Alzheimer's disease (AD), ABSTRACT the leading cause of dementia in the elderly, is a devastating neurodegenerative disease. The hallmarks of this devastating disease are the accumulation of amyloid plaques and neurofibrillary tangles, as revealed by standard histopathologic examination at postmortem. A large number of strides have been made in past years to identify and validate biomarkers for AD. Based on PET and CSF measures of the plaques and tangles of AD, we are now able to measure AD pathology in vivo at all stages: AD dementia, mild cognitive impairment (MCI), and preclinical AD. Notably, the recent NIA/AA AT(N) research framework focused on the diagnosis of AD with biomarkers in living individuals and encouraged the continued development of new, unrecognized AD biomarkers. Amide proton transfer (APT) imaging is a relatively new protein-based MRI technique that can generate contrast based on endogenous mobile proteins and peptides in tissue. Numerous previous studies have demonstrated that APT-weighted (APTw) imaging can detect malignant brain tumors based on increased cell density and acute cerebral ischemia due to tissue acidosis or decreased pH. Our effort has successfully developed this important MRI technology into an FDA-approved sequence on Philips 3T MRI systems for clinical use with brain cancer. Further translating this innovative protein-based technology to AD and non-AD proteinopathies, such as dementia with Lewy bodies (DLB), is encouraging. It is known that both extracellular amyloid and intracellular tau first exist as soluble monomers (APT-detectable). Our preliminary studies have clearly demonstrated that the abnormal accumulation of these proteins in MCI resulted in an increased APT effect and AD dementia had APTw-MRI signal characteristics distinct from DLB. The overall goals of this application are to refine quantitative whole-brain APT-MRI methodologies on 3T clinical MRI scanners and to demonstrate the feasibility and potential of protein-based APT-MRI as a surrogate biomarker for the characterization and diagnosis of AD and other forms of dementia, such as DLB. We have formulated three specific aims that we plan to address in the coming five years: (i) develop a time-efficient APT-MRI protocol for an imaging study of AD; (2) quantify the accuracy of APT-MRI in characterizing and diagnosing MCI; and (3) quantify the accuracy of APT-MRI in distinguishing between AD dementia and DLB. This proof-of-concept study will lay the foundation for a full validation study that will assess the impact of APT imaging on clinical decision-making in patients with AD and related dementias.