Metformin provides superior neuroprotective potential compared to semaglutide in preventing diabetes-associated Alzheimer's disease via dual actions.

BACKGROUND: Alzheimer's disease (AD) and Diabetes Mellitus Type II (DM2) share overlapping biological mechanisms, and diabetes increases the risk of developing AD. Treatments that modify the course of diabetes, such as metformin and semaglutide, have been proposed to protect the brain, but their effectiveness in preventing AD remains uncertain. This study aimed to systematically compare the potential of diabetes therapies to reduce the risk of AD. METHODS: We developed an integrative framework combining comparative network pharmacology to evaluate 39 diabetes therapies in relation to AD. The analysis examined how each treatment influenced shared molecular pathways between the two conditions and measured their comparative impact score and validated key findings using gene expression data. RESULTS: Here we show that metformin is the most promising therapy for protection against AD, while semaglutide ranks among the least effective, based on comparative analysis within the DM2-AD pathway-pathway comorbidity network. Metformin's effects are mediated through AMPK, insulin, and adipocytokine signaling, that influence key Alzheimer's-related processes. In contrast, semaglutide, despite its growing clinical prominence as a weight loss therapy, exhibits minimal engagement with core neurodegenerative pathways within the DM2-AD comorbidity network. Certain combination therapies, such as insulin glargine with lixisenatide and insulin degludec with liraglutide, display effects comparable to metformin. CONCLUSIONS: These findings reveal that diabetes therapies differ in their ability to protect against AD. Metformin shows the strongest potential, supporting its prioritization for targeted studies in people with diabetes who are at high risk of AD, and highlighting the importance of precision medicine in future prevention trials.