Blood-Brain Barrier Crossing Renin-Angiotensin Drugs and Cognition in the Elderly: A Meta-Analysis

Abstract

Hypertension is an established risk factor for cognitive decline and dementia in older adults, highlighting the potential importance of antihypertensive treatments in prevention efforts. Work surrounding antihypertensive treatments has suggested possible salutary effects on cognition and neuropathology. Several studies have specifically highlighted renin-angiotensin system drugs, including AT1-receptor blockers and angiotensin-converting-enzyme inhibitors, as potentially benefiting cognition in later life. A small number of studies have further suggested renin-angiotensin system drugs that cross the blood-brain barrier may be linked to lower dementia risk compared to their nonpenetrant counterparts. The present meta-analysis sought to evaluate the potential cognitive benefits of blood-brain barrier crossing renin-angiotensin system drugs relative to their nonpenetrant counterparts. We harmonized longitudinal participant data from 14 cohorts from 6 countries (Australia, Canada, Germany, Ireland, Japan, United States), for a total of 12 849 individuals at baseline, and assessed for blood-brain barrier crossing potential within antihypertensive medications used by cognitively normal participants. We analyzed 7 cognitive domains (attention, executive function, language, verbal memory learning, recall, mental status, and processing speed) using ANCOVA (adjusted for age, sex, and education) and meta-analyses. Older adults taking blood-brain barrier-crossing renin-angiotensin drugs exhibited better memory recall over up to 3 years of follow-up, relative to those taking nonpenetrant medications, despite their relatively higher vascular risk burden. Conversely, those taking nonblood-brain barrier-penetrant medications showed better attention over the same follow-up period, although their lower vascular risk burden may partially explain this result. Findings suggest links between blood-brain barrier crossing renin-angiotensin drugs and less memory decline.

Protective Effect of Renin-Angiotensin System Inhibitors on Parkinson’s Disease: A Nationwide Cohort Study

“…Moreover, some experimental studies on the effects of telmisartan and candesartan, which are typical ARBs known to penetrate the BBB, showed an improvement in dopaminergic and mitochondrial functions in an animal PD model (Sekar et al, 2018;Ray et al, 2021). Previous clinical studies on dementia also showed that BBB-crossing RAS inhibitors have better neuroprotective effects than non-BBB-crossing agents (Ho et al, 2021;Ouk et al, 2021). Thus, our real-world evidence suggests the potential value of BBB-crossing ARBs as a prophylactic or disease-modifying therapy for PD.…”

Dysregulation of ACE-1 in Normal Aging and the Early Stages of Alzheimer’s Disease

“…A recent clinical trial of losartan, a classical AGTR1-receptor blocker, did not reduce rates of brain atrophy or cognitive decline compared to placebo in patients with mild-moderate AD ( 13 ). In view of recent studies indicating that BBB penetrating RAS agents better preserve memory compared to nonpenetrant BBB ( 48 , 49 ), future clinical trials should focus on RAS modifiers known to cross the BBB.…”

Visit-to-Visit Blood Pressure Variability and Longitudinal Tau Accumulation in Older Adults

“…lood pressure (BP) and its modulation by antihypertensive treatment has been extensively investigated in relation to cognitive decline and dementia. [1][2][3][4][5][6][7] The role of BP elevation in dementia risk has garnered substantial attention in part because of the clinical availability of BP measures, the high rates of hypertension in older adults, and the wide availability of antihypertensive medications. [8][9][10] Recent randomized controlled trial results from the SPRINT study (Systolic Blood Pressure Intervention Trial) indicate aggressive BP lowering prevents cognitive impairment, relative to standard BP control, 11 underscoring the potential importance of BP and its modulation in the prevention of cognitive decline.…”