This study found monocyte GCase activity is lower in GBA1-PD versus non-GBA PD but that peripheral monocytic GCase does not correlate with cognition or regional cholinergic PET measures in early-stage PD.

It shows peripheral monocyte GCase reflects GBA1 genotype but is unlikely to be a useful peripheral biomarker of cognitive decline or central cholinergic dysfunction, steering therapeutic biomarker efforts toward central measures or alternative targets for GCase-modulating interventions.

BACKGROUND: The GBA1 gene encodes the lysosomal enzyme glucocerebrosidase (GCase). Parkinson's disease (PD) patients carrying a GBA1 variant (GBA-PD) exhibit faster cognitive decline, linked to cholinergic degeneration. OBJECTIVES: The aim was to investigate whether GCase activity, measured in monocytes, correlates with cognitive dysfunction or regional brain cholinergic innervation in early-stage PD patients. METHODS: A total of 137 PD patients underwent a complete neuropsychological assessment, blood sampling, brain magnetic resonance imaging, and 18F-fluoroethoxybenzovesamicol positron emission tomography (PET). Monocytic GCase activity was quantified using flow cytometry with the substrate 5-pentafluorobenzoylamino fluorescein di-β-d-glucopyranoside. RESULTS: Monocytes from GBA-PD (n = 42) patients exhibited significant lower GCase activity (P = 0.007) compared to those from non-GBA-PD individuals (n = 95). However, GCase activity did not correlate with cognition. Similarly, voxel-wise and volume-of-interest PET analyses did not reveal associations with monocytic GCase activity. CONCLUSIONS: Monocytic GCase activity does not appear to be a reliable biomarker for cognitive decline in early-stage PD and is not linked to regional cholinergic denervation. Peripheral measurements do not reflect central processes underlying cholinergic dysfunction. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.