ADRC Developmental Projects

Dementia due to Alzheimer’s disease (AD) is a devastating neurological disorder associated with the accumulation of tau and beta-amyloid in the brain. However, alpha-synuclein (aSyn) deposition that is typically associated with Parkinson’s disease commonly co-occurs in people with AD. The co-occurrence of these pathologies in the brain has been associated with worse cognitive and functional outcomes. Until recently, measuring aSyn was only possible at autopsy. However, a novel approach called aSyn-seed amplification assay (aSyn-SAA) to measure aSyn in the cerebrospinal fluid is highly sensitive and specific for differentiating individuals with aSyn pathology from those without. Here we propose to measure aSyn-SAA in the cerebrospinal fluid from people with neuropathology confirmed AD with and without aSyn pathology and separately in people who have been followed at the UPenn ADRC and have extensive clinical characterization. The purpose is to validate in an independent cohort the association between aSyn-SAA and aSyn pathology, to further describe associations between aSyn-SAA and quantitative aSyn pathology in different brain regions, and to determine associations between aSyn-SAA and clinical progression. These findings will support future research grant applications to understand how best to deploy the use of amyloid-specific therapies considering the potential impact of non-AD pathologies on AD course.

Alzheimer’s disease (AD) is a common yet devastating form of dementia that affects over 5 million Americans and will have increasing prevalence as our population ages. Despite the profound impact of AD on our patients, their families, and society, we have very limited treatment options. Changes in our genetic sequence, or DNA, can alter our risk of developing AD. Understanding the genetics of AD will not only help predict risk of disease, but will uncover the factors that cause AD that could help us develop better treatments.

Our understanding of how these sequence changes affect AD risk has largely focused on simple single letter changes to our DNA sequence. However, there are more complex ways in which our DNA can differ, including changes in the one million repeated sequence elements called short tandem repeats (STRs), which have not been explored in AD. I have already performed analyses in nearly 3,000 individuals with and without AD and identified thousands of STRs in our DNA that influence risk for AD.

In this work, I study how these STRs may continue to mutate in the brains of patients with AD and whether this may lead to certain parts of the brain and/or cells in the brain to become more vulnerable to damage in AD. Understanding what makes some cells and parts of the brain more vulnerable to damage in AD could help us develop treatments to slow or even stop degeneration in patients with AD.

Overall, my work will uncover how these STRs contribute to damage in the brains of patients with AD. These insights that result from this work could lead to more effective treatment for this devastating condition. Moreover, the approaches developed in this study can be broadly applied to other diseases such as heart disease and cancer.

• 2022-2023
  Single Extracellular Vesicle BEAMing for Early Diagnosis of Alzheimer’s Disease
  PI: Jina Ko, PhD