Blood Biomarker Development and Validation in Chronic Traumatic Encephalopathy and Alzheimer's Disease and Alzheimer's Disease Related Dementias

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Each year, millions of people are exposed to repetitive head impacts (RHI) through contact sports, military service, and physical violence. These impacts can confer risk for Alzheimer’s disease (AD) and related dementias (ADRD) including chronic traumatic encephalopathy (CTE). The unique pathological lesion of CTE includes phosphorylated tau (p-tau) in neurons around small blood vessels at the sulci. CTE still cannot be diagnosed during life. Research diagnostic criteria for the clinical syndrome of CTE were developed by our team, known as traumatic encephalopathy syndrome (TES). The TES criteria are non-specific and were developed without biomarkers. To date, efforts on biomarkers for CTE have focused on those with low scalability and poor accessibility (e.g., PET). It is now possible to detect AD/ADRD proteins in the blood, representing an accessible alternative for disease detection. Research on plasma-brain associations in AD/ADRD is still in its infancy. The literature on plasma biomarkers for CTE is even more nascent and plasma-to-autopsy studies are scarce, which are vital for biomarker development and validation. This R01 will examine the ability of plasma biomarkers of p- tau, Aβ, and neurodegeneration to detect CTE and its clinical syndrome (TES), and predict AD/ADRD pathology in the brain. We will leverage the Brain Donation Registry (BDR) that is hosted online by the Concussion Legacy Foundation (CLF). BDR individuals pledge their brain to research and are funneled to the Veteran Affairs-Boston University (BU)-CLF brain bank—the largest repository of RHI tissue in the world (>1250 donors). We will ask BDR individuals (n=1000; 800 RHI, 200 non-RHI; all 40+ years) to have a phlebotomy at a Quest lab for banking at BioSEND. They will complete the UCSF-BU internet-based Brain Health Registry-Head Impact & Trauma Surveillance Study for clinical characterization. The sample of 1000 will facilitate our long-term infrastructure goal of large-scale blood banking on people at risk for CTE and AD/ADRD who agree to brain donation and are clinically characterized. To test the R01 aims, plasma biomarker analyses will be done on 300 of the 1000: 200 RHI and 100 matched people without RHI. We will measure six p-tau epitopes (181+199+202+205+217+231), Aβ40/42, total tau, glial fibrillary acidic protein, and neurofilament light. Of the 1000, we expect 100 brain donations during the grant and the same analytes will be measured in blood and brain. 120 brain donors from our BU ADRC bank have these plasma biomarkers available and will be used for autopsy-proven AD and non- AD comparators. Aim 1 will compare plasma biomarkers between the 200 RHI and 100 non-RHI and test plasma biomarker and clinical associations. Aim 2 will include plasma-to-autopsy studies using the 100 brain donations enriched for CTE (people from the BDR) and the 120 BU ADRC donors with autopsy-proven AD and non-AD. Aim 3 will test RHI and plasma biomarker associations. This R01 will lead to unprecedented data to develop and validate plasma biomarkers for CTE. Large-scale blood banking from people across diverse exposures to RHI who agreed to brain donation will create a unique resource to address unmet needs in AD/ADRD including CTE.