Alzheimer’s disease is a complex disease characterised by build ups of protein plaques and tangles within and around neurons, but has multiple other components affecting disease onset and progression.
One of the major components of Alzheimer’s disease is related to blood flow to and within the brain, with high blood pressure (hypertension) in midlife and late life increasing the risk of developing Alzheimer’s or a similar dementia. This gives key insights into the importance of cardiovascular and neurovascular health, and supports the evidence that stroke and neurovascular damage can lead to or progress the damage caused by dementia.
A pioneering clinical trial aims to treat Alzheimer’s disease pathology through use of a blood pressure lowering drug, losartan.
The phase 2 ‘Reducing pathology in Alzheimer’s Disease through Angiotensin taRgeting’ (referred to as RADAR) trial is an ongoing clinical trial which recruits men and women above 55 years of age, at locations across the UK, to be treated with losartan or a placebo for a 12-month period.
The RADAR trial chief investigator, Professor Pat Kehoe (Bristol, UK), is lead author on a recent publication outlining the rationale and design of the clinical research. This publication outlines the methodology used for the trial along with the crucial outcome measures.
Losartan is a currently licensed anti-hypertensive drug which has been shown to treat many aspects of cardiovascular hypertension (including reduced blood flow to the brain); but is able to cross the blood-brain barrier and is likely to affect multiple cellular and molecular pathways independent of systemic action.
The specific target of losartan is the renin-angiotensin system, which regulates the blood pressure throughout the body. The drug binds and blocks the action of an angiotensin type 1 receptor causing an increase in vessel diameter and reducing the blood pressure to the both the cardiovascular and neurovascular systems.
The Renin-angiotensin System
Interestingly, compared to other classes of blood pressure lowering drugs, losartan has been shown to be more effective in reducing Alzheimer’s risk. This correlates with evidence that many factors of the renin-angiotensin system are associated with Alzheimer’s disease, and findings that losartan reduces neuron damage following stroke in rats.
Outcome measures can be split into primary and secondary measures; with primary measures answering the most important question from the research, and secondary measures allowing for assessment of other relevant outcome measures for the trial.
Within the RADAR trial the primary outcome is to assess whether losartan affects the rate of brain volume loss (characteristic in Alzheimer’s disease) using magnetic resonance imaging (MRI), and the secondary measures focus on assessing the rate of cognitive decline and quality of life, as well as a range of measures which monitor the blood flow to the brain and indicators of brain injury.
The correlations between cognitive assessments to overall brain structure and functional changes within the brain can provide useful information, indicating the effect of losartan on both the brain physically and cognitively.
The hope is that this treatment can be used to either prevent or delay Alzheimer’s disease onset and progression, and will also provide better understanding of the disease on a cellular and molecular level.
The importance of the renin-angiotensin pathway in Alzheimer’s disease could lead to the establishment of biomarkers and other new therapeutics to treat the disease. In addition, this could validate the use of losartan (or similar drugs affecting vasculature) in a combination based therapy for Alzheimer’s treatment; using different drugs to target the multiple pathologies of the disease.
Kehoe PG, Blair PS, Howden B, Thomas DL, Malone IB, Horwood J, Clement C, Selman LE, Baber H, Lane A, Coulthard E, Passmore AP, Fox NC, Wilkinson IB, Ben-Shlomo Y. The Rationale and Design of the Reducing Pathology in Alzheimer’s Disease through Angiotensin TaRgeting (RADAR) Trial Journal of Alzheimer’s Disease. 19 December 2017. DOI: 10.3233/JAD-170101
Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester. Image: U.S. National Oceanic and Atmospheric Administration