Ambroxol Engages Target in Parkinson’s Dementia but Shows No Cognitive Benefit
In a year-long phase II trial, Ambroxol, a widely used cough medicine in Europe, showed target engagement in patients with Parkinson’s disease dementia, increasing GCase levels by chaperoning the enzyme. However, it did not improve cognitive function compared to placebo. The drug was found to be safe and well-tolerated. The study was published in JAMA by Carolina and colleagues.
The study, which was carried out at one referral center, recruited patients aged 50 or more with a diagnosis of Parkinson's disease for at least a year prior to developing dementia. Patients must have mild to moderate cognitive impairment, be on stable medication, and have a study partner to enroll. The trial directly examined the safety, tolerability, and effectiveness of two ambroxol doses, 525 mg/day (low dose) and 1050 mg/day (high dose) versus a placebo.
75 people were screened for inclusion in the study, of whom 55 were eventually randomized into treatment arms. Of these, 31 people received ambroxol: 8 on low dose (mean age: 78.8 years; all men) and 22 on high dose (mean age: 70.7 years; 86.4% men). One patient receiving a high dose was excluded because they were misdiagnosed with progressive supranuclear palsy. The placebo group consisted of 24 patients (mean age: 72.7 years; 79.2% men).
Subjects were monitored for 52 weeks, and the main outcome measures were changes in Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-Cog-13) and Clinician's Global Impression of Change (CGIC). Pharmacokinetic assessments also tracked the levels of ambroxol in plasma and cerebrospinal fluid (CSF), and β-glucocerebrosidase enzyme activity was assessed at week 26.
Ambroxol was safe and well tolerated in patients with dementia in Parkinson's disease.
In all participants combined, those who received ambroxol had 23 gastrointestinal adverse events out of 193 total (12%), whereas the placebo group had 9 events out of 172 (5%).
The most prominent safety issue was increased gastrointestinal but did not result in discontinuation in the majority.
Pharmacokinetic findings indicated that ambroxol plasma concentrations averaged 7.48μM (SD: 3.17μM; 95% CI: 6.08–8.87μM) for the high-dose group, and cerebrospinal fluid concentrations averaged 0.73μM (SD: 0.07μM; 95% CI: 0.64–0.81μM) at the completion of titration.
Notably, the high-dose ambroxol group showed elevated β-glucocerebrosidase activity at week 26, averaging 12.45 nmol/h/mg (SD: 1.97; 91% CI: 11.54–13.36) vs 8.50 nmol/h/mg (SD: 1.96; 91% CI: 7.65–9.34) in the placebo group (P = 0.05).
This validated biological target engagement in patients.
This randomized clinical trial proved that ambroxol was safe, well tolerated, and exhibited effective biological target engagement in Parkinson's disease dementia patients. Ambroxol was not, however, associated with measurable cognitive benefits over 52 weeks. These findings suggest that although ambroxol modulates the biochemical pathways involved in PDD, its role in clinical symptom management remains to be fully established. Further investigation is warranted to explore its long-term cognitive effects and potential use in earlier stages of disease.
Reference:
Silveira CRA, Coleman KKL, Borron K, et al. Ambroxol as a Treatment for Parkinson Disease Dementia: A Randomized Clinical Trial. JAMA Neurol. Published online June 30, 2025. doi:10.1001/jamaneurol.2025.1687
