Project Summary Post-mortem and in-vivo neuroimaging studies have shown that beta-amyloid (Aβ) and tau pathology are associated with neurodegeneration and cognitive decline in typical aging and Alzheimer’s disease (AD). Though previous work suggests that Aβ plays a role in driving tau pathology spread and that this interaction is key to the development of AD, Aβ accumulates multifocally across the neocortex whereas tau deposits in the medial temporal lobe and spreads in stereotyped patterns to highly connected cortical projections. Given the spatiotemporal differences of Aβ and tau accumulation, it is unclear how these two pathological proteins remotely interact, especially in the earliest stages of disease, to promote regional vulnerability to further protein accumulation underlying aging and AD. Previous studies have identified distinct intrinsic brain networks and functional connectivity patterns associated with early AD pathology deposition and spread, suggesting vulnerability to AD pathology and subsequent spread may be dependent on brain activity. The current project will use positron emission tomography (PET) imaging and resting-state fMRI (rsfMRI) to investigate mechanisms of Aβ and tau interactions via functional networks. The goal of this study is to examine how network connectivity is associated with AD risk, longitudinal pathology accumulation, and aging. Aim 1 will use regions of early AD pathology deposition identified in older adult (OA) PET scans as seeds to construct Aβ and tau-seeded functional networks in young adult (YA) rsfMRI data. Then, functional network connectivity between early Aβ and tau-seeded networks will be examined in relation to AD risk (APOEε4) in YA. Aim 2 will apply the networks constructed in Aim1 to OA rsfMRI data and investigate how network connectivity of early Aβ and tau- seeded networks is related to longitudinal AD pathology accumulation measured by PET imaging. Aim 3 will explore how properties of Ab and tau-seeded networks change with age and how these age-related changes are associated AD pathology accumulation and cognitive decline in OA. Overall, this proposal will allow the applicant to develop skills in: (1) acquisition and advanced analysis of multimodal neuroimaging data, (2) statistics and data analysis, (3) clinical impairment and pathophysiology of AD, (4) science communication, and (5) teaching and mentorship. The UC Berkeley Helen Wills Neuroscience Institute is at the forefront of cutting- edge research and provides access to world-class facilities and experts in neuroimaging, cognitive neuroscience, and biostatistics, which will support the applicant in the completion of this project and training plan. The sponsor, Dr. William Jagust, is an expert in using multimodal neuroimaging to investigate aging and AD and is uniquely suited to oversee the proposed project and training plan. He has successfully mentored many trainees who are now leaders in the field. The proposed research and train...