2024 Alzheimer's Association Clinical Scientist Fellowship to Promote Diversity (AACSF-D)
Genetic Risk of Mixed Pathology in Alzheimer’s Disease in Multi-Ethnicities
Can novel genetic analyses better predict Alzheimer’s risk and progression in diverse people with multiple brain disorders?
Jung-Min Pyun, Ph.D.
Soon Chun Hyang University Hospital
Seoul, Korea (Republic of)
Background
Alzheimer’s disease (AD) is associated with specific brain changes, such as the accumulation of beta-amyloid and tau proteins into abnormal plaques and tangles, respectively. Studies, however, indicate that many other factors play a significant role in one’s risk for Alzheimer’s. Genome-wide association studies (or GWAS), which use datasets from large groups of individuals to identify genetic factors associated with Alzheimer’s risk, have discovered numerous dementia-related genes. Studies have also found that the risk and progression of Alzheimer’s disease may be impacted by “mixed pathology,” or the presence of other brain disorders that often occur alongside AD. These disorders include Lewy body disease (a type of dementia) and small vessel disease (a disorder characterized by damaged brain blood vessels). In addition, the way genetic variation and mixed pathology affect Alzheimer’s risk and progression may vary depending on an individual’s race or ethnicity.
Because of the variety of factors involved in determining Alzheimer’s risk, scientists are looking to develop better, more accurate diagnostic tools that can take these factors into account. In preliminary studies, Dr. Jung-Min Pyun and colleagues have been working with two novel tools called polygenic risk scores (or PRS, a measure of how likely an individual is to develop a disease based on their genes) and a transcriptional risk scores (or TRS, a measure of how likely an individual is to develop a disease based on differences in how gene activity is tuned “on” and “off” within cells). These tools can be used to predict how various brain diseases affect genetic make-up and activity in the brain (brain-based PRS and TRS) and the blood (blood-based PRS and TRS). Preliminary results found that both tools, especially TRS, can help diagnose Alzheimer’s in older adults by predicting both the presence of beta-amyloid build-up and declines in memory and other cognitive functions.
Research Plan
Dr. Pyun and colleagues will now use their research grant to conduct a larger assessment of their PRS and TRS tools. For this effort, they will collect brain scan, blood and cognitive data from diverse older adults who had mixed pathology that involved Alzheimer’s disease, Lewy body disease and small vessel disease. They will then analyze the data to develop blood-based and brain-based PRS and TRS models for each of the three mixed pathology diseases. They will also determine how the models may differ among different ethnicities (Black American, Hispanic American, Asian American and White). Next, the researchers will test how well the different models can predict how each disease (alone and in combination) can predict cognitive decline and dementia-related brain changes in the various ethnic groups. The team will also compare how well brain-based PRS and TRS perform compared with blood-based PRS and TRS.
Impact
Dr. Pyun’s study could clarify the genetic underpinnings of how different brain diseases interact to promote the onset and progression of dementia in different populations. Ultimately, it could lead to novel diagnostic and treatment strategies that are more closely targeted to individuals in these population groups.