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. 2025 Jun:135:107854.
doi: 10.1016/j.parkreldis.2025.107854. Epub 2025 Apr 29.

Combined assessment of blood glucocerebrosidase activity and α-synuclein levels in GBA1 mutation carriers: A novel potential biomarker

M Avenali  1 , S P Caminiti  2 , M Gegg  3 , S Cerri  4 , P Mitrotti  5 , L Bandirali  2 , M Toffoli  3 , D Hughes  6 , C Cerami  7 , C Tassorelli  5 , E M Valente  8 , A H V Schapira  3 , F Blandini  9
Affiliations

Combined assessment of blood glucocerebrosidase activity and α-synuclein levels in GBA1 mutation carriers: A novel potential biomarker

M Avenali et al. Parkinsonism Relat Disord. 2025 Jun.

Abstract

Introduction: Heterozygous variants in the GBA1 gene encoding the glucocerebrosidase enzyme (GCase) are the most frequent genetic risk factor for Parkinson's Disease (PD). Yet, only a minority of GBA1 carriers will eventually develop overt PD, and the mechanisms underlying such reduced penetrance are still largely unexplored. Decreased GCase and increased α-synuclein levels are individually considered promising prognostic blood biomarkers for GBA-PD. Here, we aim to assess the combined role of decreased GCase activity and increased α-synuclein levels as a potential biochemical signature of worse outcome in GBA1 population.

Methods: Ninety-eight subjects (30 GBA-nonPD, 29 GBA-PD and 39 healthy controls) underwent a detailed clinical assessment, as well as measurement of GCase activity and total α-synuclein levels in peripheral blood mononuclear cells (PBMCs). ROC curve analysis and a two-step clustering analysis were performed to classify subjects based on their combined GCase and α-synuclein biochemical profile. Clinical scores were analysed across clusters.

Results: ROC curve analysis based on α-synuclein/GCase activity ratio was able to discriminate GBA1 positive individuals from healthy controls. We identified two separate biochemical clusters - a benign (high GCase/mid-low α-synuclein) and a malignant (low GCase/high α-synuclein) cluster. All healthy controls belonged to the benign cluster, while 59% of GBA-PD and 47% of GBA-nonPD fell into the malignant cluster. GBA-nonPD within the malignant cluster had greater depressive symptoms, and GBA-PD showed worse cognitive performance.

Conclusions: We report for the first time that the combined assessment of blood GCase activity and α-synuclein levels can define two distinctive biochemical clusters able to discriminate GBA-nonPD subjects with greater preclinical non-motor symptoms and GBA-PD patients with a worse cognitive profile. Longitudinal studies are needed to confirm the accuracy of this potential biomarker.

Keywords: Biomarkers; GBA1; Glucocerebrosidase; Parkinson disease; Prodromal; α-synuclein.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

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