Entorhinal cortex atrophy mediates the association of plasma p-tau181, GFAP, and NfL with cognitive impairment in Parkinson's disease.
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BACKGROUND: Cognitive impairment is a major determinant of disability in Parkinson's disease (PD), underscoring the need for biomarkers that reflect its underlying pathophysiology. Plasma biomarkers, including phosphorylated tau at threonine 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), are promising candidates, yet their independent predictive value and the pathways by which they relate to cognitive function in PD remain unclear. METHODS: We enrolled 89 PD patients without dementia (37 with normal cognition and 52 with mild cognitive impairment) and 40 healthy controls. Plasma biomarkers were measured using single-molecule array technology. All participants underwent high-resolution structural magnetic resonance imaging and cognitive assessment with the Montreal Cognitive Assessment (MoCA). Hierarchical regression evaluated the independent contribution of each biomarker to MoCA scores. Mediation and moderated mediation analyses were then conducted to test whether atrophy in brain regions of interest mediates the effects of biomarkers on cognitive function and whether these pathways were moderated by cognitive status. RESULTS: Plasma p-tau181, GFAP, and NfL were each independently associated with worse global cognition. The effects of all three biomarkers were significantly and specifically mediated by atrophy of the entorhinal cortex (ERC), but not by other tested regions. Critically, the mediation pathway for NfL was specifically moderated by cognitive status, being significant only in PD patients with mild cognitive impairment. CONCLUSION: The associations of plasma p-tau181, GFAP, and NfL on cognitive impairment in PD converges on ERC atrophy. The association between NfL and cognition via ERC atrophy is dynamically potentiated at the mild cognitive impairment stage, positioning NfL as a stage-specific biomarker. An integrative model combining these plasma biomarkers with ERC integrity could enhance risk stratification for cognitive impairment in PD.