AMBROXOL was safe, well-tolerated, and increased β-glucocerebrosidase levels in patients with Parkinson’s disease dementia (PDD), but did not improve cognitive outcomes.
This randomised clinical trial evaluated the safety and potential cognitive benefits of ambroxol in patients with Parkinson’s disease dementia (PDD), a condition strongly linked to reduced levels of the enzyme β-glucocerebrosidase. Ambroxol, a molecular chaperone, has been shown in preclinical models to raise levels of this enzyme and reduce α-synuclein accumulation, a key pathological hallmark in Parkinson’s. The aim of the trial was to determine whether ambroxol could be a viable treatment to slow or improve cognitive decline in individuals living with PDD.
The Phase II, 52-week, double-blind, placebo-controlled study enrolled 55 participants over the age of 50, all with established PDD. Participants were randomised to receive either a low dose (525 mg/day), high dose (1,050 mg/day) of ambroxol, or a placebo. Safety was assessed via recorded adverse events, and efficacy was measured using the Alzheimer Disease Assessment Scale–Cognitive Subscale (ADAS-Cog-13) and the Clinician’s Global Impression of Change (CGIC). While ambroxol increased β-glucocerebrosidase levels significantly at week 26 compared with placebo (mean 12.45 versus 8.50 nmol/h/mg, P=0.05), no statistically significant improvements were observed in cognitive function or global impression scores. Adverse events were mostly gastrointestinal and more frequent in the ambroxol group (12% versus 5% of events in placebo), but overall tolerability remained good. Pharmacokinetic data confirmed adequate plasma and cerebrospinal fluid concentrations of ambroxol at the high dose.
Although ambroxol demonstrated clear target engagement and an acceptable safety profile, no clinical benefit was observed in terms of cognitive outcomes. These findings suggest that while ambroxol may influence disease-relevant biology, it does not translate to measurable improvements in cognition over a one-year period. Future studies may explore longer treatment durations, earlier intervention, or combination therapies. For clinical practice, ambroxol should not currently be considered a cognitive treatment for PDD, but its disease-modifying potential remains a topic for further exploration.
Reference
Silveira CRA et al. Ambroxol as a treatment for Parkinson disease dementia: a randomized clinical trial. JAMA Neurol. 2025. DOI:10.1001/jamaneurol.2025.1687
