Uncovering the regulatory roots of orphaned familial Alzheimer's Disease

The recent development of FDA-approved therapies that reduce the burden of amyloid plaques in the brains of Alzheimer’s disease patients has brought new hope for an otherwise untreatable disease. However, these therapies have provided minimal clinical benefit in individuals with established disease, leading many to believe that earlier intervention is key to therapeutic success. But how do we identify who will develop disease before it starts? In Alzheimer’s disease, most of the risk for disease is dictated by genetics. Using a combination of deep learning and functional genomics screens, my laboratory seeks to uncover the genetic drivers of Alzheimer’s disease scattered throughout our genomes. These discoveries will simultaneously identify new genetic drivers of disease that could serve as therapeutic targets, and guide earlier and more accurate clinical risk stratification. As the AD therapeutic landscape evolves over the next decade and more options exist for patients, this improved risk stratification and novel target identification will form the backbone of earlier and more effective interventions that are targeted towards individuals at risk for AD, rather than those already suffering from the irreversible neurodegeneration that is its hallmark.

Dr. Ryan Corces is a molecular and computational biologist studying the genetic alterations that increase our risk for developing neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. He is an assistant investigator at the Gladstone Institute of Neurological Disease and an assistant professor in the Department of Neurology at the University of California San Francisco. The Corces Lab uses a mixture of computational and functional approaches to predict and refine which genetic alterations might be impactful in controlling our risk for disease. They maintain a particular focus on alterations in the noncoding genome, which controls how and when genes are expressed. Dr. Corces trained in molecular biology and computer science at Princeton University. He earned his PhD in cancer biology at Stanford University, where he studied the genetic evolution of leukemias under the mentorship of Dr. Ravi Majeti. He went on to complete his postdoctoral training in the laboratories of Drs. Howard Chang and Thomas Montine studying the role of the epigenome in disease. His work has and continues to leverage donated human tissues to make fundamental discoveries on what causes disease.

Alzheimer’s disease (AD) is often classified as either “familial” or “sporadic”. In medical terms, “familial AD” often refers to disease caused by inherited mutations in a small number of genes, whereas “sporadic” disease lacks a clear genetic origin. These familial mutations are rare, and by this definition, familial AD makes up just 1-2% of AD cases. But this number does not match how most of us experience AD – we see our grandparents and then our parents develop AD and we fear we too will follow in their footsteps. New studies now show that over 25% of AD cases could be classified as familial based on the occurrence of disease in multiple close relatives. However, more than half of these AD families do not carry mutations in any gene previously associated with AD. This suggests that our current understanding of what drives familial AD is incomplete and that many families harbor genetic causes of AD that remain to be discovered.

The reason for this knowledge gap is that geneticists up to now were only able to look for the causes of AD in a limited part of the genome – mostly the part that codes for proteins. But the vast majority of the genome consists instead of DNA sequences that control when and where proteins are made. We focus on this “noncoding” genome to ferret out novel mutations that may cause familial AD. The difficulty is that aside from being vast, the noncoding genome is also littered with harmless mutations. To sift the needles from this haystack, we will develop artificial intelligence tools that identify mutations most likely to cause disease and a cutting-edge experimental platform that confirms their impact on brain cells. Our work will make it possible to more accurately predict who will develop AD before it starts, providing clarity to the many families living with a strong family history of AD but no known genetic cause and, in the long term, new paths toward treatment for AD.

"The MIND Prize will provide critical support to uncover novel genetic drivers of AD hidden in parts of the genome that have been difficult to tackle previously."