The original theory offered by Braak & Braak (1991)—that neurofibrillary tangle pathology proceeds along well- defined predilection sites beginning in the medial temporal cortex—has been modified by the same author to suggest that the pathologic process instead commences in the lower brainstem (Braak et al 2011). The first visible pathologic changes are now thought to occur in the locus coeruleus (LC) and then spread via its axonal projections to transentorhinal/entorhinal cortex (TEC). We propose to study LC change using a novel computational morphology method, combined with novel methods of measuring white matter microstructural tractography and functional connectivity to TEC. These new methods are designed to overcome major shortcomings in current neuro-MRI analysis methods that limit the ability to detect subtle structural and functional changes associated with early AD. Such alterations across the aging-MCI-AD continuum, as well as in those cognitively normal individuals with risk factors for AD (e.g., CSF AD biomarkers;; apolipoprotein E e4 carriers), would provide significant advances in our understanding of the pathogenesis of AD across clinical transition points and perhaps during this ‘silent’ period (i.e., prior to the occurrence of traditional AD biomarker positivities). Using our newly developed diagnostic and MRI metrics, we propose to quantify variations in LC morphology and its projections to TEC (which we term the LC-TEC system). Aim 1. Examine locus coeruleus morphology, contrast, and associated cortical thickness. Morphological variations will be characterized by spherical wave decomposition (SWD) of high-resolution anatomical MRI data supplemented by recent contrast ratio (Takahashi et al. 2015) analyses of T1 Fast Spin Echo MRI scans. Aim 2. Examine structural connectivity of the LC-TEC system. Neural connectivity will be characterized by our novel diffusion tensor imaging (DTI) tractography method (geometric-optic based entropy spectrum pathways, GO-ESP DTI) to quantify afferent and efferent pathways between the LC and TEC, and efferent projections from the LC to cerebellum and cortex. Aim 3. Examine functional connectivity of the LC-TEC system. Resting state functional modes and connectivity will be derived from our novel entropy field decomposition (EFD) analysis of rsFMRI data guided by the prediction that AD tauopathy in its earliest phases is not determined by large losses of neurons but by enormous numbers of nerve cells that survive with limited functionality (Braak & Del Tredici 2015);; alterations in functional connectivity of the LC-TEC system will serve as a surrogate marker of this limited functionality. Demonstrations of improvement in diagnostic and imaging precision in Preclinical AD will have an important impact on prospective design of future studi...