Journal article
Safety and biomarker effects of candesartan in non-hypertensive adults with prodromal Alzheimer's disease
Brain communications, v 4(6), pp fcac270-fcac270
02 Nov 2022
PMID: 36440097
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Observational studies suggest that angiotcnsin 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-beta 42, amyloid-beta 40, total tau and phospho-tau). Additional exploratory outcomes included PET imaging (Pittsburgh Compound-B (C-11-PiB) and F-18-flortaucipir), brain MRI (structural and connectivity measures) and cognitive functioning. Analyses used intentionto-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 A beta 40 (between-group mean difference: 1211.95 pg/ml, 95% confidence interval: 313.27, 2110.63) and A beta 42 (49.51 pg/ml, 95% confidence interval: - 98.05, -0.98) reflecting lower brain amyloid accumulation. Candesartan was associated with decreased 1 C-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.
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Details
- Title
- Safety and biomarker effects of candesartan in non-hypertensive adults with prodromal Alzheimer's disease
- Creators
- Ihab Hajjar - The University of Texas Southwestern Medical CenterMaureen Okafor - Emory UniversityLimeng Wan - Emory UniversityZhiyi Yang - Emory UniversityJonathon A. Nye - Emory UniversityAnastasia Bohsali - Center for Translational Research in Neuroimaging and Data ScienceLeslie M. Shaw - University of PennsylvaniaAllan Levey - Emory UniversityJames J. Lah - Emory UniversityVince D. Calhoun - Center for Translational Research in Neuroimaging and Data ScienceRenee H. Moore - Emory UniversityFelicia C. Goldstein - Emory University
- Publication Details
- Brain communications, v 4(6), pp fcac270-fcac270
- Publisher
- Oxford University Press
- Number of pages
- 12
- Grant note
- K24 AG062786; AG049752; RF1AG051633 / Alzheimer's Drug Discovery Foundation (ADDF) National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Epidemiology and Biostatistics
- Web of Science ID
- WOS:000892582800004
- Scopus ID
- 2-s2.0-85144785884
- Other Identifier
- 991021448166304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Clinical Neurology
- Neurosciences