Background: Neurodegenerative diseases, such as the Alzheimer and the Parkinson's, currently lack effective pharmacotherapies. They are posing a significant global health threat, and it is urgent to discover and develop effective pharmacotherapies for patients. However, due to pathogenic mechanisms are poorly understood, the interventional drug clinical trials for neurodegenerative diseases have high failure rates.

Methods: This study explored a new approach for discovering pharmacotherapies for neurodegenerative diseases—repurposing those anti-cancer agents which could potentially treat neurodegenerative diseases. The core implication is that existing anti-cancer drugs, which have already undergone extensive safety and efficacy testing, could be repurposed, potentially accelerating the drug development pipeline for neurodegenerative diseases. By leveraging the hypothesized inverse correlation between cancer and Alzheimer's, and applying a rigorous computational systems biology approach (specifically, the link prediction on a heterogeneous bipartite drug-disease network), the study has unveiled promising anti-cancer drug-neurodegenerative disease potential therapeutic association drug-disease pairs. Eight distinct link prediction algorithms were rigorously tested on the heterogenous bipartite drug-disease therapeutic linkage network. Predictors’ performance was assessed using a leave-one-out cross-validation strategy, analyzing the mean and standard deviation of rank scores.

Results: The Rooted PageRank predictor emerged as the most effective algorithm during benchmarking and was subsequently chosen for predicting novel drug-disease therapeutic association linkages. The identification of specific drug-disease pairs, such as Oblimersen sodium for Alzheimer's disease, validated by existing literature, provides concrete starting points for further preclinical and clinical investigations.

Conclusions: This innovative computational approach not only broadens the scope of potential therapeutic molecules for neurodegenerative diseases, pinpointing anti-cancer drugs as potential therapeutic candidates, but also validates the utility of systems biology and network medicine in identifying novel drug-disease therapeutic relationships, ultimately providing concrete starting points for further preclinical and clinical investigations for neurodegenerative disease pharmacotherapies, and offering hope for new treatments for millions affected by neurodegenerative disorders.