Rewiring mTOR signaling in Alzheimer's disease: emerging mTOR modulators beyond oncology

While Alzheimer's disease (AD) is the most common cause of dementia, curative treatments remain unavailable. Despite distinct pathologies between AD and cancer, shared dysregulation of the PI3K-AKT-mTOR signaling pathway promotes both disease states. mTOR activity significantly contributes to AD hallmarks, including amyloid-beta production, tau hyperphosphorylation, and altered metabolism and autophagy through mTOR-mediated signaling and downstream targets such as BACE-1, GSK-3β, and AChE. Consequently, mTOR-modulating compounds, demonstrating promising results in oncology, present a viable strategy to potentially halt or reverse AD progression. This review discusses the potential application of 37 mTOR pathway-modulating compounds, many originally developed for cancer treatment, given their shared molecular targets. We systematically classified the compounds based on their origin as marine, plant-derived, structural analogs, and synthetic compounds. This framework reveals a fundamental trade-off, as the structural novelty and pleiotropic effects of natural products are often counterbalanced by poor pharmacokinetics, whereas the pharmacological precision of synthetic compounds is frequently limited by compensatory feedback loops. Furthermore, we analyze translational challenges, including balancing efficacy with toxicity, limitations in blood-brain barrier penetration, and the need for patient stratification using robust biomarkers. We conclude that the most promising therapeutic approach for AD involves synergistically combining natural products with rational synthetic design. Leveraging natural products as a source of novel chemical scaffolds and employing targeted synthetic engineering to overcome their pharmacokinetic limitations, this strategy moves beyond blunt pathway inhibition. Ultimately, this enables a highly nuanced modulation of the mTOR network, providing the basis for future preclinical and clinical drug development in AD.