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Background: Medications that modify the renin–angiotensin system may reduce Alzheimer’s disease pathology and reduce the rate of disease progression., Objective: This study investigated whether taking the antihypertensive drug losartan, in addition to normal care, would slow the progression of Alzheimer’s disease when compared with a placebo., Design: A double-blind multicentre randomised controlled trial, after a 4-week open-label phase, with follow-up at 14 days and at 3, 6, 9 and 12 months. The primary outcome was based on measured imaging differences in brain volume between baseline and 12 months., Setting: Twenty-three NHS hospital trusts across England, Scotland and Northern Ireland., Participants: Patients diagnosed with mild-to-moderate Alzheimer’s disease were eligible to participate if they met the following criteria: (1) aged ≥ 55 years; (2) a Mini Mental State Examination score of 15–28; (3) a modified Hachinski Ischaemic Score of ≤ 5; (4) a previous computerised tomography, single-photon emission computed tomography or magnetic resonance imaging scan consistent with a diagnosis of Alzheimer’s disease; (5) a study companion who was willing to participate in the study; and (6) capacity to consent for themselves. Patients were ineligible if they were (1) taking or intolerant to renin–angiotensin system-related medications, (2) unlikely to undergo magnetic resonance imaging or (3) unlikely to complete the trial protocol. People who had blood pressure outside the normal ranges, defined cardiovascular issues, impaired liver or renal function, or a primary neurodegenerative disease that was not Alzheimer’s disease were also excluded, as were women who had not reached menopause and were unwilling to take relevant protocol-specific safety precautions., Intervention: The intervention was either 100 mg of overencapsulated losartan (Teva Pharmaceuticals Industries Ltd, Petah Tikva, Israel) daily or a matched placebo for 12 months., Main Outcome Measures: Difference in brain atrophy, represented by measurement of whole-brain volume before and following 12 months of treatment post randomisation, was measured using volumetric MRI and determined by boundary shift interval analysis. Secondary outcomes included changes in rates of Alzheimer’s disease progression (as assessed using the ADAS-Cog, Mini Mental State Examination and Neuropsychiatric Inventory), the volume of white matter hyperintensities, cerebral blood flow (assessed by magnetic resonance imaging), blood pressure, magnetic resonance imaging measures of atrophy and association with measures of cognitive decline, and drug compliance and tolerability., Results: A total of 261 participants entered the open-label phase, of whom 211 were randomised to the intervention ( n  = 105) or placebo ( n  = 106) arms. Of the 197 people (93%) who completed the study, 81% ( n  = 171) had a valid primary outcome. The difference in brain volume between arms was consistent with chance (–2.79 ml, 95% confidence interval –6.46 to 0.89 ml; p  = 0.19), and there was no evidence of benefit for any of the secondary outcome measures., Limitations: Our study had 82% power to detect treatment-based changes and, as a result, may have been underpowered or, more likely, the intervention, which may not have crossed the blood–brain barrier as much as expected, may have been given too late or for an insufficient amount of time in the disease process to influence the outcomes., Conclusions: Losartan administered over 12 months did not alter brain atrophy in Alzheimer’s disease., Future Work: Other related ‘sartans’ could be tested in patient groups with mild cognitive impairment and for longer to fully test this hypothesis., Trial Registration: Current Controlled Trials ISRCTN93682878 and EudraCT 2012-003641-15., Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation ; Vol. 8, No. 19. See the NIHR Journals Library website for further project information., (Copyright © Queen’s Printer and Controller of HMSO 2021. This work was produced by Kehoe et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.)