PROJECT ABSTRACT Neurofibrillary tau is consistently linked to neurodegeneration and cognitive decline in Alzheimer’s disease (AD) over a range of clinical presentations and anatomical phenotypes, including patients with primary impairment in memory, visuospatial, language, and somatomotor domains. One model of tau progression that has attracted recent attention involves region-to-region transport of pathologic tau along axonal white matter (WM) connections; however, evidence for axonal transport in murine models may not translate to the complex biology of AD in humans. One potential test of the axonal transport hypothesis is whether changes in WM connections predict disease progression between tau-positive and tau-negative regions. If axonal transport is a common mechanism of tau spread, it should leave signature WM changes consistent with a patient’s anatomical and clinical phenotype. However, WM changes are underinvestigated in non-amnestic mild cognitive impairment (MCI) and AD and rarely studied in the context of longitudinal tau changes. Moreover, imaging markers of WM change may reflect features of the AD pathologic process or co-occurring cerebrovascular disease. We propose a multimodal clinical, imaging, and pathologic investigation to test the hypothesis that WM changes predict region-to-region tau spread independent of CVD. Aim 1 will combine longitudinal positron emission tomography (PET) imaging of tau progression with 3-Tesla MR imaging of WM changes using diffusion MRI to assess evidence that WM changes mediate tau spread in a syndrome-specific manner. The axonal transport model predicts that longitudinal changes in diffusion MRI will mediate region-to- region tau PET progression in syndrome-specific brain networks. Aim 2 will use high-resolution 7-Tesla MRI of CVD-related brain changes, including WM hyperintensities and microbleeds, to quantify vascular disease burden across amnestic and non-amnestic AD and to assess CVD co-pathology as a potential confound that would explain WM changes in AD. Based on preliminary data, we hypothesize that all clinical variants of AD will exhibit age-related CVD including WM hyperintensities and microbleeds but will not fully explain tau-related WM changes. Finally, Aim 3 will provide postmortem validation of imaging findings and advance digital pathologic methods to quantify AD- and CVD-related pathology in amnestic and non-amnestic AD. In this aim, the axonal transport model predicts that longitudinal change in grey matter tau will be mediated by tau deposition and degeneration in connecting WM tracts, but not by CVD pathologic burden. By comparing heterogeneous phenotypes and cognitive networks, we seek to demonstrate that WM-mediated tau spread is a generalizable mechanism of disease progression across cognitive subtypes of MCI/AD and is independent of CVD-related changes. This research will contribute to multiple milestones in AD and related dementias (ADRD) by investigating relationships bet...