Cough medicine may help some with Parkinson’s dementia: Trial
Cognitive benefits seen for those with GBA1 mutations
Ambroxol, a common cough medicine, may help stabilize neuropsychiatric symptoms in Parkinson’s disease dementia (PDD) and shows cognitive promise for patients with mutations in the GBA1 gene, according to results from a Phase 2 clinical trial.
While ambroxol is widely used in Europe to treat respiratory conditions, it’s not approved in Canada or the U.S. Because it increases the activity of the enzyme beta-glucocerebrosidase (GCase), which is often deficient in people with Parkinson’s disease, researchers have been investigating its potential as a brain-targeting therapy.
The placebo-controlled study, led by researchers at St. Joseph’s Health Care London in Ontario, showed that ambroxol was safe and well tolerated and engaged its biological target. There was a trend toward stabilization of neuropsychiatric symptoms in patients taking ambroxol, while those receiving the placebo showed clinically meaningful worsening. Three of five patients with GBA1 mutations who received ambroxol saw clinically meaningful cognitive improvements.
“Our goal was to change the course of Parkinson’s dementia,” Stephen Pasternak, MD, PhD, a cognitive neurologist at St. Joseph’s Lawson Research Institute, said in a St. Joseph’s news story. “This early trial offers hope and provides a strong foundation for larger studies.”
The results were published in a study, “Ambroxol as a Treatment for Parkinson Disease Dementia: A Randomized Clinical Trial,” in JAMA Neurology.
Cough medicine boosts enzyme activity
Mutations in GBA1, the gene that contains instructions for cells to produce GCase, are among the most common genetic causes of Parkinson’s. When GCase function is impaired, waste products accumulate in brain cells, potentially triggering cellular damage and contributing to Parkinson’s symptoms. One such waste product, alpha-synuclein, can misfold and clump into toxic aggregates known as Lewy bodies, which are closely linked to cognitive decline and dementia, including the nonmotor symptoms of Parkinson’s disease.
Ambroxol boosts GCase activity, which may help prevent the buildup of toxic waste products like alpha-synuclein and reduce the formation of Lewy bodies. “This research is vital because Parkinson’s dementia profoundly affects patients and families,” Pasternak said. “If a drug like Ambroxol can help, it could offer real hope and improve lives.”
In the Phase 2 trial (NCT02914366), Pasternak and his team recruited participants with PDD, 24 of whom received a placebo and 22 a high dose of ambroxol.
Ambroxol was found generally safe and well tolerated, although participants in the treatment group experienced more gastrointestinal side effects. GCase activity was significantly higher in the treatment group after 26 weeks of daily dosing. This effect remained after a year, but was no longer statistically significant.
Despite this, ambroxol did not lead to a significant change in the study’s primary cognitive outcome, the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-Cog). The researchers noted that this measure, commonly used in Alzheimer’s trials, may not be sensitive enough to detect changes in PDD over a one-year period, especially in patients with mild symptoms. Participants in the placebo group also showed little to no decline on the ADAS-Cog during the study.
Positive trends emerged in secondary outcomes. After one year, patients receiving ambroxol appeared to experience a stabilization of neuropsychiatric symptoms, while those in the placebo group showed a clinically meaningful worsening. Although this difference did not reach statistical significance, it points to a potential benefit.
Similarly, a molecular marker of neural damage increased in the placebo group but not in the ambroxol group. This indicates potential neuroprotective effects, according to the team.
Five people in the treatment group had mutations in GBA1, and three of these saw clinically meaningful differences in ADAS-Cog scores. The researchers hypothesized that the medication may be more effective in that group, as GBA1 is directly related to GCase, and noted that future studies could build on the findings by recruiting more people with GBA1 mutations to test efficacy in that subgroup.
“These findings suggest Ambroxol may protect brain function, especially in those genetically at risk,” Pasternak said. “It offers a promising new treatment avenue where few currently exist.”
While the trial had several limitations, including a relatively short duration and the fact that it didn’t look at how the severity of starting cognitive symptoms affected results, several ongoing studies “will contribute further knowledge regarding the potential of ambroxol in improving cognitive outcomes,” the researchers wrote.
These include a Phase 3 study (NCT05778617) assessing if ambroxol can slow Parkinson’s progression and a Phase 2 study (NCT05287503) focused on people with GBA1 mutation-related Parkinson’s.
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