ABSTRACT Disordered awareness of cognitive and behavioral deficits, i.e. anosognosia, is a common symptom of Alzheimer’s disease (AD) that is particularly frustrating to families, and may impact early detection. There is a growing yet incomplete understanding of the neurobiological mechanisms that underlie the breakdown of memory self-awareness in AD. Recent neuroimaging findings, including our own work, suggest that anosognosia in AD not only reflects functional alteration in discrete brain regions but likely results from functional connectivity disruption between different brain regions, i.e. network breakdown, particularly in the brain networks subserving self-referential processing. The proposed research aims to test our central hypothesis that anosognosia occurs as a symptom of functional, structural and pathological changes in self- referential brain networks. To address these aims, self-awareness of memory measures will be related to multi- tracer Positron Emission Tomography (PET) to assess amyloid burden and tau burden, and functional magnetic resonance imaging during rest (rsfc-MRI) as well as diffusion-weighted imaging (dMRI), obtained from a total of 150 older subjects ranging from clinically normal to mild cognitive impairment and mild AD individuals. Specifically, in Aim 1 we will assess the functional integrity of brain networks (as assessed with rsfc-MRI) recruited during self-referential processing and examine the extent memory self-awareness predicts the resting state intrinsic connectivity strength across the clinical spectrum of early AD. We will also investigate whether executive skills might influence this relationship as well as the specificity of the functioning of the self- referential networks as compared to other brain networks to insight of memory abilities. In Aim 2 we will use dMRI to investigate the structural integrity of white tracts that are critical for self-referential processing and investigate whether decoupling between local structural and functional connectivity is related to altered memory self-awareness. Finally, in Aim 3 we will investigate the role of molecular pathology e.g. fibrillary amyloid (Aβ) deposition (as assessed with PiB-PET) and tau deposition (as assessed with flortaucipir PET, FTP-PET or T807) in the decoupling process and its relation to altered memory self-awareness across the clinical spectrum of AD. This project may provide critical information about factors contributing to decline in functional status, development of disability, and loss of independence. As such, the results from this study may have important clinical and practical implications for patients and their families, particularly for the development and use of dementia management interventions.