Development of EV-based biomarkers for AD and related disorders

Background Biological markers, or 'biomarkers,' are a substance, structure or process that reflects a biological process that can be measured and may be an indicator of the presence or progression of different markers of health. Blood-based biomarkers, or biomarkers measured using an individual's blood, represent a low-cost and accessible way to measure the presence and progression of Alzheimer's and other dementias. While blood-based biomarkers are being used to study and diagnose some types of dementia, specifically Alzheimer's, there remain challenges with reliable blood-based biomarkers that can distinguish different causes of dementia related to tau accumulation. Tau is a protein that helps maintain the structure of brain cells. In Alzheimer's and other brain diseases, the shape of tau protein becomes modified or 'misfolded,' a change that may contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. Brain diseases believed to result from abnormal modification of the tau protein are referred to as 'tauopathies' and this includes Alzheimer's, frontotemporal dementia, Parkinson's disease, and others. Tau tangles are associated and likely contribute to increased nerve cell damage. Nerve cells release extracellular vesicles (small, bubble-like sacks containing things like proteins, DNA, etc.) and these can be isolated from the blood. The contents of these vesicles released by nerve cells change during brain diseases, including during different tauopathies. It has been proposed that studying these changes may shed light on potential blood-based biomarkers for distinguishing different tauopathies. Research Plan Dr. Tsuneya Ikezu and colleagues will study extracellular vesicles from nerve cells to determine what is included in these vesicles to see if they can come up with reliable signature of blood biomarkers for different brain diseases involving tau. To do this, the researchers will take blood samples from individuals with different tau-related diseases and isolate extracellular vesicles from nerve cells that can be found in the blood. Next, the researchers will study the different proteins that are inside these extracellular vesicles using a specialized technique called proteomics, or the study of the structure and function of different proteins. Finally, the team will use advanced machine learning to uncover which proteins found inside the extracellular vesicles of nerve cells may be associated with specific tau-related diseases. Based on what the researchers identify, they will evaluate the proteins or other changes identified as potential candidates for becoming a biomarker for each tau-related disease. Dr. Ikezu and colleagues will then test each of these candidate proteins to see if they make a valid blood-based biomarker for differentiating specific tauopathies and should be moved into larger clinical trials. To do this, the research team will study blood samples from individuals with confirmed cases of each tauopathy of interest as well as from individuals with no tauopathies. The study personnel will then analyze a blood sample to see if the presence of the previously identified candidate protein biomarkers can accurately detect the presence or absence of different tau-related diseases.