PROJECT SUMMARY/ABSTRACT Alzheimer disease (AD) is the leading cause of dementia, which is expected to impact the lives of hundreds of millions of people worldwide by 2050. AD causes synaptic and neuronal losses that manifest in symptoms such as cognitive impairment, behavior changes, and eventually loss of motor coordination, which create overwhelming physical, emotional, and financial burdens to the patients and their families. At present, there is no substantially effective therapeutics or preventions for AD. Since aging is the leading risk factor of AD, a rapidly aging world population will continue to drive up the overall societal burden of dementia for years to come. To facilitate the development of successful AD therapies, discovery and refinement of noninvasive biomarkers will continue to play an essential role in understanding the therapeutic effects of existing treatments and investigating alternative therapeutic targets. In particular, vascular biomarkers that reflect the health and integrity of the cerebral vasculature – which permeate almost all aspects of AD – will remain a crucial tool for understanding and treating AD. However, despite the strong clinical evidence of significant impact on AD, vascular biomarkers remain poorly explored and are often overlooked in both preclinical and clinical studies of AD. One reason is that currently there is lack of a noninvasive, in vivo imaging method that provides both structural (e.g., static vascular morphology, microhemorrhages) and functional (e.g, blood brain barrier leakage, vessel hemodynamics, microhemorrhages) vascular biomarkers with high spatial resolution deep into the brain. To this end, we propose to develop a new ultrasound-based super-resolution microvascular imaging technique based on both contrast enhanced microbubbles (MBs) and phase-changing nanodrops (NDs) for AD brain imaging. The study seeks to address several AD-specific technical challenges for conventional ultrasound localization microscopy (ULM), including low imaging repeatability, high computational cost associated with data acquisition and beamforming, and the lack of extravascular imaging capability that precludes conventional ULM from measuring important AD vascular biomarkers such as vessel integrity. Our approach includes the development of a new 3D ULM imaging platform and an adaptive MB injection method to maximize ULM imaging repeatability between different imaging sessions across different days; development of a GPU-based computing platform for ultrafast ultrasound data acquisition and beamforming for AD applications of ULM; and develop a new ND-based extravascular super- resolution ULM imaging method for assessing AD-induced loss of vascular integrity. Successful completion of the study will lead to a new noninvasive AD brain imaging technique that provides whole brain structural and functional vascular imaging at a microscopic spatial resolution.