Tau Phosphorylation in Preclinical and Symptomatic Alzheimer Disease

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.

Alzheimer disease (AD) is characterized by accumulation of amyloid and deposition of neurofibrillary tangles, which arise from excessive phosphorylation of tau. While research typically focuses on total tau and pT181, phosphorylation occurs at over 80 sites and little is known regarding the relationship between novel sites and established biomarkers arising during the transition from preclinical to clinical AD. For example, during this transition, brain network organization begins to deteriorate, leading to cognitive decline. However, it is unknown how various p-tau sites are associated with alterations in brain network organization and whether they contribute to tau propagation through brain networks. Using neuroimaging, cerebrospinal fluid, and cognitive markers, this study will characterize and stage the temporal and spatial progression of tauopathy occurring during this transition period in autosomal dominant AD. It is hypothesized that a) changes at particular phosphorylation sites will occur in a specific temporal order and will follow distinct trajectories over time; and b) associations with brain networks will be greatest in regions where tau deposition occurs. This study will ultimately aid in determining a signature of p-tau pathology and lead to more accurate staging of disease progression, thus informing therapeutics that are more sensitive to targeting AD pathology and the optimal time window to apply such therapeutics.

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, ev

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.