The Effects of Ramipril in Individuals at Risk for Alzheimer's Disease: Results of a Pilot Clinical Trial

Abstract

Research shows that certain antihypertensives taken during midlife confer Alzheimer’s disease (AD) related benefits in later life. We conducted a clinical trial to evaluate the extent to which the angiotensin converting enzyme inhibitor (ACE-I), ramipril, affects AD biomarkers including CSF amyloid β levels (Aβ) and ACE activity, arterial function and cognition in participants with a parental history of AD. This four month randomized, double-blind, placebo-controlled, pilot clinical trial evaluated the effects of ramipril, a blood-brain-barrier (BBB) crossing ACE-I, in cognitively healthy individuals with mild, or Stage I hypertension. Fourteen participants were stratified by gender and apolipoprotein E ε4 (APOE ε4) status and randomized to receive 5mg of ramipril or matching placebo daily. Participants were assessed at baseline and month 4 on measures of CSF Aβ1–42 and ACE activity, arterial function and cognition. Participants were middle-aged (mean 54yrs) highly educated (mean 15.4yrs), and included 50% men and 50% APOEε4 carriers. While results did not show a treatment effect on CSF Aβ1–42 (p=0.836), data revealed that ramipril can inhibit CSF ACE activity (p=0.009) and improve blood pressure (BP), however there were no differences between groups in arterial function or cognition. In this study, ramipril therapy inhibited CSF ACE activity and improved BP, but did not influence CSF Aβ1–42. While larger trials are needed to confirm our CSF Aβ results, it is possible that prior research reporting benefits of ACE-I during midlife may be attributed to alternative mechanisms including improvements in cerebral blood flow or the prevention of Angiotensin II-mediated inhibition of acetylcholine.

Modulation of Renin‐Angiotensin System May Slow Conversion from Mild Cognitive Impairment to Alzheimer's Disease

“…Some prior studies have suggested cognitive and functional benefits of BBB‐crossing RAS‐acting antihypertensive medications. Epidemiological, histopathological, and more recently, clinical data suggest that the RAS is involved in AD incidence and progression, potentially through direct actions on A β neuropathology . Another study assessed the ability of 55 different antihypertensives to reduce A β oligomerization in vitro in hippocampal neurons from Tg2576 AD mice and found that RAS‐acting medications (valsartan) attenuated oligomeric A β pathology and A β ‐mediated cognitive deterioration .…”

“…The contribution of BBB permeability to cognitive impairment, as well as the salutary influence of BBB‐crossing RAS‐acting medications on cognition, have been reported . Moreover, BBB‐crossing RAS‐acting medications significantly reduce ACE levels in the brain in individuals at risk for AD by virtue of parental history …”

Defining the Relationship Between Hypertension, Cognitive Decline, and Dementia: a Review

“…Extended treatment and follow-up periods and larger sample sizes will likely be needed to reliably detect the effects of BP lowering on cognitive measures. By comparison, neurodegenerative and dementia-specific biomarkers (e.g., hippocampal atrophy and CSF-tau) may be more sensitive to treatment-related effects, but their validity as intermediate endpoints remains a subject of debate [181,182]. Future studies may also benefit from making use of a more comprehensive cognitive battery.…”

Ameliorative potential of angiotensin-converting enzyme inhibitor (ramipril) on chronic constriction injury of sciatic nerve induced neuropathic pain in mice

“…67 Ramiprilat penetrates from the blood into the CSF which inhibits the activity of soluble ACE at the spinal cord region. 68,69 Therefore, neuropathic pain parameters have assessed on the peripheral site (paw pain sensitivity response) as well as in the central site (tail pain sensitivity response).…”