Network-based stage-specific drug repurposing for Alzheimer's disease

Area of Science:

• Neuroscience
• Pharmacology
• Computational Biology

Background:

• Alzheimer's disease (AD) is a leading cause of dementia with a significant and growing healthcare burden.
• Current treatments for AD are limited, necessitating innovative therapeutic discovery approaches.
• Effective therapies require drugs that can penetrate the Blood Brain Barrier (BBB).

Purpose of the Study:

• To propose stage-specific, candidate repurposed drugs for Alzheimer's disease (AD).
• To develop and apply a novel network-based drug repurposing methodology tailored for different AD severity stages.
• To identify potential therapeutic agents that exhibit Blood Brain Barrier (BBB) permeability.

Main Methods:

• A network-based approach was used to rank candidate repurposed drugs based on structural similarity to existing drugs.
• Candidate drugs were re-ranked using functional, structural, and a priori information.
• Drug candidates were further evaluated and re-ranked for their ability to cross the Blood Brain Barrier (BBB).

Main Results:

• The methodology identified 10 candidate repurposed drugs for each AD stage, with 26 elite candidates identified across all stages.
• Retrospective validation on drugs in clinical trials up to 2016 successfully ranked a drug that entered trials the following year.
• The approach demonstrated high ranking of a drug that subsequently entered clinical trials.

Conclusions:

• The proposed network-based drug repurposing method effectively identifies promising candidate drugs for AD.
• The methodology provides a valuable tool for prioritizing experimental validation of repurposed drugs for AD.
• This approach is expected to be applicable to drug discovery for other neurological disorders beyond AD.