Baseline CSF and plasma glucocerebrosidase activity predict longitudinal cognitive decline in Parkinson's disease: A...

Cognitive decline in Parkinson's disease (PD) is heterogeneous, and biomarkers that identify patients at higher risk are needed. GBA1 variants are linked to cognitive decline, but genotype may not fully represent functional lysosomal biology. We examined whether baseline CSF and plasma glucocerebrosidase (GCase) activity predicts longitudinal cognitive decline.

We analysed PD participants from the Parkinson's Precision Medicine Initiative (PPMI) with baseline CSF or plasma GCase activity and repeated cognitive assessments. The primary outcome was longitudinal Montreal Cognitive Assessment (MoCA); secondary outcomes were SDMT, LNS, HVLT delayed recall, and BJLOT. Linear mixed-effects models tested time × baseline log-transformed, z-standardised GCase activity, adjusting for age, sex, education, and disease duration. Sensitivity models additionally adjusted for APOEε4 dosage and GBA carrier status. Progranulin was analysed as a comparator lysosomal marker.

The CSF cohort included 169 participants with 1,111 MoCA observations; the plasma cohort included 132 participants with 795 observations. Higher baseline CSF GCase activity predicted slower MoCA decline (β = 0.067 points/year per 1 SD higher GCase, 95% CI 0.023-0.111; p = 0.003), as did plasma GCase (β = 0.108, 95% CI 0.032-0.183; p = 0.005). These associations remained significant after additional adjustment for APOEε4 dosage and GBA carrier status. Domain analyses linked CSF GCase most strongly to executive/working memory trajectory, while plasma GCase showed broader associations with processing speed, verbal memory, and executive/working memory. Progranulin was not associated with cognitive trajectory.

Baseline CSF and plasma GCase activity predict longitudinal cognitive decline in PD, supporting GCase activity as a functional biomarker.