Journal of Alzheimer's Disease - Volume 61, issue 2

Authors: Kehoe, Patrick G. | Blair, Peter S. | Howden, Beth | Thomas, David L. | Malone, Ian B. | Horwood, Jeremy | Clement, Clare | Selman, Lucy E. | Baber, Hannah | Lane, Athene | Coulthard, Elizabeth | Passmore, Anthony Peter | Fox, Nick C. | Wilkinson, Ian B. | Ben-Shlomo, Yoav

Article Type: Research Article

Abstract: Background: Anti-hypertensives that modify the renin angiotensin system may reduce Alzheimer’s disease (AD) pathology and reduce the rate of disease progression. Objective: To conduct a phase II, two arm, double-blind, placebo-controlled, randomized trial of losartan to test the efficacy of Reducing pathology in Alzheimer’s Disease through Angiotensin TaRgeting (RADAR). Methods: Men and women aged at least 55 years with mild-to-moderate AD will be randomly allocated 100 mg encapsulated generic losartan or placebo once daily for 12 months after successful completion of a 2-week open-label phase and 2-week placebo washout to establish drug tolerability. 228 participants will provide …at least 182 subjects with final assessments to provide 84% power to detect a 25% difference in atrophy rate (therapeutic benefit) change over 12 months at an alpha level of 0.05. We will use intention-to-treat analysis, estimating between-group differences in outcomes derived from appropriate (linear or logistic) multivariable regression models adjusting for minimization variables. Results: The primary outcome will be rate of whole brain atrophy as a surrogate measure of disease progression. Secondary outcomes will include changes to 1) white matter hyperintensity volume and cerebral blood flow; 2) performance on a standard series of assessments of memory, cognitive function, activities of daily living, and quality of life. Major assessments (for all outcomes) and relevant safety monitoring of blood pressure and bloods will be at baseline and 12 months. Additional cognitive assessment will also be conducted at 6 months along with safety blood pressure and blood monitoring. Monitoring of blood pressure, bloods, and self-reported side effects will occur during the open-label phase and during the majority of the post-randomization dispensing visits. Conclusion: This study will identify whether losartan is efficacious in the treatment of AD and whether definitive Phase III trials are warranted. Show more

Keywords: Alzheimer’s disease, clinical trial, hypertension, parental history, renin-angiotensin system, vascular risk

DOI: 10.3233/JAD-170101

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 803-814, 2018

Authors: Wharton, Whitney | Goldstein, Felicia C. | Tansey, Malú G. | Brown, Alexandra L. | Tharwani, Sonum D. | Verble, Danielle D. | Cintron, Amarallys | Kehoe, Patrick G.

Article Type: Research Article

Abstract: Research indicates that certain antihypertensive medications alter Alzheimer’s disease (AD) biomarkers in Caucasians. The renin angiotensin system (RAS) regulates blood pressure (BP) in the body and the brain and may directly influence AD biomarkers, including amyloid-β (Aβ) neuropathology, cerebral blood flow (CBF), and inflammatory markers. This hypothesis is supported by studies, including ours, showing that antihypertensives targeting the RAS reduce the risk and slow the progression of AD in Caucasians. While mounting evidence supports a protective role of RAS medications in Caucasians, this mechanism has not been explored in African Americans. To assess the mechanism by which RAS medications modify …the brain RAS, cerebrospinal fluid (CSF) Aβ, CBF, and inflammatory markers in African Americans, we are conducting an eight month, Phase Ib randomized, placebo controlled trial, enrolling 60 middle-aged (45–70 years), non-demented individuals, at risk for AD by virtue of a parental history. Participants include normotensive and treated hypertensives that have never been exposed to a RAS medication. Participants are randomized (1 : 1:1) by gender and BP medication use (yes/no) to one of three groups: placebo, or 20 mg, or 40 mg telmisartan (Micardis), to determine the dose required to penetrate the CNS. Our overarching hypothesis is that, compared to placebo, both doses of telmisartan will penetrate the CNS and produce salutary, dose dependent effects on the brain RAS as well as CSF Aβ, CBF, and CSF inflammatory markers in African Americans, over eight months. This manuscript describes the trial rationale and design. Show more

Keywords: Alzheimer’s disease, clinical trial, hypertension, parental history, renin angiotensin system, vascular risk

DOI: 10.3233/JAD-161198

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 815-824, 2018

Authors: Jang, Hyemin | Ye, Byoung Seok | Woo, Sookyoung | Kim, Sun Woo | Chin, Juhee | Choi, Seong Hye | Jeong, Jee Hyang | Yoon, Soo Jin | Yoon, Bora | Park, Kyung Won | Hong, Yun Jeong | Kim, Hee Jin | Lockhart, Samuel N. | Na, Duk L. | Seo, Sang Won

Article Type: Correction

DOI: 10.3233/JAD-179010

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 825-825, 2018