2022 Zenith Fellows Award Program (ZEN)

Detailed Proteomic Landscape of Alzheimer Disease

How are different proteins involved in biological pathways active in Alzheimer’s?

Carlos Cruchaga, Ph.D.
Washington University in St.Louis
St. Louis, MO - United States

Background

Large-scale genome-wide association studies (called GWAS) use data from large groups of individuals to identify genetic factors associated with different diseases, including increased or decreased risk of developing Alzheimer’s. GWAS for Alzheimer’s have identified several genes associated with disease risk; however, even for known risk genes, little is understood about how genetic variation leads to changes in biological pathways resulting in brain cell death (neurodegeneration).

Gene variations can have widespread impacts on biological pathways, including gene activity and protein production. Researchers use advanced computational methods known as “omics” to study some of these factors. For example, proteomics is the study of the structure and functions of proteins made by cells, while transcriptomics is the study of how gene activity is turned “on” or “off” within a cell. A new approach involves using multiple omics analyses on the same dataset (e.g., combining genomics, proteomics, and transcriptomics) in order to reveal the underlying biological mechanisms associated with gene variations.

Research Plan

Dr. Carlos Cruchaga and colleagues will use genetic and omic data to better understand how genetic variation leads to neurodegeneration and cognitive impairment in Alzheimer’s. In particular, the researchers will generate and analyze the proteomic (protein) profiles of biological samples from individuals who had Alzheimer’s. 

First, Dr. Cruchaga and team will identify proteomic signatures associated with Alzheimer’s, as well as proteomic signatures unique to individuals with specific genetic risk factors for Alzheimer’s. They will use samples including blood, cerebrospinal fluid (CSF, the biological fluid surrounding the brain and spinal cord), and brain tissue from individuals in the Knight-Alzheimer’s Disease Research Center, the Dominantly Inherited Alzheimer Network (DIAN), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Next, the researchers will use a statistical method called quantitative trait locus analysis; this method allows the research team to identify the genes and gene variations associated with the identified proteins. 

Finally, Dr. Cruchaga and colleagues will validate their findings using a specialized type of stem cell collected from adult human tissue called iPSCs (induced pluripotent stem cells), which can be reprogrammed to grow into any type of cell in the body the researchers will induce iPSCs from individuals with Alzheimer’s into nerve cells and brain support cells grown in laboratory dishes. This study will work to validate their initial omics work.

Impact

This project may uncover new genes, proteins, and biological pathways involved in Alzheimer’s. The findings may also lead to the identification of new biological markers (“biomarkers”) of Alzheimer’s and new therapeutic targets for the prevention or treatment of the disease.