Role of angiotensin-converting enzyme in cognitive aging: evidence from preclinical and clinical studies

Angiotensin-Converting Enzyme (ACE, EC 3.4.15.1), also termed as kininase II or dipeptidyl carboxypeptidase I, is a crucial component of the Renin angiotensin system (RAS). ACE is extensively recognized for its role in the regulation of the cardiovascular system. Emerging evidence supports a neurobiological role of ACE, promoting investigations into its central functions responsible for the modulation of memory and cognitive function, particularly through the use of clinically approved ACE inhibitors (ACE-Is). This review comprehensively analyzes preclinical and clinical findings to date to evaluate the contribution of ACE to cognitive processes and discusses its potential as a therapeutic target for cognitive improvement. Mechanistically, ACE influences cognition through regulation of angiotensin II (Ang II) signaling, as well as modulating other neuropeptides such as substance P. These pathways intersect with processes implicated in cognitive decline, including oxidative stress, neuroinflammation, and cholinergic neurotransmission. Pre-clinical studies consistently demonstrate that ACE-Is confer neuroprotective effects by attenuating Ang II-mediated signaling, restoring redox and inflammatory balance, and improving synaptic plasticity. Clinical evidence provides partial support to these findings, although results remain heterogeneous. Variability in clinical outcomes appears to depend on factors such as patient age, baseline comorbidities, and central availability of the ACE-I. Collectively, this study highlights a non-canonical role of central ACE inhibition in modulating cognitive function, suggesting its promise as a therapeutic strategy for addressing age and disease-associated cognitive dysfunction. Future research should thus prioritize delineation of tissue-specific actions of ACE along with comprehensive examination of ACE genotype-drug interactions, and head- to-head comparison of centrally active ACE-Is with other RAS modulators for their nootropic potential.