Dementia with Lewy bodies: emerging drug targets and therapeutics

ABSTRACT

Introduction: Dementia with Lewy bodies (DLB) is characterized by the toxic accumulation of α-synuclein protein inside neural cells; this results in neurodegeneration which is clinically accompanied by behavioral and psychological changes. DLB shares features with Parkinson’s disease (PD) and Parkinson’s disease dementia (PDD), but also overlaps neurochemically and pathologically with Alzheimer’s disease. Symptomatic treatments for LBD differ in their effectiveness while disease-modifying and curative approaches are much needed.

Areas covered: We explore emerging therapeutics for DLB through the lens of repurposing approved drugs and survey their potential for disease modifying actions in DLB. Given the complexity of DLB with multiple pathologies, potential therapeutic targets that could affect Lewy body pathology, or metabolism or neurotransmitters or immunomodulation were surveyed. We queried PubMed and ClinicalTrials.gov searches 2017–2020.

Expert opinion: DLB is not simply aredux ofAD or PD; hence, treatments should not be exclusively duplicative ofAD or PD directed treatments. This opens amyriad of possibilities for therapeutic approaches that are disease specific or repurposed.

KEYWORDS:

• Clinical trials
• dementia with Lewy bodies
• drug repurposing
• drug development
• Lewy body dementia
• Parkinson’s disease
• dementia
• synucleinopathy
• drug targets

Article highlights

• Drugs developed for purposes excluding treatment of neurodegenerative diseases have demonstrated the potential to serve as disease modifying treatments for DLB and PDD

• Several drugs, compounds, and drug classes have demonstrated efficacy, safety, and tolerability in neurodegenerative diseases: monoclonal antibodies against α-synuclein, ambroxol, metformin, nilotinib/bosutinib, rasagiline, salbutamol, liraglutide, exenatide, candesartan/telmisartan, etanercept, fasudil, and immunomodulators

• Although these drugs have thus far demonstrated the potential as effective therapeutics, their clinical benefits and side effects in the DLB population require further inquiry

• Genetic risk factors can be ameliorated by these drugs, though further research is necessary to fully understand their mechanisms of action in neurodegenerative diseases

• Monoclonal antibodies against α-synuclein have been proven safe and effective and may delay or impede the development of DLB and PD

This box summarizes key points contained in the article.

Acknowledgments

The research of the authors is supported by NIH COBRE 5P20GM109025, NIH P20 AG068054, NIH R01AG059008, and the Keep Memory Alive Foundation.

Declaration of interest

M Sabbagh has stock and stock options in Brain Health Inc, NeuroReserve, NeuroTau, Optimal Cognitive Health Company, uMethod Health, Versanum, and Athira. He is also a Consultant for Alzheon, Neurotrope, Biogen, Cortexyme, Danone, Regenerone, Roche Genentech, Stage 2 Innovations, Acadia and is on Speaker’s Bureau for Health and Wellness Partners and Joyce Knapp Communications. The author(s) have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose