Metformin Shows Greater Potential Than Semaglutide in Reducing Alzheimer’s Risk in Diabetes Type II via Dual Actions: Tackling Disease Pathways and Environmental Herpesvirus Triggers

Alzheimer’s disease (AD) and Diabetes Mellitus Type II (DM2) share overlapping pathological mechanisms, with DM2 increasing AD risk. Disease-modifying therapies (DMTs) for DM2, including Metformin and Semaglutide, have been explored for neuroprotection, yet their efficacy in AD remains unclear. Here, we introduce a novel integrative framework combining comparative network pharmacology, Mendelian Randomization (MR), and transcriptomic validation to systematically assess the therapeutic impact of 39 DM2 DMTs in preventing AD in DM2. Metformin emerged as the top-ranked therapy, whereas Semaglutide ranked among the least effective based on comparative analysis within the DM2-AD pathway-pathway comorbidity network. Notably, a two-sample MR analysis finds no evidence supporting a genetic liability to either drug being associated with AD risk, suggesting that their benefits may arise through non-direct mechanisms or that their relationship could be confounded by third factors. Metformin’s neuroprotective impact is mediated through AMPK, insulin, and adipocytokine signaling, which regulate key AD-related processes. Additionally, Metformin may indirectly affect herpesviruses, emerging environmental contributors to AD, potentially enhancing its neuroprotective effects. 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, highlighting variability in neuroprotective potential across DM2 DMTs. Furthermore, specific dual-action therapies (e.g., Insulin Glargine and Lixisenatide, Insulin Degludec and Liraglutide) exhibit efficacy comparable to Metformin, reinforcing the need for a precision medicine approach. These findings challenge the assumption that all DM2 DMTs confer equal neuroprotection, revealing significant differences in their impact on AD-related pathways. While some show strong potential for AD prevention, others appear far less effective. Metformin’s effects depend on genotype, disease state, and environmental factors, underscoring the need to re-evaluate DM2 DMTs for AD prevention in population-specific clinical trials. Metformin stands out as a strong candidate for targeted investigations in DM2 patients at high risk of AD.