Background

Candesartan is an angiotensin II receptor antagonist used around the world to treat elevated blood pressure and congestive heart failure. Approved in 1997, the drug is available in generic form. The most common side effects are dizziness and headache. Candesartan crosses the blood-brain barrier.

Managing hypertension with medications reduces the risk of mild cognitive impairment (Jan 2019 news). Candesartan and 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, and 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 another study, use of ARBs was associated with slower amyloid accumulation in cognitively normal, amyloid positive people, but not in those with mild cognitive impairment or dementia (Ouk et al., 2021).

Preclinical work in models of chronic hypertension, stroke, kidney disease, and postoperative cognitive dysfunction support the idea that candesartan acts in the brain to attenuate brain inflammation and cognitive impairment, independent of its effect on blood pressure (Ahmed et al., 2018; Ahmed et al., 2018; Li et al., 2014).

In one AD mouse model, the ARB losartan improved memory and reduced plaque load (Wang et al., 2007), though in a similar model, candesartan reduced neuroinflammation but failed to reduce amyloid plaque or improve cognitive function (Trigiani et al., 2018). In 5XFAD mice, intranasal candesartan reduced brain inflammation and reduced amyloid burden by increasing Aβ uptake into microglia; this study did not assess cognition (Torika et al., 2018). A study of mice expressing human APOE4, with or without high Aβ, found candesartan improved memory and hippocampal inflammation in females, but not males (Scheinman et al., 2021).

Findings

Several large studies have evaluated candesartan and cognitive decline in older adults. In the SCOPE trial of nearly 5,000 elderly people with mild hypertension, candesartan reduced nonfatal stroke by one-third compared to other hypertension treatment regimens, but did not change the trajectory of cognitive decline measured by change in the MMSE (Lithell et al., 2003). More extensive cognitive testing in a subset of 257 patients found a small slowing of decline on tests of attention and memory, but no difference in working memory or executive function (Saxby et al., 2008).

In the HOPE3 study of 2,361 older adults with marginally elevated blood pressure, no difference was detected in the rate of decline on tests of executive function or the Montreal Cognitive Assessment in people taking candesartan or placebo for six years (Mar 2019 news; Bosch et al., 2019).

The first trial to evaluate candesartan in people selected for mild cognitive impairment began in January 2008. The Phase 2 AVEC trial compared candesartan to the ACE inhibitor lisinopril or the diuretic hydrochlorothiazide on outcomes of cognition and blood flow in 53 older people with hypertension and cognitive impairment, but without dementia (Hajjar et al., 2009). Candesartan was titrated to a maximum of 32 mg daily, for one year, and all groups received additional anti-hypertensives as needed to achieve a target blood pressure of 140/90. The primary outcomes were tests of executive function and memory, cerebral blood flow, and vasoreactivity. The trial ran at one senior care facility in Massachusetts. According to published results, treatment with candesartan, but not lisinopril or hydrochlorothiazide, led to improved cerebral blood flow and performance on the Trail Making Test Part B measure of executive function (Hajjar et al., 2013).

From August 2014 to December 2018, the same investigators ran a Phase 2 trial comparing candesartan to lisinopril in people over 55 with high blood pressure and executive mild cognitive impairment. Named CALIBREX, this study enrolled 176 participants who received a maximum dose of 32 mg candesartan daily, with other medications as needed to achieve the target blood pressure. The primary outcome was change in executive function measured with the Trail Making Test Part B and the EXAMINER battery. Secondary measures included tests of episodic memory, language, and attention, MRI measures of white-matter hyperintensity, resting-state functional MRI, and ASL-MRI to measure cerebral perfusion. In groups with equally effective blood-pressure control, the candesartan-treated patients did better on the Trail Making Test Part B and HVLT, but not the EXAMINER battery, compared to those on lisinopril (Hajjar et al., 2020).

In June 2016, the Phase 2 CEDAR trial began to test candesartan’s effects in people with Alzheimer’s disease who do not have high blood pressure. The trial enrolled 77 participants with mild cognitive impairment and PET or CSF evidence of brain amyloid, for a one-year, placebo-controlled treatment. Participants received the highest tolerated dose that maintained blood pressure above 100/40 and did not produce symptoms of hypotension, to a maximum of 32 mg daily. The primary outcomes measured tolerability, including symptoms of hypotension, changes in serum creatine or potassium, and the number of people who discontinue drug. Secondary outcomes include changes in CSF pTau181, Aβ42, and cytokines, plus measures of arterial and aortic stiffness. Other outcomes are clinical dementia rating, and tests of executive function and memory, MRI, and functional MRI. In January 2020, amyloid and tau PET were added. The study finished in August 2020; results are published (Hajjar et al., 2022). Candesartan was safe, causing no significant increase in symptoms of hypotension, renal failure, or low serum potassium compared to placebo. Treatment was associated with an increase in CSF Aβ40 and Aβ42. Candesartan did not change brain-wide amyloid PET signals, but did reduce accumulation in the parahippocampal region, and led to an increase in subcortical network functional connectivity. Cognitive tests revealed a transient improvement at six months in the Trail Making Part B test of executive function, and a trend toward improvement in a composite cognitive score. Candesartan did not change CSF tau, hippocampal volume, memory measures, or the CDR-SB.

In both the CALIBREX and CEDAR trials, candesartan treatment led to  improved cerebral microvascular function. This was measured by cerebrovascular reactivity to carbon dioxide using blood-oxygenation-level-dependent (BOLD) imaging. In both studies, candesartan treatment was associated with improved whole-brain cerebrovascular reactivity, independent of changes in blood pressure (Henley et al., 2023).

For more details, see clinicaltrials.gov.