The two most important risk factors for development and progression of cognitive impairment and dementia, including both vascular cognitive impairment (VCI) and Alzheimers disease (AD) are advanced age and hypertension. VCI, which includes post-stroke cognitive impairment (PSCI), is the 2nd leading cause of dementia worldwide and covers between 25-30% of total dementia cases. Unfortunately, no specific FDA approved treatments for VCI/PSCI exist. Clinical trial evidence supports that Angiotensin receptor blockers (ARBs), prevent cognitive and functional declines in older adults and lower risk of dementia. However, the role of ARB treatment in the acute phase of stroke has been complicated by its blood pressure (BP) lowering effect. The direct AT2R agonist C21 would achieve these protective effects without affecting BP.The aim of this dissertation was to investigate the potential role of RAS modulation/AT2R stimulation on occurrence and progression of VCI/ PSCI in young hypertensive and aged animals. This was accomplished with a set of long-term 2X2, randomized, double blind pre-clinical trials. Therapeutic agents were administeredchronically and in a manner in which they might be used in actual patients, with functional study outcomes also chosen to match those of published clinical trials.The experiments of this dissertation establish that treatment with RAS modulators effectively preserves cognitive function in young hypertensive and aged animals post-stroke. These agents also reduce cytotoxicity and prevent chronic reactive microgliosis in young hypertensive animals; even when treatment is delayed. Furthermore, daily administration of C21 prevents accumulation of A1-42 in young hypertensive and aged animals post-stroke as well as in aged hypertensive animals with chronic cerebral hypoperfusion. Aged SHR with chronic cerebral hypoperfusion exhibited considerable structural brain changes, including global and hippocampal atrophy, white matter lesions and ventricular enlargement on MRI scans. These changes were significantly lower in animals treated for 8 weeks with RAS modulators. Collectively, our findings demonstrate that RAS modulators effectively preserve cognition and prevent VCI/PSCI, even when treatment is delayed.