Dissecting Mitochondrial Mechanisms of Alzheimer's Disease Using Gene Dependency Network and Its Implications for Discovering Nutrients Combatting the Disease.

Abstract

Alzheimer's disease (AD) is the leading cause of dementia, with its prevalence increasing as the global population ages. AD is a multifactorial and intricate neurodegenerative disease with pathological changes varying from person to person. Because the mechanism of AD is highly controversial, effective treatments remain a distant prospect. Currently, one of the most promising hypotheses posits mitochondrial dysfunction as an early event in AD diagnosis and a potential therapeutic target. Here, we adopted a systems medicine strategy to explore the mitochondria-related mechanisms of AD. Then, its implications for discovering nutrients combatting the disease were demonstrated. We employed conditional mutual information to construct AD gene dependency networks. Furthermore, the GeneRank algorithm was applied to prioritize the gene importance of AD patients and identify potential anti-AD nutrients targeting crucial genes. The results suggested that two highly interconnected networks of mitochondrial ribosomal proteins (MRPs) play an important role in the regulation of AD pathology. The close association between mitochondrial ribosome dysfunction and AD was identified. Additionally, we proposed seven nutrients with potential preventive and ameliorative effects on AD, five of which have been supported by experimental reports. Our study explored the important regulatory role of MRP genes in AD, which has significant implications for AD prevention and treatment.