Candesartan is associated with lower amyloid accumulation in non‐hypertensive prodromal Alzheimer's disease. (31st December 2021)

• Record Type: Journal Article
• Authors: Okafor, Maureen; Wan, Limeng; Saleh, Sabria; Moore, Renee' H; Shaw, Les M; Goldstein, Felicia C; Hajjar, Ihab
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 9
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-31
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.056594
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: We have previously reported that candesartan improves executive function and memory in hypertensives with MCI. It is unclear if this drug has an effect on AD mechanisms or biomarkers. Method: This randomized double‐blind clinical trial enrolled 77 non‐hypertensive participants (mean age: 68.1 years; n=48, 62% women; n=15, 20% African American) with prodromal AD. Individuals were screened and underwent cognitive and physical assessments, lumbar puncture, and blood collection at baseline, 6 months and 12 months. All participants were randomized to escalating doses of candesartan (up to 32 mg daily) or matching placebo. We investigated the target engagement of 1‐year treatment of candesartan vs placebo in MCI patients neither clinically diagnosed nor taking medication for hypertension, who have evidence of AD pathology. We assessed the effect of candesartan vs placebo on CSF AD biomarkers (amyloid‐β (Aβ)42, Aβ40, total tau, and phospho‐tau181 (p‐tau181 )) analyzed on the Fujirebio Lumipulse platform using Fujirebio immunoassay reagents. Outcome analyses were conducted following an intent‐to‐treat approach with linear mixed models adjusted for group*time and cholinesterase inhibitors or memantine use. Result: Participants randomized to candesartan developed fewer symptoms of hypotension compared to placebo (18% vs 26%) and there was no discontinuation from the trial due to adverse event from candesartan compared to placebo (0% vs 2.6%). After 1 year, the candesartan group had significantly higher CSF Aβ40 (‐1211.95, p‐value=0.009) and Aβ42 (‐49.51, p‐value=0.046) levels (Figure) vs placebo, reflecting lower brain amyloid accumulation. CSF Aβ42/Aβ40 showed a trend with an increased ratio in candesartan vs a decreased ratio in placebo, but did not reach statistical significance. Participants randomized to candesartan also showed a trend for decreases in CSF total tau and p‐tau181 and increases in Aβ42/total tau and Aβ42/p‐tau181 levels. Although the within groups were significant, the between groups did not reach significance for the tau‐based biomarkers. Conclusion: In this first human study in non‐hypertensive prodromal AD, candesartan treatment demonstrates target engagement and a reduction in brain amyloid accumulation compared to placebo. These findings may be useful in the prevention of AD or the slowing of disease progression. A larger trial is urgently needed for candesartan in AD.