Carlos CruchagaCarlos Cruchaga, Ph.D.
Assistant Professor of Psychiatry, Washington University in St. Louis, recipient of a 2011 New Investigator Research Grant

The research of Dr. Carlos Cruchaga has been inspired by the Human Genome Project and his own concerns about the devastating impact of Alzheimer’s disease. 

Research focus

The Human Genome Project was an international collaborative research effort to read and map all of the genes in the human body, which together are known as the human genome. Genes are made of a molecule called DNA (deoxyribonucleic acid) which contains the instructions for making every protein in the body. Proteins are large, complex molecules that control the structure and function of all cells in the body.

By studying the human genome, scientists can shed light on our risk for deadly diseases and identify novel ways to diagnose and treat these diseases. Certain genetic variations are known to promote some forms of early-onset Alzheimer's disease. Because these genetic variations are inherited, some families have many individuals with the same form of the disease. However, early-onset Alzheimer’s is relatively uncommon. People develop the late-onset form of Alzheimer’s in far larger numbers. Thus, it is important to understand the genetic factors that may increase risk for developing late-onset Alzheimer’s disease.

Recent studies have identified families that appear to develop inherited forms of late-onset Alzheimer's. With funding from a 2011 New Investigator Research Grant from the Alzheimer’s Association, Dr. Carlos Cruchaga and his team searched for dementia-related genetic variations in some of these families. Their results were published in 2014 in the journals Nature and Nature Medicine. The team identified variations in genes called phospholipase D3 (PLD3) and UNC5C that appear to promote the risk of late-onset Alzheimer’s disease. These findings have inspired the team to search for other genes involved in increased risk for developing Alzheimer’s disease.

The Genetic Basis of Late-Onset Alzheimer’s

Dr. Cruchaga received his Association grant in 2011 for a study entitled "Exome Sequencing of Late-Onset Alzheimer's Disease Families." The exome is the part of the genome that contains exons — the portion of the gene that directly codes for making proteins. Disease-related genetic variations often occur in the exome, making it a key focus of medical research in recent years. Dr. Cruchaga selected 14 families known to have inherited forms of late-onset Alzheimer's disease. They then analyzed the exomes from certain members of these families, searching for gene variations linked to Alzheimer’s.

This process initially identified a variation in PLD3 that was shown to double the risk of Alzheimer’s disease in some cases. Previous research has found that people with Alzheimer’s tend to have lower than normal levels of the PLD3 protein in their brains. This finding indicates that PLD3 may protect the brain against Alzheimer’s-like changes. Specifically, PLD3 protein may help regulate the processing of another molecule called amyloid precursor protein (APP). APP is the “parent” molecule of beta-amyloid, a protein fragment associated with the brain cell damage and death that occurs in Alzheimer’s. By regulating how APP is processed, PLD3 protein may help prevent beta-amyloid levels from becoming abnormally high. Dr. Cruchaga hypothesizes that certain variations of the PLD3 gene make it less active than normal, which in turn may result in lowered PLD3 protein activity, increased beta-amyloid production in the brain and an increased risk for Alzheimer’s disease.

After identifying their initial Alzheimer’s-related gene, Dr. Cruchaga and colleagues performed genetic analyses of other large groups of individuals. These efforts yielded further noteworthy results. First, the researchers found additional PLD3 variations that may increase Alzheimer’s risk. They are now conducting experiments to learn more about the structure and function of PLD3 — and why certain PLD3 variations are so closely linked to the development of late-onset Alzheimer’s disease. Second, Dr. Cruchaga’s team identified a variation in another gene called UNC5C that may also double one’s risk for Alzheimer’s. People with this variation tend to be more susceptible to brain cell death from a variety of toxic molecules in the brain, including beta-amyloid. Moreover, the variation is highly expressed in the hippocampus, a brain region vital for learning and memory and highly vulnerable in early stages of Alzheimer’s disease. Dr. Cruchaga is now expanding his research efforts to analyze more than 300 families with inherited late-onset Alzheimer’s, with the hope of identifying still more gene variations linked to Alzheimer’s disease risk.

In addition, funding from the Alzheimer’s Association enabled Dr. Chuchaga’s research team to provide genetic data to a study led by Rita Guerreiro, Ph.D. Her study led to the identification of variations in the gene called TREM2 (triggering receptor expressed on myeloid cells) which have also been shown to increase Alzheimer’s risk. Dr. Guerreiro’s study was published in 2013 in the New England Journal of Medicine.

Unlocking the Secrets of the Human Genome

Dr. Cruchaga first became interested in Alzheimer’s research after finishing his Ph.D. at the University of Navarra in Spain. He was inspired by the Human Genome Project, which began in 1990 and was completed in 2003. “I was fascinated by the Human Genome Project and its implication in human diseases. The genes causing Alzheimer’s disease in early-onset families were already identified, but not much was known about the genetic component of late-onset Alzheimer’s disease. I was overwhelmed that such a devastating and important disease, in terms of impact on the population, had no cure at all. For other complex diseases, genetic findings were key to identifying and validating new treatments. Therefore, I wanted to investigate the potential impact that all the new knowledge from the Human Genome Project could have in Alzheimer’s disease.”

Dr. Cruchaga soon moved to Washington University in St. Louis, where he began searching for genes associated with Alzheimer’s risk in the laboratory of Dr. Alison Goate. By 2010, he had become an Assistant Professor of Psychiatry there—a position he holds today.

Impact of Association funding
For Dr. Cruchaga, support from the Alzheimer’s Association has had significance beyond his 2011 grant. It has also been crucial to the growth of his laboratory. “As a result,” he says, “now my lab is funded by the NIH (National Institutes of Health), the Michael J. Fox Foundation and BrightFocus Foundation. The research goals are still the identification and characterization of novel genes for neurodegenerative disease, but now we have the tools, personnel and funding to carry out (these) studies.” Dr. Cruchaga plans to search for biological links between Alzheimer’s disease and Parkinson’s disease. He notes that the two disorders “share some characteristics like protein aggregation and neuronal death,” and that they may share genetic components as well. His search for these genetic factors is now being supported by the Alzheimer’s Association in collaboration with the Michael J. Fox Foundation and the Weston Brain Institute.

Dr. Cruchaga also credits his success, in part, to the yearly Alzheimer’s Association International Conference (AAIC). At AAIC, he has met with and shared ideas with colleagues around the world who are working on similar research efforts. For him, such meetings have led to several “very productive collaborations and projects.”

For Dr. Cruchaga, the “genetics of Alzheimer’s Disease … is a very exciting and dynamic field. The technology is evolving extremely quickly and … it is difficult to be up to date about all the new advances. The good thing is that these advances allow us to do studies that were almost unconceivable a year ago. These studies will help to … understand the biology of the pathogenic events that lead to disease and identify new therapeutic targets. We think that by (studying) the genetic basis of Alzheimer’s disease, Parkinson’s disease and other neurodegenerative diseases, we will unravel the biological processes behind those diseases.” Such knowledge could improve our understanding of how Alzheimer’s and other dementias develop in the brain. It could also lead to more targeted, effective therapies for these devastating disorders.

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