BP drug Candesartan lowers amyloid deposition and improves cognition in Alzheimer's patients

USA: A study suggested the safety of Candesartan among non-hypertensive prodromal Alzheimer's disease individuals. The researchers advocated its role in decreasing brain amyloid biomarkers, enhancing subcortical brain connectivity, and having favorable cognitive effects.

The study is published in BRAIN COMMUNICATIONS by Oxford Academic.

The renin-angiotensin system (RAS) is related to cognition and neurodegeneration. Candesartan is an angiotensin receptor blocker (ARB) modulating RAS. It exerts positive neurocognitive effects, especially in hypertension and mild cognitive impairment (MCI) cases. There needs to be more data on their cognitive effects in non-hypertensive individuals.

ARBs have a pleiotropic effect and selectively block angiotensin receptor type 1 (AT1), whose activation leads to vasoconstriction, endothelial dysfunction, and smooth muscle hypertrophy while AT2 activation decreases superoxide production, activates neuronal repair systems and neurite growth, and decreases inflammation and axonal degeneration. This positively affects cognition. This is the AT2 hypothesis and can be leveraged to develop treatments for Alzheimer's disease(AD). ARBs may uniquely activate the ACE2/MAS and angiotensin IV axes and exhibit neurocognitive protection.

There is a therapeutic need to determine Candesartan's potential, safety, and efficacy in engaging the amyloid cascade in non-hypertensive cases. Previous preclinical animal and human autopsy studies have shown modulation with ARBs may affect AD biomarkers. However, no clinical trials have been conducted to analyze the effects of Candesartan on cerebrospinal fluid (CSF) biomarkers.

Against the above background, a study was conducted by a team of researchers led by Dr. Hab Hajjar from the Department of Neurology at Emory University School of Medicine and the Department of Neurology from the University of Texas Southwestern in biomarker-positive AD individuals to assess the safety, tolerability, and candesartan effects compared to placebo on AD biomarkers following 1-year treatment in non-hypertensive older adults in prodromal Alzheimer's disease.

The study points at a glance are:

• The study was a double-blind, randomized trial.

• The study participants were 77 non-hypertensive older adults.

• The mean age of the participants was 68 years.

• The study included 62 % women, and 20 % were African American.

• The participants had mild cognitive impairment due to Alzheimer's disease.

• The participants were given 32 mg of Candesartan.

• The endpoints at baseline were six months and 12 months.

• The study period was one year, after which follow-up was done.

• The primary study outcomes were safety and tolerability of Candesartan and CSF biomarkers (amyloid-β42, amyloid-β40, total tau, phospho-tau).

• Additional outcomes were PET imaging, brain MRI and cognitive functioning.

• Candesartan had no significant difference in safety measures, including hypotension symptoms, renal failure, or hyperkalemia.

• Candesartan was associated with increases in CSF Aβ40. The mean difference between-group was 1211.95 pg/ml, and Aβ42 was 49.51 pg/ml.

• Candesartan was related to decreased 11C-PiB in the parahippocampal region.

• Candesartan improved executive function performance (-11.41 seconds) and global cognitive functioning. In the placebo group, there was continued deterioration of cognitive functions.

• Four patients in Candesartan and one in the placebo group experienced symptomatic hypotensive episodes.

The researchers said, "We did not observe significant effects on tau levels, hippocampal volume, or other cognitive measures."

The co-researcher Dr. Maureen Okafor from the Department of Neurology at Emory University School of Medicine, finally wrote, "Candesartan lowers brain Aβ indicators and shown favorable neurocognitive and brain connectivity measures without any significant safety concerns in our study. This shows that it has a high potential for offering both disease-modifying and symptomatic effects in early Alzheimer's disease."

They mentioned that Candesartan might have a significant therapeutic role in Alzheimer's disease, which warranted further investigation to establish clarity for the treatment options. More extensive trials should be conducted to develop the therapeutic aspects of AD.

Further reading:

Ihab Hajjar, Maureen Okafor, Limeng Wan, Zhiyi Yang, Jonathon A Nye, Anastasia Bohsali, Leslie M Shaw, Allan I Levey, James J Lah, Vince D Calhoun, Reneé H Moore, Felicia C Goldstein, Safety and biomarker effects of Candesartan in non-hypertensive adults with prodromal Alzheimer's disease, Brain Communications, 2022; fcac270.