Ambroxol as a Treatment for Parkinson Disease Dementia: A Randomized Clinical Trial

Carolina R A Silveira^{1

2}, Kristy K L Coleman^{1

2

3}, Kathy Borron^{1

2}, Rommel G Tirona^{2

4}, Charles A Rupar^{2

5

6

7}, Guangyong Zou^{3

8}, Robert A Hegele^{2

8

9}, Cheryl Wellington^{10

11}, Sophie Stukas^{10

11}, Elizabeth C Finger^{1

2

12}, Robert Bartha^{8

13}, Sarah A Morrow^{1

2

12

14}, Jennie L Wells^{2

15}, Michael J Borrie^{2

15}, Don Mahuran¹⁶, Penny A MacDonald¹², Mary E Jenkins^{2

12}, Mandar S Jog^{2

12}, George Dresser⁹, Susan Fox¹⁷, Richard Camicioli¹⁸, Brian Feagan^{8

19}, Daniel A Mendonça¹, Michael Mayich^{2

20}, Manas D Sharma²⁰, Sachin K Pandey²⁰, Stephen H Pasternak^{1

2

8

12}

Affiliations

¹ Cognitive Neurology and Alzheimer's Disease Research Centre, Parkwood Institute, London, Ontario, Canada.
² Lawson Research Institute, St Joseph's Health Care London, London, Ontario, Canada.
³ Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁴ Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁵ Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁶ Department of Pediatrics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁷ Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁸ Robarts Research Institute, Western University, London, Ontario, Canada.
⁹ Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹⁰ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
¹¹ Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
¹² Department of Clinical Neurological Science, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹³ Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹⁴ Department of Clinical Neurosciences Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
¹⁵ Division of Geriatric Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹⁶ Laboratory of Medicine and Pathobiology, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁷ Krembil Brain Institute, UHN, Division of Neurology, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Department Medicine (Neurology) and Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
¹⁹ Alimentiv Inc, London, Ontario, Canada.
²⁰ Department of Medical Imaging, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

PMID: 40587145
PMCID: PMC12210149 (available on 2026-06-30)
DOI: 10.1001/jamaneurol.2025.1687

Ambroxol as a Treatment for Parkinson Disease Dementia: A Randomized Clinical Trial

Carolina R A Silveira et al. JAMA Neurol. 2025.

. 2025 Jun 30;82(8):797-807.

doi: 10.1001/jamaneurol.2025.1687. Online ahead of print.

Authors

Affiliations

¹ Cognitive Neurology and Alzheimer's Disease Research Centre, Parkwood Institute, London, Ontario, Canada.
² Lawson Research Institute, St Joseph's Health Care London, London, Ontario, Canada.
³ Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁴ Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁵ Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁶ Department of Pediatrics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁷ Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁸ Robarts Research Institute, Western University, London, Ontario, Canada.
⁹ Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹⁰ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
¹¹ Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
¹² Department of Clinical Neurological Science, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹³ Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹⁴ Department of Clinical Neurosciences Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
¹⁵ Division of Geriatric Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹⁶ Laboratory of Medicine and Pathobiology, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁷ Krembil Brain Institute, UHN, Division of Neurology, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Department Medicine (Neurology) and Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
¹⁹ Alimentiv Inc, London, Ontario, Canada.
²⁰ Department of Medical Imaging, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

PMID: 40587145
PMCID: PMC12210149 (available on 2026-06-30)
DOI: 10.1001/jamaneurol.2025.1687

Abstract

Importance: Carrying a variation in the gene for β-glucocerebrosidase is a major risk factor for Parkinson disease dementia (PDD), and raising β-glucocerebrosidase levels lowers α-synuclein in cell and animals. Ambroxol is a chaperone for β-glucocerebrosidase, which increases the levels of β-glucocerebrosidase.

Objective: To examine the safety and tolerability of ambroxol in PDD, test the efficacy of ambroxol in improving or slowing the progression of cognitive deficits, and acquire pharmacological data.

Design, setting, and participants: This was a 52-week, phase 2, double-blind, placebo-controlled, randomized clinical trial conducted from February 2015 to June 2023. The study took place at a single center and was referral based. Included were patients with PDD who were older than 50 years, had Parkinson disease for at least 1 year before cognitive impairment, had mild to moderate dementia, were taking stable medications, and had a study partner.

Interventions: Ambroxol low dose (525 mg per day), high dose (1050 mg per day), or placebo.

Main outcomes and measures: Safety and tolerability outcomes were adverse events. Primary efficacy outcomes were the Alzheimer Disease Assessment Scale-cognitive subscale, version 13 (ADAS-Cog-13) and Clinician's Global Impression of Change (CGIC).

Results: A total of 75 patients were screened, and 55 were randomized. Thirty-one individuals received ambroxol, with 8 patients (mean [SD] age, 78.8 [3.4] years, all male) in the low-dose group and 22 patients (mean [SD] age, 70.7 [7.6]; 19 male [86.4%]) in the high-dose group. One patient was excluded from the high-dose group due to a diagnosis of progressive supranuclear palsy. A total of 24 patients (mean [SD] age, 72.7 [6.3] years; 19 male [79.2%]) were included in the placebo group. Participants receiving ambroxol (23 of 193 adverse events [12%]) showed more gastrointestinal adverse events than those receiving placebo (9 of 172 adverse events [5%]). Statistical analyses compared ambroxol high dose vs placebo. There was no evidence to suggest differences between groups on primary or secondary outcomes. Mean (SD) ambroxol high-dose concentrations were 7.48μM (3.17μM; 95% CI, 6.08-8.87μM) in plasma and 0.73μM (0.07μM; 95% CI, 0.64-0.81μM) in cerebrospinal fluid at the end of titration. Mean (SD) β-glucocerebrosidase levels were higher at week 26 (ambroxol, 12.45 [1.97] nmol/h/mg; 91% CI, 11.54-13.36 nmol/h/mg); placebo, 8.50 [1.96] nmol/h/mg; 91% CI, 7.65-9.34 nmol/h/mg; P = .05) in the ambroxol group compared with placebo.

Conclusions and relevance: Results of this randomized clinical trial reveal that ambroxol was safe, well-tolerated, and demonstrated target engagement. However, the effect of ambroxol on cognition was not confirmed.

Trial registration: ClinicalTrials.gov Identifier: NCT02914366.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Bartha reported receiving grants from Weston Family Foundation during the conduct of the study. Dr Borrie reported receiving advisory board fees from Eisai and Eli Lilly outside the submitted work. Dr Fox reported receiving research funding from Michael J Fox Foundation for Parkinson Research, National Institutes of Health (Dystonia Coalition), Parkinson Canada, and Weston Foundation; honoraria from the International Parkinson and Movement Disorder Society; consultancy/speaker fees from AbbVie, Lundbeck, and Sunovion; and royalties from Oxford University Press. Dr Camicioli reported receiving grants from Canadian Institute for Health Research for research related to Parkinson disease and dementia and related disorders, Parkinson Canada and Brain Canada Canadian Open Parkinson Network as side co–lead investigator, Weston Foundation Clinical trial in Mild Cognitive Impairment, and National Institutes of Health site for clinical trial in Parkinson disease outside the submitted work. Dr Feagan reported receiving consulting from AbbVie, Abivax, Adiso, AgomAB Therapeutics, Akros, Alira Health, Ally Bridge Group, AnaptysBio, Apini Therapeutics, Argenx, Attovia Tx, Avoro Capital Advisors, Belmore Law, BioFactura, BioJamp, Biora Therapeutics, Blackbird Laboratories, Boehringer Ingelheim, Boxer Capital, Celsius Therapeutics, Celgene/BMS, Celltrion, Clarivate, Connect BioPharma, Disc Medicine, Duality, EcoR1, Eli Lilly, Ensho Therapeutics, Equillium, Evida, Enveda, Faes Farma, First Wave, Forbion, Galapagos, Galen Atlantica, Genentech/Roche, General Atlantic, Genesis Therapeutics, Gilead, Gossamer Pharma, GSK, Imhotex, ImmiDomics, Immunic Therapeutics, Intercept, Janssen, Japan Tobacco Inc, Klick Health, LifeMine Therapeutics, Mage Biologics, Merck, Mestag, Mirador Therapeutics, Mobius Care, Monte Rosa Tx, Morphic Therapeutics, Nexys Therapeutics, Nighthawk Therapeutics, Nimbus Therapeutics, Novartis, OncoC4, OrbiMed, Orphagen, Palisade Bio, Pendopharm, Pfizer, Protagonist, 32 Bio, REDX, Roche, Roivant/Televant, Sanofi, Sobi, Sorriso, Spyre Therapeutics, SRT Therapeutics, Sun Pharma, Surrozen Inc, Synedgen, Takeda, Teva, Triastek, Trex Bio, TR1X Inc, TVM Lifesciences, Ventyx Biosciences, Versant Ventures, Vida Ventures, and Zagbio. Dr Pasternak reported receiving grants from Weston Brain Institute, Canadian Institute for Health Research, and Zywie Bio outside the submitted work; having a patent for Zywie Bio pending; and being a shareholder in Zywie Bio. No other disclosures were reported.

References

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Ambroxol as a Treatment for Parkinson Disease Dementia: A Randomized Clinical Trial

Affiliations

Ambroxol as a Treatment for Parkinson Disease Dementia: A Randomized Clinical Trial

Authors

Affiliations

Abstract

Conflict of interest statement

References

Associated data

LinkOut - more resources

Full Text Sources

Medical