New biomarkers for late diagnosis and differentiation from ad dementia

The National Institute on Aging awarded North Carolina Central University $673,720 on September 4, 2026, under the Aging Research program (CFDA 93.866) to develop fluid biomarkers for diagnosing limbic-predominant age-related TDP-43 encephalopathy (LATE) and differentiating LATE from Alzheimer's disease dementia. The project will develop TDP-43 seed amplification assay and tau-SAA as diagnostic tests for LATE, characterize the effects of co-existing TDP-43 pathology on tau pathology across different neurofibrillary tangle Braak and LATE stages, and develop new phospho-tau fluid biomarkers for differentiating LATE from normal controls and AD dementia. The recipient will test new biomarkers using both discovery and validation cohorts of premortem cerebrospinal fluid and plasma samples. Place of performance is Durham, North Carolina, with a period of performance extending from the award date through August 31, 2028.

Abstract

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.