Summary: A 12-month clinical trial led by Lawson Research Institute suggests that Ambroxol, an over-the-counter cough medication widely used in Europe, may slow aspects of cognitive decline in people with Parkinson’s disease dementia (PDD). The randomized, double-blind study found that Ambroxol stabilized psychiatric symptoms, limited a blood marker of brain damage, and produced cognitive improvements in participants carrying high-risk GBA1 gene variants.
Ambroxol acts as a pharmacological chaperone for the enzyme glucocerebrosidase (GCase), which is often reduced in Parkinson’s disease. Restoring GCase activity can reduce toxic protein buildup in brain cells. Although Ambroxol is approved for respiratory use in Europe and has an established safety record there, it is not approved for medical use in Canada or the United States.
Key Findings
- Symptom stabilization: Psychiatric and behavioral symptoms worsened in the placebo group but remained stable among those receiving Ambroxol.
- Genetic benefit: Participants with GBA1 gene variants—who are at higher risk of PDD—showed cognitive improvement while taking Ambroxol.
- Evidence of neuroprotection: Levels of GFAP, a blood marker associated with brain cell injury, increased in the placebo group but remained stable in the Ambroxol group.
Source: Lawson Research Institute
Background
Dementia related to Parkinson’s disease causes memory loss, altered thinking, hallucinations and mood changes. Nearly half of people diagnosed with Parkinson’s disease will develop dementia within a decade, creating substantial challenges for patients, families and health care systems. Current treatments address symptoms but do not halt the disease process. Researchers at Lawson Research Institute in London, Ontario investigated whether Ambroxol could be repurposed to support brain function in PDD by boosting GCase activity and reducing toxic protein accumulation.
Study design
Published in JAMA Neurology, the trial was a 52-week, phase 2, double-blind, placebo-controlled, randomized clinical study carried out at a single referral center between February 2015 and June 2023. Fifty-five participants with mild to moderate Parkinson’s disease dementia, aged over 50 and with at least one year of Parkinson’s symptoms prior to cognitive impairment, were randomized to receive Ambroxol or placebo. Dosing arms included a low dose (525 mg/day), a high dose (1,050 mg/day), and placebo. Investigators tracked cognitive performance, psychiatric symptoms, safety and pharmacological markers, including cerebrospinal fluid and plasma drug levels and enzyme activity.
Primary outcomes and safety
Primary efficacy measures included the ADAS-Cog-13 cognitive scale and the Clinician’s Global Impression of Change (CGIC). Safety was assessed through adverse event monitoring. Ambroxol was generally safe and well tolerated. Gastrointestinal events were more common among Ambroxol recipients (12% of adverse events) than placebo recipients (5%). Drug concentrations at the end of titration averaged 7.48 μM (plasma) and 0.73 μM (cerebrospinal fluid) for the high-dose group, indicating central nervous system penetration.
Clinical and biomarker results
Overall group comparisons did not show statistically significant differences on all primary or secondary cognitive outcomes. However, subgroup analyses revealed that participants with high-risk GBA1 variants experienced cognitive improvements on Ambroxol. Enzyme activity measured as β-glucocerebrosidase increased in the Ambroxol group compared with placebo at week 26 (ambroxol: 12.45 nmol/h/mg; placebo: 8.50 nmol/h/mg; P = .05). The blood marker GFAP rose in placebo-treated participants but remained stable among those on Ambroxol, consistent with potential protection against brain injury.
Interpretation
Lead investigator Dr. Stephen Pasternak and the Lawson team emphasize that Ambroxol demonstrated target engagement—raising GCase levels—and was safe in the studied population. While the trial did not confirm a clear cognitive benefit across all participants, the stabilization of psychiatric symptoms, the biomarker signals, and the improvement seen in genetically at-risk individuals support further, larger trials focused on cognition and neuroprotection.
Pasternak noted, “Our goal was to change the course of Parkinson’s dementia. This early trial offers hope and provides a strong foundation for larger studies.” A follow-up trial concentrating on cognitive outcomes is planned later this year. The study was funded by the Weston Foundation.
About this neuropharmacology and Parkinson’s disease research news
Author: Debora Flaherty
Source: Lawson Research Institute
Contact: Debora Flaherty – Lawson Research Institute
Image credit: Neuroscience News
Original research: Closed access. “Ambroxol as a Treatment for Parkinson Disease Dementia: A Randomized Clinical Trial” by Stephen Pasternak et al., JAMA Neurology. Clinical trial registration: NCT02914366.
Abstract
Ambroxol as a Treatment for Parkinson Disease Dementia: A Randomized Clinical Trial
Importance
Variants in the gene encoding β-glucocerebrosidase (GCase) are major risk factors for Parkinson disease dementia. Increasing GCase levels reduces α-synuclein accumulation in cellular and animal models. Ambroxol acts as a chaperone for β-glucocerebrosidase and can raise enzyme levels.
Objective
To evaluate the safety and tolerability of Ambroxol in PDD, to assess its effect on cognitive decline, and to collect pharmacological and biomarker data.
Design, Setting, and Participants
A 52-week, phase 2, double-blind, placebo-controlled randomized clinical trial at a single referral center. Participants were patients with PDD over age 50, with at least one year of Parkinson disease prior to cognitive impairment, mild to moderate dementia, stable medications, and a study partner.
Interventions
Ambroxol low dose (525 mg/day), high dose (1,050 mg/day), or placebo.
Main Outcomes and Measures
Safety and tolerability (adverse events); primary efficacy outcomes included the ADAS-Cog-13 and CGIC.
Results
Seventy-five patients were screened and 55 randomized. Thirty-one received Ambroxol (8 low dose, 22 high dose after one exclusion); 24 received placebo. Ambroxol recipients experienced more gastrointestinal adverse events than placebo. No definitive differences were found on primary or secondary cognitive outcomes across the full cohort. High-dose Ambroxol reached measurable concentrations in plasma and cerebrospinal fluid, and β-glucocerebrosidase activity was higher in the Ambroxol group at week 26 (P = .05).
Conclusions and Relevance
Ambroxol was safe, well tolerated, and showed target engagement by increasing GCase activity. The trial did not confirm a definitive effect on cognition for the overall cohort, but biomarker changes and subgroup cognitive benefits support further investigation.
Trial Registration
ClinicalTrials.gov Identifier: NCT02914366