Munc 18–1 is a multifaceted therapeutic target for dementia

Dementia is a complex and multifactorial neurodegenerative condition, characterized by overlapping and interlinked pathophysiological implications including amyloid-β (Aβ) accumulation, Synaptic dysfunction, Lewy body formation, Tauopathy, neuroinflammation and oxidative stress. This complexity is one of the main reasons why single-target therapeutic strategies have largely failed to provide curative outcomes. As a result, there is a growing emphasis on identifying convergent molecular hubs that integrate multiple pathological pathways. In this context, Munc18–1 (STXBP1), a key regulator of synaptic vesicle exocytosis via SNARE complex assembly, has emerged as a central node connecting multiple facets of dementia pathology. Beyond its canonical role in neurotransmitter release, Munc18–1 influences amyloid precursor protein (APP) processing, modulates Tau phosphorylation through CDK5, and acts as a molecular chaperone for α-synuclein, thereby impacting amyloidogenic, Tauopathic, and Synucleinopathic pathways. Its dysfunction impairs synaptic integrity, disrupts BDNF signalling, and promotes neuroinflammatory responses through excitotoxicity and vesicle-mediated immune signalling. Notably, reductions or mutations in Munc18–1 have been consistently associated with cognitive decline in various dementia models. In the present article, we attempted to address that Munc18–1 could be a master regulator of multiple pathophysiologies associated with dementia and emerging therapeutic approaches that stabilize Munc18–1 and restore its multifaceted functions can be a novel strategy for the treatment of dementia.