ABSTRACT: Therapeutic Reduction of Cerebral Amyloid Angiopathy Pathologies in ADRD Cerebrovascular Amyloid Angiopathy or CAA is a common cerebral small vessel disease that is prevalent in the elderly, a prominent comorbidity of patients with Alzheimer's disease (AD), and an important driver of vascular cognitive impairment and dementia (VCID) that are collectively known as ADRDs (AD and Related Dementias). Despite the growing recognition of the contribution of CAA to dementia in AD and in VCID, no effective therapeutic interventions currently exist for this condition. CAA uniquely contributes to cognitive decline in VCID and AD in several manners. For example, in response to deposited fibrillar Aßeta in CAA, cognitive impairment is worsened by a chronic state of perivascular neuro-inflammation that is characterized by reactive astrocytes and activated microglia that produce pro-inflammatory cytokines, chemokines, reactive oxygen and nitrogen species. Also, CAA increases perivascular expression and activation of certain proteolytic enzymes that contribute to microinfarcts, disruption of vessel wall integrity and cerebral hemorrhage, which are all highly deleterious manifestations of the disease. Thus, perivascular neuroinflammation and harmful vascular events such as hemorrhage and/or vessel occlusions that are associated with cerebral vascular amyloid represent potential therapeutic targets to treat CAA/VCID/ADRD. We reported that mimetic peptides of apolipoprotein-E displayed robust anti-inflammatory and neuroprotective activities in models of stroke and intracranial hemorrhage (ICH), which share many characteristics with CAA/VCID/ADRD. To improve this apoE-mimetic approach, we modified COG1410 to generate RGN728, a new apoE-mimetic with improved anti-inflammatory and neuroprotective activity in rat and non-human primate models of stroke. We now propose a collaborative effort to test whether the novel rat CAA model created by Van Nostrand and colleagues will improve when treated with our anti-inflammatory and neuroprotective RGN728 created by Li and Vitek. Behavioral, pathological and biochemical outcomes will be measured to determine whether there is a statistically significant improvement upon RGN728 treatment. Successful improvement of outcomes will lay the foundation for advanced preclinical efficacy and safety tests to enable human clinical trials of the novel neuroprotective and anti-inflammatory agent, RGN728 in CAA/VCID.