Reducing pathology in Alzheimer’s Disease through Angiotensin TaRgeting

Study Code / Acronym
Award Number
Award Type
EME Researcher Led
Efficacy and Mechanism Evaluation
Status / Stage
1 March 2013 -
1 August 2019
Duration (calculated)
06 years 05 months
Funding Amount
Funder/Grant study page
Contracted Centre
North Bristol NHS Trust
Principal Investigator
Professor Patrick Kehoe
PI Contact
WHO Catergories
Development of novel therapies
Improving clinical trials
Disease Type
Alzheimer's Disease (AD)

CPEC Review Info
Reference ID166
ResearcherReside Team


Study Code / AcronymRADAR
Award Number11/47/03
Status / StageCompleted
Start Date20130301
End Date20190801
Duration (calculated) 06 years 05 months
Funder/Grant study pageNIHR
Contracted CentreNorth Bristol NHS Trust
Funding Amount£1,840,961.68


A two arm blinded placebo-controlled randomised controlled trial (RCT). Study population: RADAR will study incident and prevalent cases of mild-to-moderate AD diagnosed according to revised NINCDS-ADRDA criteria. Participants can be hypertensive or normotensive and on any existing dementia drugs with no age restrictions. Inclusion requires an MMSE score of 15-24; a modified Hachinski score of 4 or less, a previous CT or MRI scan supporting a diagnosis of AD and the presence of care-giver in daily contact. Exclusion criteria include anyone already taking other renin angiotensin acting drugs or potassium diuretics; contraindications or conditions that make MRI unfeasible; a BP of < 120/75 mmHg, > 160/110 mmHg and/or postural hypotension (BP drop of >20/10 mmHg after 3-5 minutes); prior history of stroke or transient ischaemic attacks; unstable congestive heart failure; severe renal or hepatic impairment or a history of gout; other primary neurodegenerative or psychiatric disorders other than AD or other possible primary causes of dementia; a recent history of untreated clinically significant hypothyroidism or hyperthyroidism (patients are euthyroid and stable are eligible). Interventions: Patients will be randomised to either encapsulated 100mg generic losartan or placebo once daily for 12 months after a 1 month open label phase which establish drug tolerability. Outcomes: Primary outcome measures will be the rate of whole brain atrophy as a surrogate measure of cognitive decline. Secondary outcomes: (i) white matter hyperintensities (WMH) volume and cerebral blood flow (CBF) (also surrogate markers of cognitive decline and disease progression); (ii) performance on a standard battery of assessments of memory, cognitive function, activities of daily living and quality of life; (iii) changes to levels of plasma protein markers of AD (Abeta, acetylcholinesterase) and AngII pathway-linked AD-related markers (ACE, NEP, TNFalpha, CRP). Major assessments (for all outcomes) will be at baseline and 12 months while an added interim 6 month visit will include cognitive assessments only. Safety monitoring for blood pressure and side effects will occur at weekly intervals of the open-label phase and at 14 days, 3, 6 and 9 months post-randomisation. Based on recent studies conducted within ADNI to optimise protocols for imaging use in clinical trials of AD, we will recruit a sample size of 228 participants (recruited over 15 months) to 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 to measure our outcomes, measuring between-group estimates of effectiveness derived from appropriate (linear or logistic) multivariable regression models adjusting for minimisation variables and value of outcome at baseline and at the end of the study (12 month follow-up for all primary and secondary outcomes) and for the 6 month cognitive assessment data.

Plain English Summary

Alzheimer’s disease (AD) profoundly affects memory and brain function in older individuals. It is a slow progressive disease which can last for a number of years – a heart-breaking, exhausting and often costly reality for family and health services. With an ageing population, AD health care provision needs will significantly rise. Existing treatments only temporarily treat specific imbalances in the brain but as yet there is no cure for AD. We will undertake a clinical trial at Bristol (in collaboration with University College London (UCL)) to see if losartan, a well tolerated blood pressure drug, can complement current treatments for AD. We believe losartan will slow down the progression of AD by improving brain blood flow and altering chemical pathways that cause brain cell damage, brain shrinkage and memory problems in AD. This study will use brain imaging to measure if losartan reduces brain shrinkage which is already known to be strongly linked with reduced memory function. We will also investigate if losartan alters the profile and activity of various blood-borne proteins which may be predictive of rates of disease progression. We want to study losartan because human and animal studies tell us reduced brain blood flow is a very common and early feature in AD and contributes to memory failure. Losartan blocks a chemical pathway (angiotensin II) to improve memory problems in mice designed to have Alzheimer’s features and in people given chemicals to temporarily affect their memories. Losartan is thought to stop angiotensin II from preventing the release of vital memory chemicals in the brain. We recently found that people who have previously taken losartan, or similar drugs, have lower risk of developing AD compared to other blood pressure drugs. These drugs also slow the rate of deterioration in patients with Alzheimer’s. However clinical trials of losartan and related drugs in people with high blood pressure have shown little evidence of a reduced risk of cognitive decline or dementia in general. These studies however did not include or specifically identify AD patients and would have had many patients with mainly vascular dementia patients which have not benefited. There are no major ethical issues in this study. It may also appear costly for a small study, but it uses expensive surrogate markers of disease that can be studied in a shorter time. RADAR will offer great value for money if this cheap (3-4p per day) well tolerated drug is found to be beneficial in AD. RADAR will also provide the requisite evidence needed to justify the much larger multi-centre trial (which will use cheaper measures of disease over a longer study time) that will be needed to provide the final proof of losartan’s benefit in AD. This trial which involves leading international centres for angiotensin research in dementia (Bristol) and imaging (UCL) should provide such evidence.