Neuro-renin-angiotensin-aldosterone system axis in alzheimer's disease: from molecular dysregulation to therapeutic redirection.

Alzheimer's disease (AD) is characterized by progressive neurodegeneration marked by tau hyperphosphorylation, amyloid-beta (Aβ) buildup, neuroinflammation, and blood-brain barrier (BBB) dysfunction. Although much attention is paid to understanding amyloid and tau pathologies, there are still no disease-modifying solutions. Recent evidence indicates that the brain-specific Renin-Angiotensin-Aldosterone System (RAAS), conventionally involved in the regulation of cardiovascular diseases, could be central in controlling the key neuropathological alterations in AD. This review explains the binary roles of the classical (ACE/Ang II/AT₁R) and alternative (ACE 2 /Ang-(1-7)/MasR) axis of the RAAS in the central nervous system (CNS), including how overactivation of the classical axis intensifies oxidative stress and Aβ plaque formation, tau hyperphosphorylation, and BBB disruption, and how the alternative axis is neuroprotective, anti-inflammatory, and vasodilatory effects. We integrate molecular, cellular, and translational information about RAAS-mediated regulation of neurovascular integrity, glial activation, and synaptic resilience. We also discuss the repurposing of centrally acting ACE inhibitors and angiotensin II receptor blockers (ARBs), as well as next-generation MasR agonists and recombinant ACE2, as promising tools to re-establish neuro-RAAS balance. These findings together support a paradigm shift of the RAAS as a system-level therapeutic axis in AD. Conclusively, there is a need to highlight the necessity of specific CNS biomarkers and the accuracy of medicine models that can direct interventions on RAAS-related actions and redesign AD administration beyond symptom resolution to modify the disease.