New biomarkers for LATE diagnosis and differentiation from AD dementia

Project Summary Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently characterized neurodegenerative disease defined by TDP-43 proteinopathy, primarily affecting individuals aged eighty and above. Alzheimer’s disease (AD) and LATE are both common brain pathologies associated with dementia and both present with an amnestic syndrome primarily affecting memory function, often leading to misdiagnosis. Currently, there are no reliable biomarkers for premortem diagnosis of LATE and differentiating LATE from AD. Accurate diagnosis of LATE, AD, and other ADRD's is critical for selection of patients for targeted therapies. To address this urgent unmet need, we propose to develop fluid biomarkers for diagnosing LATE and differentiating LATE from AD by detecting TDP-43 and p-tau epitopes in CSF and plasma; specifically, we propose the following aims: 1) develop TDP-43 seed amplification assay (SAA) and tau-SAA as diagnostic tests for LATE, 2) characterize the effects of co-existing TDP-43 pathology on tau pathology across different NFT Braak and LATE stages, 3) develop new phospho-tau fluid biomarkers for differentiating LATE from normal controls and AD dementia. We will test our new biomarkers with both discovery and validation cohorts of premortem CSF and plasma samples. We expect that the successful implementation of this study will not only develop novel diagnostic tests for LATE, but also for differentiation of LATE from AD dementia. Successful translation of our findings from bench to bedside will address these urgent unmet medical needs.