Title:Tau Phosphorylation in Preclinical and Symptomatic Autosomal Dominant Alzheimer Disease
Date of Request:08/05/2023
Aim 1:Temporal progression of tauopathy. Tau sites (e.g., pT181, pT202, pT205, pT217) will be assessed in relation to preclinical AD biomarkers (e.g., CSF Ab42) and biomarkers of symptom onset (e.g., CSF total tau, RS-FC, cognitive performance), and EYO. Longitudinal changes in variables will also be plotted against EYO to determine temporal trajectories and to assess how biomarkers change relative to one another across disease progression. It is hypothesized that elevation of each site will occur at varying stages of the disease process and will follow distinct individual trajectories over time. Specifically, it is expected that relative to other tau sites, elevation in CSF pT217 and pT181 levels will arise first and will most strongly associate with preclinical biomarkers, such as CSF Ab42, while other tau sites will become elevated later in the disease process and will most strongly associate with biomarkers of symptom onset.
Aim 2:Spatial progression of tauopathy in ADAD. Compared to established biomarkers (e.g., amyloid and total tau), it is unknown how phosphorylated tau sites differentially relate to and drive alterations in resting state brain network dynamics during the preclinical and clinical phases of ADAD. To determine whether specific tau sites are associated with alterations in brain network RS-FC organization, tau sites will be cross-sectionally correlated with within-network and between-network RS-FC. Longitudinal changes in tau sites and RS-FC will additionally be correlated and plotted against EYO to determine whether changes in tau sites and RS-FC arise in a specific pattern, and more specifically to elucidate the spatial progression of tauopathy. It is hypothesized that elevated levels of CSF tau sites will be associated with a local to diffuse pattern of decreases in RS-FC, and that associations between tau sites and RS-FC will be greatest in regions where tau deposition occurs, as measured by tau positron emission tomography (PET).