Crosstalk in Alzheimer's-delirium nexus: Molecular mechanisms and therapeutic repurposing.

摘要

Alzheimer's disease (AD) and delirium, though distinct in clinical tempo, converge mechanistically at the intersection of neurovascular dysfunction, glial activation, and metabolic collapse. This chapter explores the integrative framework of neurovascular-glia crosstalk, emphasizing how endothelial injury, astrocytic reactivity, and microglial hyperactivation collectively undermine brain energy metabolism. We highlight evidence that blood-brain barrierc (BBB) breakdown, mitochondrial insufficiency, and oxidative stress establish a "metabolic vulnerability state" predisposing the AD brain to delirium. Single-cell and transcriptomic analyses delineate shared molecular circuits involving MAPK, TP53, APOE, and δ-secretase (LGMN)-the latter regulated by disease-relevant miRNAs such as miR-124 and miR-146a. These networks couple neuroinflammation with impaired energy dynamics, bridging chronic neurodegeneration and acute encephalopathic stress. We further discuss how tyrosine-kinase signaling, serotonergic dysregulation, and glial-vascular miscommunication coalesce into a unified pathophysiological axis. Therapeutic repurposing strategies-ranging from tyrosine kinase inhibitors (nilotinib, imatinib) to metabolic modulators (metformin, pioglitazone)-offer promising cross-disease interventions. Finally, we underscore the transformative role of artificial intelligence (AI) and large language models (LLMs) in accelerating drug repurposing through integrative omics and pathway-based reasoning. Together, these advances redefine the AD-delirium nexus as a systems-level disorder of energy and communication, opening translational avenues for precision therapeutics that restore neurovascular balance and cognitive resilience.