The Brain AT2R—a Potential Target for Therapy in Alzheimer’s Disease and Vascular Cognitive Impairment: a Comprehensive Review of Clinical and Experimental Therapeutics

Dementia is a potentially avertable tragedy, currently considered among the top 10 greatest global health challenges of the twenty-first century. Dementia not only robs individuals of their dignity and independence, it also has a ripple effect that starts with the inflicted individual’s family and projects to the society as a whole. The constantly growing number of cases, along with the lack of effective treatments and socioeconomic impact, poses a serious threat to the sustainability of our health care system. Hence, there is a worldwide effort to identify new targets for the treatment of Alzheimer’s disease (AD), the leading cause of dementia. Due to its multifactorial etiology and the recent clinical failure of several novel amyloid-β (Aβ) targeting therapies, a comprehensive “multitarget” approach may be most appropriate for managing this condition. Interestingly, renin angiotensin system (RAS) modulators were shown to positively impact all the factors involved in the pathophysiology of dementia including vascular dysfunction, Aβ accumulation, and associated cholinergic deficiency, in addition to tau hyperphosphorylation and insulin derangements. Furthermore, for many of these drugs, the preclinical evidence is also supported by epidemiological data and/or preliminary clinical trials. The purpose of this review is to provide a comprehensive update on the major causes of dementia including the risk factors, current diagnostic criteria, pathophysiology, and contemporary treatment strategies. Moreover, we highlight the angiotensin II receptor type 2 (AT2R) as an effective drug target and present ample evidence supporting its potential role and clinical applications in cognitive impairment to encourage further investigation in the clinical setting.