Tau Phosphorylation in Preclinical and Symptomatic Alzheimer Disease
MentorBeau Ances, MD, PhD, MSc Washington University School of Medicine
This study will characterize and stage the temporal and spatial progression of tauopathy occurring during the transition from preclinical to symptomatic Alzheimer disease. Using neuroimaging, cerebrospinal fluid (CSF), and cognitive markers, this study will characterize and stage the temporal (Aim 1) and spatial progression (Aim 2) of tauopathy occurring in autosomal dominant Alzheimer disease (AD). For Aim 1, tau sites will be assessed in relation to preclinical AD biomarkers (e.g., CSF Ab42) and biomarkers of symptom onset (e.g., CSF total tau, resting-state functional connectivity [RS-FC], cognitive performance), and estimated years to symptom onset (EYO). For Aim 2, tau sites will be cross-sectionally correlated within and between network RS-FC.
This proposal will be the first to quantitatively assess phosphorylated tau sites in relation to changes arising during the transition from preclinical to symptomatic Alzheimer disease (AD), such as increases in CSF Ab42, alterations in resting-state functional connectivity (RS-FC), and cognitive decline. Because AD research typically focuses on total tau and pT181, including novel tau sites in analytic models with other biomarkers will offer a more comprehensive and informative representation of AD-related processes and will lead to more precise staging of disease progression. Furthermore, This study will provide critical insights into the temporal and spatial evolution of tauopathy in AD, which in turn can be used to develop tau-based therapies. AD-therapies targeting amyloid have yielded limited results making it clear that new areas of therapeutic research should be pursued. By determining a signature of p-tau pathology, we will more accurately stage disease progression, thus informing therapeutics that are more sensitive to targeting AD pathology as well as the optimal time window to apply such therapeutics.