Associations of Monocyte Glucocerebrosidase with Cognition and Cholinergic Innervation in GBA1 Parkinson's Disease.

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.