Safety and biomarker effects of candesartan in non-hypertensive adults with prodromal Alzheimer’s disease
Authors: Hajjar Ihab , Okafor Maureen , Wan Limeng , Yang Zhiyi , Nye Jonathon A , Bohsali Anastasia , Shaw Leslie M , Levey Allan I , Lah James J , Calhoun Vince D , Moore Reneé H , Goldstein Felicia C 
Published: October 2022

Abstract
Observational studies suggest that angiotensin receptor blockers in hypertensive adults are associated with lower post-mortem indicators of Alzheimer’s disease pathology. Candesartan, an angiotensin receptor blocker, has a positive cognitive effect in mild cognitive impairment with hypertension. However, its safety and effects in non-hypertensive individuals with Alzheimer’s disease are unclear. This is the first double-blind randomized placebo-controlled trial aimed to assess safety and effects of 1-year therapy of candesartan on biomarkers and clinical indicators of Alzheimer’s disease in non-hypertensive individuals with biomarker-confirmed prodromal Alzheimer’s disease. Seventy-seven non-hypertensive participants 50 years or older (mean age: 68.1 years; 62% women; 20% African American) with mild cognitive impairment and biomarker confirmed Alzheimer’s disease were randomized to escalating doses of once daily oral candesartan (up to 32 mg) or matched placebo. Main outcomes included safety and tolerability of candesartan, cerebrospinal fluid biomarkers (amyloid-β42, amyloid-β40, total tau and phospho-tau). Additional exploratory outcomes included PET imaging (Pittsburgh Compound-B (11C-PiB) and 18F-flortaucipir), brain MRI (structural and connectivity measures) and cognitive functioning. Analyses used intention-to-treat approach with group comparisons of safety measures using Chi-square test, and repeated measures mixed effects models were used to assess candesartan effects on main and exploratory outcomes (ClinicalTrials.gov, NCT02646982). Candesartan was found to be safe with no significant difference in safety measures: symptoms of hypotension, renal failure or hyperkalemia. Candesartan was also found to be associated with increases in cerebrospinal fluid Aβ40 (between-group mean difference: 1211.95 pg/ml, 95% confidence interval: 313.27, 2110.63) and Aβ42 (49.51 pg/ml, 95% confidence interval: −98.05, −0.98) reflecting lower brain amyloid accumulation. Candesartan was associated with decreased 11C-PiB in the parahippocampal region (−0.1104, 95% confidence interval: −0.19, −0.029) which remained significant after false discovery rate correction, and with an increase in functional network connectivity in the subcortical networks. Candesartan was further associated with improved executive function (Trail Making Test Part B) performance (−11.41 s, 95% confidence interval: −11.94, −10.89) and trended for an improved global cognitive functioning reflected by a composite cognitive score (0.002, 95% confidence interval: −0.0002, 0.005). We did not observe significant effects on tau levels, hippocampal volume or other cognitive measures (memory or clinical dementia rating scale-sum of boxes). In conclusion, among non-hypertensive prodromal Alzheimer’s disease, candesartan is safe and likely decreases brain amyloid biomarkers, enhances subcortical brain connectivity and has favourable cognitive effects. These findings suggest that candesartan may have an important therapeutic role in Alzheimer’s disease, and warrant further investigation given the lack of clear treatment options for this devastating illness.