A silent RAGE: The inflammatory pathway to dementia in Parkinson’s disease

Cognitive decline in Parkinson's disease (PD), progressing from mild cognitive impairment (PD-MCI) to severe dementia (PD-D), is a debilitating core feature driven by complex neuropathological interactions. While α-synuclein accumulation is the disease's hallmark, co-pathologies involving amyloid-β and tau, alongside chronic neuroinflammation, are critical accelerators of cognitive collapse. This review positions the receptor for advanced glycation end products (RAGE) as a key molecular orchestrator bridging these disparate pathological events. Functioning as a multi-ligand sensor, RAGE binds proteotoxic aggregates (α-synuclein, amyloid-β, and tau) and damage-associated molecular patterns like HMGB1. We discuss how RAGE can drive early synaptic failure through four interconnected mechanisms: (1) triggering a "two-hit" hyperinflammatory microglial response along with TLRs; (2) initiating non-canonical intracellular neuroinflammation through RAGE-RIPK1 complex; (3) acting as a neurovascular gateway to actively transport peripheral amyloid-β and recruit circulating monocytes into the central nervous system; and (4) directly blocking long-term potentiation (LTP) and degrading dendritic spines prior to overt neuronal death. Furthermore, clinical evidence highlights the depletion of protective soluble RAGE (sRAGE) in dementia, reinforcing the prognostic value of the RAGE axis. By reframing RAGE as a convergence point for proteinopathy, neurovascular breakdown, and synaptic dysfunction, this review highlights its valuable translational potential. We conclude by exploring how selective interventions—such as RAGE-RIPK1 uncoupling peptides and sRAGE modulation—could effectively intercept the molecular cascades that precipitate dementia in prodromal PD cohorts.