Efficacy and safety of N-acetylcysteine in patients with mild cognitive impairment undergoing exercise-based cardiac rehabilitation program: a randomized controlled trial.

2026-04-27
Alzheimer's research & therapy 18(1)
- Damien Gallagher
- Yejin Kang
- Nathan Herrmann
- Alex Kiss
- Sandra E Black
- Paul Oh
- Susan Marzolini
- Jennifer S Rabin
- Ana Andreazza
- Joel Ramirez
- Fuqiang Gao
- Mark Rapoport
- Jinghan Jenny Chen
- Kate Survilla
- Danielle Vieira
- Ethan Mah
- Walter Swardfager
- Krista L Lanctôt

PubMed: 42045982
DOI: 10.1186/s13195-026-02062-z

Study Design

Type: Randomized Controlled Trial (RCT)
Sample size: n = 59
Population: 59 participants with possible vascular mild cognitive impairment enrolled in an exercise-based cardiac rehabilitation program
Methods: Randomized, double-blind, placebo-controlled trial; 24 weeks of oral N-acetylcysteine (2400 mg/day) or placebo; cognition assessed via neuropsychological battery
Blinding: Double-blind
Duration: 24 weeks
Funding: Unclear

BACKGROUND: Oxidative stress is implicated in the etiology of mild cognitive impairment. We hypothesized that oral supplementation with N-acetylcysteine, a precursor to the antioxidant glutathione, would improve cognitive outcomes among individuals with mild cognitive impairment. METHODS: n this 24-week randomized, double-blind, placebo-controlled trial, participants enrolled in an exercise-based cardiac rehabilitation program with possible vascular mild cognitive impairment were randomized to receive either oral N-acetylcysteine (2400 mg/day) or placebo. Cognition was assessed using a neuropsychological battery, with a standardized executive function composite score as the primary outcome. Secondary outcomes included verbal memory, working memory, non-verbal memory, attention and global cognition. Data were analyzed using linear mixed-effects models, adjusting for relevant covariates. RESULTS: A total of 59 participants [mean (SD) age = 67.6 (7.7), male (%) = 69.5%, mean (SD) Montreal Cognitive Assessment = 22.5 (3.2)] were randomized. The executive function composite score improved over time (B = 0.31, 95% CI = [0.14, 0.48], p < 0.001), with no significant differences between N-acetylcysteine and placebo (B = -0.04, 95% CI = -0.28 to 0.20, p = 0.8) or in other cognitive domains. N-acetylcysteine was generally well-tolerated, with adverse events comparable between groups. CONCLUSION: N-acetylcysteine supplementation did not provide additional cognitive benefits beyond that of cardiac rehabilitation alone among patients with vascular mild cognitive impairment. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov on August 31, 2017 (NCT03306979).

Research Insights

N-Acetyl Cysteine→Improved Attention Span
with no significant differences between N-acetylcysteine and placebo (B=-0.04, 95% CI=-0.28 to 0.20, p=0.8) or in other cognitive domains.
Effect
Neutral
Effect size
Small
Dose
2400 mg/day
N-Acetyl Cysteine→Improved Cognitive Function
The executive function composite score improved over time (B = 0.31, 95% CI = [0.14, 0.48], p < 0.001), with no significant differences between N-acetylcysteine and placebo (B = -0.04, 95% CI = -0.28 to 0.20, p = 0.8)
Effect
Neutral
Effect size
Small
Dose
2400 mg/day
N-Acetyl Cysteine→Improved Executive Function Composite Score
The executive function composite score improved over time (B=0.31, 95% CI=[0.14, 0.48], p<0.001), with no significant differences between N-acetylcysteine and placebo (B=-0.04, 95% CI=-0.28 to 0.20, p=0.8)
Effect
Neutral
Effect size
Small
Dose
2400 mg/day
N-Acetyl Cysteine→Improved Global Cognition
with no significant differences between N-acetylcysteine and placebo (B=-0.04, 95% CI=-0.28 to 0.20, p=0.8) or in other cognitive domains.
Effect
Neutral
Effect size
Small
Dose
2400 mg/day
N-Acetyl Cysteine→Improved Non-verbal Memory
with no significant differences between N-acetylcysteine and placebo (B=-0.04, 95% CI=-0.28 to 0.20, p=0.8) or in other cognitive domains.
Effect
Neutral
Effect size
Small
Dose
2400 mg/day
N-Acetyl Cysteine→Improved Verbal Memory
with no significant differences between N-acetylcysteine and placebo (B=-0.04, 95% CI=-0.28 to 0.20, p=0.8) or in other cognitive domains.
Effect
Neutral
Effect size
Small
Dose
2400 mg/day
N-Acetyl Cysteine→Improved Working Memory
with no significant differences between N-acetylcysteine and placebo (B=-0.04, 95% CI=-0.28 to 0.20, p=0.8) or in other cognitive domains.
Effect
Neutral
Effect size
Small
Dose
2400 mg/day

Adverse Events Reported

N-Acetyl Cysteine→adverse events
N-acetylcysteine was generally well-tolerated, with adverse events comparable between groups.
Finding
No significant difference
N-Acetyl Cysteine→Overall tolerability
N-acetylcysteine was generally well-tolerated, with adverse events comparable between groups.
Finding
Reported