.

CIRCUITS: Functional Analysis of Alzheimer’s Disease Risk Genes Using Human-Induced Pluripotent Stem Cells

The vast majority of people with Alzheimer’s disease (AD) suffer from the sporadic, or late-onset form, which causes remain completely unknown. From studies involving thousands of people, researchers have identified a number of genetic variants that may increase one’s risk for sporadic AD. However, little is understood regarding why these small changes impact one’s risk to develop AD. In this work, we will use the cutting-edge genome editing technique CRISPR/Cas9 to introduce AD-associated genetic variants identified through genome-wide analysis into reprogrammed human stem cells.

Analytical and Statistical Tools for Sequence Analysis for Alzheimer's Disease

The availability of next generation sequencing data in large scale association studies for Alzheimer’s disease provides a unique research opportunity. The data contains the information that is required to identify causal disease susceptibility loci (DSL) for Alzheimer’s disease and many other mental health phenotypes and psychiatric diseases. In order to translate the wealth of information into DSL discovery for Alzheimer’s disease, powerful statistical methodology is required. So far, a large number of rare variant association tests have been proposed.

Search for Female-Specific Genetic Factors Contributing to Risk for Alzheimer’s Disease

This multidimensional investigation will seek to elucidate sex-linked factors that determine Alzheimer’s disease risk, age of onset and rate of progression, powerful information that would contribute to the pursuit of a cure for both sexes. Women make up more than two-thirds of the Alzheimer’s patient population, yet very little is known or understood about why this is the case or what it means about the disease’s mechanisms of action, risk factors and progression.

CIRCUITS: Whole Genome Characterization of DNA Methylation Changes in the Aged and Alzheimer’s Disease Human Brain

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. Both normal aging and Alzheimer’s disease have been correlated with changes to the patterns of DNA methylation in the brain. DNA methylation is an epigenetic mark with the capacity to stably alter gene expression. The importance of changes to DNA methylation in AD has been difficult to assess. This proposed work would characterize the alterations of genome-wide DNA methylation patterns in post-mortem human neurons in the context of normal aging and AD.

CIRCUITS: Utilizing Functional Maps to Prioritize Therapeutic Targets in Alzheimer’s Disease

Discovery of the causes of and treatment for Alzheimer’s is confounded by the complexity of the disease, the interplay between environment and genetic bases of disease and the disparate approaches taken by groups to look at specific aspects of the disease. Progress has been slow and there is an urgent need to deliver treatments that are effective and have few side effects. Current studies seek specific genes as treatment targets. Usually there is a strong bias by a single group as to which genes and processes they think are responsible for the disease. Failure rates are high.

CIRCUITS: Epigenetic Determinants of Human Cognitive Aging

Much like many other human traits, cognitive decline and the development of Alzheimer's disease (AD) are determined by the concerted action of genetic, epigenetic and nongenetic factors. Over the last decade, genetics research in AD has progressed at unprecedented pace owing to the application of high-throughput genotyping technologies in the context of genome-wide association studies (GWAS).

CIRCUITS: Interpreting Alzheimer’s Disease-Associated Genetic Variation at Enhancer Regions

Treating Alzheimer’s disease (AD) is one of the greatest challenges we face in the coming years; the disease has the potential to have an enormous impact on human health. Despite its importance, there still are no highly effective treatments for AD, due in large part to a limited understanding of the underlying disease mechanisms. Our laboratory, as a member of CIRCUITS (Consortium to Infer Regulatory Circuits and to Uncover Innovative Therapeutic Strategies), aims to make progress toward a cure using genomic approaches.

CIRCUITS: IPS Cells and the Human Brain

There is no doubt that iPS cells derived from peripheral cells have enormous promise for personalized medicine, biomarker development, individualized treatment strategies and fundamental understanding of neurodegenerative disease. The ability to differentiate fibroblasts, for example, into relevant central nervous system cells, including cells that appear to be neurons and glia, is fascinating new science. Yet the connection between the cells that are in the dish, and the actual neurons and glia in the brain of the same individual, is truly unknown.