Neurodegenerative diseases, including Alzheimer’s disease and other dementias, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS), pose a significant global health burden. These devastating diseases are characterized by the progressive damage and loss of brain cells that lead to a decline in cognitive function, movement, and other bodily functions over time. The exact causes of these diseases are unknown but are believed to be a combination of genetic and environmental factors.
Understanding the genetic basis of these diseases is crucial for several reasons. Identifying specific genetic markers associated with different neurodegenerative diseases can lead to earlier and more accurate diagnoses. By understanding the specific molecular mechanisms underlying disease, researchers can also develop therapies that address the root cause of the disorder rather than just treating symptoms.
While advances in genetic sequencing technologies have allowed researchers, including those at HudsonAlpha, to identify numerous genetic variations associated with these diseases, there’s still much to learn in the quest for earlier diagnostics and more effective treatments.
Understanding the regulation of known genetic contributors to disease onset and progression
HudsonAlpha Faculty Investigators Nick Cochran, PhD, and Rick Myers, PhD, are at the forefront of genomic research in neurodegeneration. They aim to understand what causes progressive brain cell damage and how it can be prevented. A leading theory in neurodegeneration is that damage is largely due to the aberrant buildup of protein aggregates, like beta-amyloid and tau, within and around brain cells.
The Cochran lab is working to understand tau at a deeper level to discover what goes amiss and how to best prevent or reverse it. In healthy brains, tau protein plays a critical role in maintaining neuronal health. However, in neurodegenerative diseases, tau undergoes pathological changes, forming protein tangles that disrupt cellular function and communication, leading to neuronal degeneration and cognitive decline.
Studies on MAPT and tau have been used to create biomarkers and design potential treatments. Cochran’s research extends beyond changes in the MAPT gene itself, focusing on regulatory elements that control whether the gene is expressed at the right time, in the right place, and in the right amount.
In a study published in January 2024 in The American Journal of Human Genetics, Cochran and his team, as well as the Myers lab, used many genomic technologies to better understand MAPT expression and identify new regulatory regions that could one day be the target of therapeutics. Through these exhaustive studies, the team identified 97 candidate regulatory elements that control MAPT expression.
In late-2024, Drs. Cochran and Myers, along with a collaborator at the University of California San Francisco, were awarded a 5-year, $3.5 million grant from the National Institutes of Health to further study MAPT. The collaborative team will use cutting-edge techniques to discover further controllers of MAPT expression, providing an innovative path for achieving tau reduction in the human brain.
Using what they’ve learned in studying MAPT, Cochran and his lab are expanding their research into the regulation of other neurodegenerative disease genes. Bri Rogers, PhD, a Postdoctoral Fellow in the Cochran lab, is leading research funded through the American Parkinson’s Disease Association to study the gene SNCA, which encodes the protein alpha-synuclein that forms damaging Lewy bodies in the brains of Parkinson’s disease patients.
Through an Alzheimer’s Association-funded grant, Cochran and his team are also studying the regulation of APP, the gene that provides instructions for amyloid protein that is involved in Alzheimer’s disease. By studying how APP is turned on or off, Dr. Cochran and his team hope to better understand the role it plays in Alzheimer’s disease risk and shed light on ways to regulate the gene through potential therapeutics.
“Diving into the regulation of genes will lead to a more holistic picture of how variation in our genomes leads to disease risk, allowing us to better understand and target the problems involved in these diseases.” -Nick Cochran
Identifying biomarkers of neurodegeneration
Because neurodegeneration is a progressive process, cell damage in the brain occurs years, sometimes decades, before symptom onset. To truly reduce the global burden of neurodegenerative disease, scientists and physicians must be able to identify early changes in the brain that indicate potential neurodegeneration.
By identifying early genetic changes associated with these diseases, scientists can develop noninvasive tests to diagnose them before much damage has occurred. Blood-based biomarkers are a promising method to identify neurodegenerative disease pathology early. A few blood-based biomarkers are currently in use for diagnosing Alzheimer’s disease, but there is a growing need for more.
Dr. Myers and his lab are involved in several research studies seeking to find blood-based biomarkers for various neurodegenerative diseases. For several years, they’ve led a study in collaboration with Crestwood Medical Center’s ALS Care Clinic in Huntsville, Alabama. Blood samples from ALS patients are analyzed alongside samples from individuals without ALS to identify and validate unique nucleic acids in the blood of ALS patients that could be used as predictive biomarkers. The team has found some exciting preliminary results that they’re working to validate in the upcoming year.
In 2024, researchers in the Myers lab launched a study in conjunction with the Smith Family Clinic for Genomic Medicine to identify biomarkers linked to Parkinson’s disease. Patients diagnosed with Parkinson’s disease, as well as unaffected family or friends, enroll at the clinic to donate blood samples for the study. As of late 2024, more than 100 samples have been collected. Once the team has a representative number of samples, they’ll start analyzing them for potential biomarkers.
In addition to diagnosing disease earlier, biomarkers are also extremely helpful in monitoring disease progression and patient response to treatments. During clinical trials, pharmaceutical companies rely on biomarkers to help identify patients who are most likely to benefit from a specific drug, measure how well a drug is working by assessing changes in specific biological markers related to the disease, and help predict clinical outcomes.
