ABSTRACT: The neuropathologic hallmarks of Alzheimer's disease (AD) are accumulations of beta-amyloid (Aβ) and tau proteins, that each have their own typical topography during disease progression. The fact that this anatomic pattern of pathology progression occurs along regions that are anatomically connected, suggests that pathology spreads via connectivity. Disappointing results from recent therapeutic efforts targeting Aβ in the prodromal phase of AD indicate the importance of intervening early and prelude an exciting opportunity: by focusing on mechanisms related to initial propagation of pathology, disease progression may be halted in the earliest stage, prior to irreversible damage has affected the brain. Autopsy data indicated that the locus coeruleus (LC) is one of the first regions affected by tau: by age 40, tau aggregation in the LC can be detected in 80% of the individuals, prior to neocortical Aβ or tau. At age 50, almost 50% of the individuals harbor tau pathology in the transentorhinal cortex (TEC), suggesting that tau has progressed from the LC to the TEC. The scientific premise supporting the current study emerges from animal and our cerebrospinal fluid (CSF) work, demonstrating that elevated metabolism of the LC may be driving tau hyperphosphorylation, and propagation to distant, connected regions, and triggering cognitive decline. The overall goal of this proposal is to examine LC metabolism and its relation to progression of tau across all stages of the AD continuum, and to model connectivity as mechanism related to progression of tau and cognitive decline. To achieve this, we will resolve two methodological barriers that so far hampered human in vivo assessment of these relationships: 1) measuring LC metabolism while taking into account the resolution of 18F-Fluorodeoxy-glucose PET and 2) identify tracts connecting the LC to the TEC among many crossing brainstem fibers. Combining these state-of- the-art novel methods with longitudinal data of Aβ, tau (PET and CSF) and cognition in two NIA-funded, rich multi-modal longitudinal datasets, the Harvard Aging Brain Study and the Alzheimer Disease Neuroimaging Initiative, will allow us to examine the following aims: Aim 1) To examine the evolution of LC metabolism as a function of Ab/tau stages or diagnostic groups, and its relationship to tau accrual over time; Aim 2A) To identify and validate tracts connecting the LC to the TEC in a consistent way across both cohorts; and examine LC-TEC tract integrity across the AD continuum; and Aim 2B) To model the successive mediation by lower LC- TEC connectivity and tau accrual on the relationship between LC metabolism and cognitive decline. Together, these aims improve our understanding of the mechanistic underpinnings of initial tau propagation, as well as its relevance for cognition. The proposed research is innovative and can have a substantial impact on our understanding of the pathophysiology of AD, and can also result in a significant...