Confirming the use of aberrant T cells as an amyloid-independent blood biomarker for potentially earlier diagnosis and tracking the progression of Alzheimer's Disease

PROJECT SUMMARY Despite enormous investment into Alzheimer’s disease (AD), all but a few AD drug trials have failed. Major reasons for these failures have been that AD diagnosis is uncertain in living patients, and is itself based on a combination of molecular biomarkers and clinical features that occur relatively late in the disease process. Molecular biomarkers such as imaging or cerebrospinal fluid (CSF) beta-amyloid (Aβ) and/or hyperphosphorylated tau (pTau), among others, help in more accurately identifying AD patients, but testing for them is technically demanding, often unavailable, and detects pathologies that can occur irrespective of AD. Promising blood-based biomarkers are in development but are at best equivalent to CSF markers, and hold similar challenges. Prominently missing from the AD biomarker portfolio are features upstream of AD molecular features, which, by their closer proximity to disease initiation, have greater potential for earlier detection and tracking of AD. A simple blood-based biomarker detectable prior to Aβ or pTau abnormalities would thus be a breakthrough in Alzheimer’s diagnostics and drug development. Alterations in age-related cytolytic (CD8) T cells could in theory impact AD pathology upstream of Aβ and pTau. We have shown in mice that certain age-related, self-peptide (Amyloid Precursor Protein; APP)-specific CD8 T cells enter the brain, initiating the accumulation of Aβ plaques, Tau+ neurofibrillary inclusions, neuroinflammation, and ultimately, profound neurodegeneration and cognitive decline resembling sporadic AD in humans. Findings from this model allowed successful prediction of previously unknown features of human AD. In this context, levels of age-related T cells responsive to a nearly identical APP antigen as in mice corresponded to sporadic AD and AD-related Mild Cognitive Impairment (MCI) in human patients, with potentially greater specificity than an emerging plasma biomarker, P-Tau217. T-Neuro has exclusively licensed this technology, with the ultimate goal of producing a T cell-based blood biomarker kit (“T-Track”) to help diagnose AD for clinical trial recruitment and primary care testing. Necessary steps to more extensively validating T-Track for such uses include initial confirmation in large, well-defined patient cohorts, as well as expansion to patients not currently suitable for the test (HLA-A2-negative). In Aim 1, we will determine the feasibility of the T-Track biomarker to sensitively and specifically track AD status in HLA-A2-positive individuals, providing necessary proof-of-concept for the T-Track assay. In Aim 2, we will expand application of the T-Track biomarker assay to HLA-A2-negative subjects, by quantifying antigen- and HLA-independent markers of age-related T cells, as well those specific for related antigenic (APP) peptides+other HLA subtypes. Upon completion of the Phase I study, we will have determined the feasibility of quantifying HLA-A2/APP-reactive CD8 T cells in blood to identify AD and progression to AD in patients and expanded the T-Track biomarker assay to other HLA subtypes. This is an initial step in more extensive T-Track validation in Phase II and will substantially de-risk its continued development into a diagnostic kit in Phase III for earliest detection and prediction of AD.