A comparison of drugs targeting the renin-angiotensin system and global cognition in aging

Background: Hypertension (HTN) is a major risk factor for Alzheimer's disease (AD) and related dementias. Renin-angiotensin system (RAS) medications, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), have been proposed to mitigate cognitive decline, but evidence remains inconsistent. Objective: Compare global cognition over time among ARB, ACEI, and non-RAS drug users. Methods: Data from the Rush Memory and Aging Project (1997–2006) included 2019 participants. Global cognition was assessed using a composite z-score of 19 cognitive tests. Participants were categorized by medication use: ARB, ACEI, or non-RAS. Analysis of covariance (ANCOVA) was performed to compare cognitive outcomes over 9 years, adjusting for baseline cognition, social determinants, and medical factors. Subgroup analyses evaluated cognitive domains and the impact of HTN. Results: At baseline, ARB and ACEI users had more vascular risk factors and medical conditions than non-RAS users. At 9 years, ARB users had slightly better global cognitive outcomes compared to ACEI (LS-mean difference: 0.015, 95% CI [−0.175, 0.205]) and non-RAS users (LS-mean difference: 0.06, 95% CI [−0.11, 0.23]), though differences were not statistically significant. ACEI users showed significant improvement in working memory compared to non-RAS users (LS-mean: 0.157, 95% CI [0.002, 0.313]). Among participants without HTN, ACEI use was associated with significantly reduced cognitive decline compared to non-RAS use. Conclusions: ARBs may benefit global cognitive function, while ACEIs may yield improvements in specific domains like working memory. Further studies are needed to confirm these findings and explore the impact of drug characteristics such as blood-brain-barrier penetration.