A New Method to Identify Protein and Genes Involved in Alzheimer's Disease

Carlos Cruchaga, PhD
Washington University in St. Louis (St. Louis, MO)
Year Awarded:
2013
Grant Duration:
July 1, 2013 to June 30, 2016
Disease:
Alzheimer's
Award Amount:
$248,172
Grant Reference ID:
A2013359S
Award Type:
Standard
Award Region:
US Midwestern

Identification of Novel CSF Endophenotypes and Genetic Variants for AD by Mendelian Randomization

Summary

The identification of the proteins and genes that cause a neurodegenerative disease, such as Alzheimer's disease, is the first step to identify potential therapeutic targets and effective treatments. Previous studies have identified clusterin and VILIP1 proteins as potential risk factors or biomakers for Alzheimer's disease. In this project, Dr. Cruchaga’s team plans to use a very innovative approach, called Mendelian randomization, to confirm whether clusterin and VILIP1 are proteins involved in causing Alzheimer's disease. The team will perform genetic studies and measure the levels of these proteins and compare with the levels of two other proteins, called APOE and FABP, which are known to be involved in the development of Alzheimer's disease. These experiments should confirm whether clusterin and VILIP1 are new informative biomarkers, and additional genetic screens should identify whether other new genes are associated with Alzheimer's disease. Therefore, Dr. Cruchaga’s team may discover new targets for developing novel therapies.

Details

Alzheimer's disease (AD) is the most common neurodegenerative disease, but there is currently no effective prevention or treatment. The identification of rare gene mutations causing early-onset familial Alzheimer’s disease, and the latest genetic studies, have been key to understanding some of the mechanisms that cause AD. The long-term goal of Dr. Cruchaga’s research is to use novel and powerful approaches to identify new genes and protein variants associated with AD. These findings will lead to better diagnosis and treatment of this devastating disease.

The most promising biomarkers for AD are the cerebrospinal fluid (CSF) levels of the tau and A-beta proteins. Interestingly, brain tau and A-beta aggregates are the main neuropathological hallmarks of AD. In a recent study, in which we used CSF tau and A-beta protein levels for genetic studies, we were able to identify novel genes and variants implicated in AD. Recent studies from Washington University and other groups have identified CSF levels of Apoliprotein E (APOE), Clusterin (CLU), Fatty-acid binding protein (FABP), and Visinin-like protein 1 (VILIP-1) as potential biomarkers for AD. In the first part of this research, Dr. Cruchaga’s team will use novel statistical analysis (called Mendelian Randomization) to analyze whether these biomarkers are simply markers of the disease or whether these proteins are clearly associated with the development and progression of AD. In the second part of this project, the team will use the latest technologies in genetics to analyze more than 7 million genetic variants and 16,000 genes. They expect to identify novel genes and protein variants that are associated with AD, and to analyze the impact of those variants and genes in AD risk and disease progression.

Combining the discovery of new biomarkers with a comprehensive genetics analysis will help Dr. Cruchaga to identify the complex relationships between genes, proteins, and disease, which, in turn, will help to identify key proteins that could be future therapeutic targets.

About the Researcher

Dr. Cruchaga is an Assistant Professor of Psychiatry at Washington University School of Medicine. He received his doctoral studies on Biochemistry and Molecular Biology at the University of Navarra (Spain). After his doctoral studies, Dr. Cruchaga became interested in the genetics of neurodegenerative disease during his postdoctoral training at the Dr. Pau Pastor laboratory (University of Navarra). He then completed his postdoctoral training at Dr. Alison Goate's laboratory. Dr. Cruchaga's interests are focused on the identification and characterization of genetic variants implicated in Alzheimer’s disease (AD). The identification of such factors will help lead to a better understanding of the pathobiology of the disease and to the identification of new therapeutic targets.