Discovery of novel tau proteoforms as biomarker candidates for AD and PSP

Project Summary Abstract Early detection and diagnosis of Alzheimer’s disease (AD) or Alzheimer’s disease and related dementias (ADRD) have been important goals of the National Plan to Address Alzheimer’s Disease since the first Advisory Council recommendations in 2012. Major breakthroughs have been accomplished over the last 10 years using blood-based biomarkers for amyloid and tau pathologies. Over this time, the Dage lab led the discovery and development of assays for unique phosphorylated proteoforms of tau (P-tau181 and P-tau217) that can differentiate AD from non-AD controls or other neurodegenerative diseases. We have demonstrated that P-tau217 is elevated 2-fold compared with controls in earliest stages of AD. These findings have been replicated by several groups using novel assays including some immunoprecipitation/mass spectrometry (IP/MS) methods. However, it is not clear if P-tau217 represents the best proteoform at the early stages of AD, correlates best with tau pathology, or if there are other proteoforms that might be more relevant to enable earlier diagnosis of non-AD tauopathies such as progressive supranuclear palsy (PSP). In fact, there has been limited success in the search for biomarkers for non-AD tauopathies such as PSP which currently lacks specific biofluid biomarkers despite it having genetic associations with tau haplotype and having tau pathology as one of its defining pathological characteristics. To address outstanding questions with P-tau217 and gaps in early detection or diagnosis of non-AD tauopathies, we have the overall objective to discover novel tau proteoforms in blood that best differentiate healthy volunteers from AD or PSP patients and have potential to enable early diagnosis of tau pathology for AD or PSP. Other groups have performed IP/MS studies on brain tissue, cerebrospinal fluid (CSF) or plasma; however, sensitivity limitations of their approach might be inhibiting the full evaluation of low abundant tau forms in blood despite enrichment with IP. To overcome this limitation, we have identified samples from completed clinical trials of tau immunotherapies (semorinemab, tilavonemab, and gosuranemab) where the levels of tau in blood was increased more than 20-fold. By combining IP/MS with samples from clinical trials in HV, AD or PSP subjects, we will overcome the sensitivity limitations and test the hypothesis that novel tau proteoforms associated with AD or PSP can be identified in blood. In this project we will identify and characterize novel tau proteoforms and make this resource available broadly to enable future research. This will enable rapid evaluation for their association with tau pathology, disease progression, earlier diagnosis of PSP, and help identify patients for clinical trials.