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

Article type: Research Article

Authors: Wharton, Whitney^{a; b; c; *} | Stein, James H.^{b; d} | Korcarz, Claudia^{b; d} | Sachs, Jane^d | Olson, Sandra R.^{a; b; c} | Zetterberg, Henrik^f | Dowling, Maritza^{a; b; g} | Ye, Shuyun^{a; g} | Gleason, Carey E.^{a; b; c} | Underbakke, Gail^h | Jacobson, Laura E.^{a; b; c} | Johnson, Sterling C.^{a; b; c} | Sager, Mark A.^{a; b; i} | Asthana, Sanjay^{a; b; c; i} | Carlsson, Cynthia M.^{a; b; c}

Affiliations: [a] Alzheimer's Disease Research Center, University of Wisconsin, Madison, WI, USA | [b] School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA | [c] Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA | [d] Division of Cardiovascular Medicine, Atherosclerosis Imaging Research Program, Madison, Wisconsin, WI, USA | [e] Population Health Institute, University of Wisconsin, Madison, WI, USA | [f] Department Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at The University of Gothenburg, Mölndal, Sweden | [g] Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA | [h] University of Wisconsin Preventive Cardiology Program, Madison, WI, USA | [i] Wisconsin Alzheimer's Institute, Madison, WI, USA

Correspondence: [*] Correspondence to: Whitney Wharton, PhD, School of Medicine and Public Health, University of Wisconsin, William S. Middleton Memorial VA Hospital, 2500 Overlook Terrace, GRECC D4211, Madison, WI 53705, USA. E-mail: [email protected].

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 cerebrospinal fluid (CSF) amyloid-β (Aβ) levels 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 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 5 mg 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 54 y) and highly educated (mean 15.4 y), and included 50% men and 50% APOE ε4 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, however, there were no differences between groups in arterial function or cognition. In this study, ramipril therapy inhibited CSF ACE activity and improved blood pressure, 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.

Keywords: Alzheimer's disease, angiotensin converting enzyme, antihypertensive, arterial function, blood pressure, clinical trial, cognition, hypertension, prevention, vascular risk

DOI: 10.3233/JAD-2012-120763

Journal: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 147-156, 2012