Synonyms: Cozaar®, MK0954
Chemical Name: 2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Approved for: Hypertension, diabetic neuropathy
Losartan is an angiotensin II receptor blocker used to treat high blood pressure. It reduces the risk of stroke in people with hypertension and heart enlargement. It is also used to protect against kidney damage due to diabetes. Approved in 1995, losartan is available in branded and generic forms. In 2017, it was the ninth most prescribed medication in the U.S. Common side effects include muscle cramps, stuffy nose, dizziness, and back pain. Losartan crosses the blood-brain barrier.
Managing hypertension with medications reduces the risk of mild cognitive impairment (Jan 2019 news). Losartan other angiotensin receptor blockers (ARBs) act on the renin-angiotensin system, which regulates blood pressure in the body and brain. Angiotensin II receptors also mediate inflammation, blood-brain barrier maintenance, neuron survival. Genetic, epidemiologic, and biological evidence implicates changes in the brain renin-angiotensin system in Alzheimer’s disease (reviewed in Kehoe 2018). ARB use is associated with a reduced incidence of cognitive impairment, dementia, and AD (e.g., Wharton et al., 2015; Barthold et al., 2018; also see Walker et al., 2020). In people with mild cognitive impairment, use of ARBs, but not other antihypertensives, is linked to lower brain amyloid load and CSF tau (Hajjar et al., 2012; Hajjar et al., 2015).
In animal models of AD, losartan given systemically attenuates brain inflammation and cognitive impairment, without affecting soluble Aβ or plaque load (e.g., Ongali et al., 2014) In another study, intranasal losartan reduced Aβ plaques and inflammatory markers in APP/PS1 mice, but no behavioral data were reported (Danielyan et al., 2010). In mice expressing a variant of the angiotensin-converting enzyme that raises the risk of AD in people, losartan prevented neurodegeneration (Oct 2020 news).
In other preclinical work, losartan reversed scopolamine-induced memory deficits in mice (Ababei et al., 2019), and reduced inflammation, perivascular Aβ deposits, and neurological deficits in hypertensive rats (Drews et al., 2019). Losartan also reportedly inhibits platelet-mediated Aβ aggregation, a possible contributor to cerebral amyloidosis (Donner et al., 2020).
Some animal studies suggest that losartan’s cognitive benefits depend on activation of the angiotensin IV receptor, which occurs downstream of angiotensin II receptor inhibition (Royea et al., 2017; Royea et al., 2020).
In 2013, the Phase 2 RADAR trial began testing the effects of one year of losartan treatment on brain structure in people clinically diagnosed with mild to moderate Alzheimer’s disease (Kehoe et al., 2018). All 228 participants started with a two-week, open-label dose titration to 100 mg losartan daily, the highest dose used for hypertension. Those who tolerated treatment went through a wash-out period, and were then randomized to drug or placebo. The primary outcome is change in whole brain volume on MRI; secondary outcomes include the number of white-matter hyperintensities and cerebral blood flow, tests of memory, cognitive function, activities of daily living and quality of life, along with safety and blood pressure monitoring. The study, carried out at multiple sites in the U.K., was completed in May 2019.
In September 2016, the Phase 2/3 Risk Reduction for Alzheimer’s Disease (rrAD) trial started to evaluate the effect of blood pressure control plus cholesterol lowering, with or without exercise, on cognitive health in people at risk for AD (Szabo-Reed et al., 2019). The trial is enrolling 513 participants without dementia but at high risk for AD due to a family history, or having self-reported subjective cognitive decline. They must be sedentary, and have high blood pressure, treated or untreated. The four-arm design will compare a regimen of supervised aerobic exercise versus stretching only, with or without losartan and a calcium channel blocker to lower blood pressure, plus atorvastatin. The trial will run for two years, with a primary endpoint of change in neurocognitive function on a composite of the ADCS-PACC and NIH Toolbox Cognition Battery. Secondary outcomes include domain-specific cognitive functions, whole brain and hippocampal volume on MRI, brain-blood flow, white-matter integrity, and functional connectivity. The trial will run through November 2021 at four sites in the U.S.
In April 2018, a Phase 2 trial began to measure the relationship between hypertension, intracranial blood flow, and Aβ accumulation in older adults. The study will compare the effects of standard blood pressure control using losartan and amlodipine to reduce systolic blood pressure to less than 130 mmHg, or intensive reduction to less than 120 mm Hg, for one year in 120 older participants with normal cognition. Primary outcomes will be changes in the variability of brain blood flow with each heartbeat, or intracranial pulsatility. Secondary outcomes include CSF Aβ and tau, brain perfusion, structural and functional MRI, measures of neurocognitive function, and patient-reported outcomes of physical and mental health. The trial is slated to end in October 2022.
Two small studies, one completed and one ongoing, are examining the effect of a single dose of losartan on emotional information processing and cognitive function, for the possible treatment of anxiety (Pulcu et al., 2019).
For details on losartan trials, see clinicaltrials.gov.
Last Updated: 23 Oct 2020
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