Development of a Plasma Biomarker for TDP-43 Proteinopathy - Summary Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that cause dementia and represent a major public health concern. Both diseases primarily affect the elderly and are becoming increasingly prevalent as the aging population grows. These disorders are associated with pathological changes in the brain, including the deposition of abnormal proteins. TDP-43 (TAR DNA-binding protein of 43 kDa) was initially linked to FTLD and has since been found in up to 60% of brains with AD. One of the most significant challenges in understanding the role of TDP-43 in neurodegeneration and developing effective treatments for these disorders is the lack of reliable biomarkers that can predict TDP-43 pathology in living FTLD and AD patients. TDP-43 is clinicopathologically heterogeneous, and the relationships among clinical phenotypes, local neurodegeneration, and TDP-43 pathology remain unclear. This heterogeneity arises from the complex molecular composition of TDP-43 inclusions. A biomarker or antibody capable of revealing the relationship between TDP-43 pathology and neurodegeneration would significantly advance the field. Through the screening of over 5,000 monoclonal antibodies (MAbs), we identified an anti-TDP-43 antibody, MAb No. 9, which recognizes novel TDP-43 pathology in FTLD and AD. Furthermore, Meso Scale Discovery (MSD) immunoassays using this antibody detected elevated TDP-43 levels in the plasma extracellular vesicles (EVs) of FTLD and AD patients, suggesting its potential as a plasma biomarker for TDP-43 proteinopathies across different dementias. The main objectives of this project are to investigate the MAb No. 9-positive TDP-43 pathology and its association with neurodegeneration in FTLD and AD and to develop plasma biomarkers for TDP-43 proteinopathies. To achieve these objectives, we will examine how MAb No. 9-positive TDP-43 pathology contributes to neurodegeneration in FTLD and AD by analyzing the relationships between MAb No. 9 positivity, inclusion types, pathology subtypes, and local neurodegeneration in brain specimens from autopsy- confirmed FTLD and AD patients. We will also establish plasma biomarkers of TDP-43 proteinopathies by measuring plasma EV TDP-43 levels using MSD immunoassays in cases of neuropathologically confirmed FTLD-TDP, FTLD-tau (a subtype of FTLD), and AD, as well as in healthy aging controls. This study has significant
