CSF Biomarkers Identify Shared LRRK2 Pathway Activation in Sporadic and LRRK2-Associated Parkinson Disease

Novel cerebrospinal fluid (CSF) biomarkers of LRRK2 pathway activity demonstrated increased phospho-Rab10 (pRab10) levels across sporadic Parkinson disease (PD), LRRK2-associated PD, and prodromal LRRK2 carriers, suggesting that LRRK2 pathway activation may represent a shared biological feature across genetically defined and sporadic forms of the disease.¹

Findings from an analysis of 2 independent cohorts presented at the 2026 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held October 4-8, in Seoul, South Korea, showed significantly higher CSF pRab10 levels in participants with sporadic PD, LRRK2-associated PD (LRRK2-PD), and prodromal LRRK2 compared with age-matched healthy controls. Investigators also found associations between pRab10 levels and genetic variation, α-synuclein seed amplification assay (SAA) status, and clinical progression.

The findings suggest that CSF measures of LRRK2 pathway activation could potentially help identify biologically defined subgroups of patients with PD who may be most likely to benefit from therapies targeting LRRK2.

Evaluating LRRK2 Pathway Activity in CSF

LRRK2 is a genetically validated target in PD, with common variants associated with sporadic disease and pathogenic variants accounting for a subset of familial PD cases. Pathogenic LRRK2 variants can increase kinase activity, while phosphorylation of Rab10 has been used as a marker of LRRK2 pathway activation. However, previous blood-based studies have not consistently detected increased pRab10 levels in sporadic PD or in carriers of the common LRRK2 G2019S variant, highlighting the need for more sensitive approaches to characterize pathway activity.¹

In the current analysis, lead author Edwin Jabbari, MRCP, PhD, academic neurologist specializing in movement disorders at UCL Queen Square Institute of Neurology, and colleagues used a novel SISCAPA-based assay to measure total LRRK2 and pRab10 in CSF from 2 independent cohorts. The first cohort included 379 participants from the Parkinson’s Progression Markers Initiative (PPMI), including 112 patients with sporadic PD, 67 with LRRK2-PD, 80 prodromal LRRK2 carriers, and 120 healthy controls. Baseline and 2-year follow-up samples were available from the PPMI cohort.

The second cohort consisted of 117 participants from the University College London (UCL) Parkinsonism cohort, including 57 patients with sporadic PD, 51 with progressive supranuclear palsy (PSP), and 9 healthy controls. Investigators additionally evaluated associations between CSF LRRK2 pathway biomarkers and common LRRK2 genetic variants, CSF α-synuclein SAA status, and measures of clinical progression in the PPMI cohort.

Increased pRab10 Levels Observed Across PD Groups

In the PPMI cohort, CSF pRab10 levels were significantly higher among participants with sporadic PD, LRRK2-PD, and prodromal LRRK2 compared with age-matched healthy controls. The finding was independently replicated in the UCL Parkinsonism cohort, where patients with sporadic PD had higher pRab10 levels than both patients with PSP and age-matched healthy controls.

The investigators also identified an association between the common PD risk variant rs76904798 and CSF LRRK2 levels. Among healthy controls and participants with sporadic PD in the PPMI cohort, carriers of the rs76904798 risk allele had significantly higher CSF LRRK2 levels than noncarriers. The results provide evidence that genetic variation affecting LRRK2 may be reflected in CSF protein levels even outside of patients carrying pathogenic LRRK2 mutations.

Additional analyses in the LRRK2-PD group showed that pRab10 levels differed according to CSF α-synuclein SAA status. Specifically, pRab10 levels were higher among participants who were SAA negative than among those who were SAA positive.

Higher Baseline pRab10 Linked to Clinical Worsening

The investigators also examined whether CSF measures of LRRK2 pathway activity were associated with longitudinal clinical outcomes. Among participants with LRRK2-PD, higher baseline pRab10 levels were associated with greater worsening over 2 years on the Montreal Cognitive Assessment (MoCA) and the Schwab and England Activities of Daily Living (SEADL) scale. Together, these findings suggest that CSF pRab10 may provide information not only about LRRK2 pathway activation, but also about biological and clinical heterogeneity within LRRK2-associated PD.

The results are particularly relevant as LRRK2-targeting therapies advance through clinical development. A phase 1 randomized controlled trial of an LRRK2-targeting antisense oligonucleotide recently demonstrated the feasibility of therapeutically targeting the pathway in patients with PD, further supporting the need for biomarkers capable of identifying pathway activity and potentially informing patient selection.

Implications for LRRK2-Targeting Therapies

According to the investigators, the findings support a model in which LRRK2 pathway activation is shared across sporadic PD and LRRK2-PD rather than being restricted to patients carrying pathogenic LRRK2 variants. Researchers concluded that stratifying patients according to LRRK2 biomarker profiles, genetic status, and α-synuclein SAA status may help identify subgroups most likely to benefit from LRRK2-targeting therapies.

Further work will be needed to establish how CSF pRab10 and total LRRK2 perform as predictive biomarkers, determine their relationship with treatment response, and establish whether biomarker-defined subgroups have distinct clinical trajectories. Nevertheless, the findings may provide additional evidence that LRRK2 pathway activity may represent a therapeutically relevant biological feature extending beyond genetically defined LRRK2-PD.

REFERENCES
1. E. Jabbari, C. Paisan-Ruiz, K. Ferber, et al. Shared LRRK2 pathway activation in sporadic and LRRK2-associated Parkinson’s disease defined by cerebrospinal fluid biomarker. Presented at: International Parkinson and Movement Disorders Society Congress (MDS); October 4-8, 2026; Seoul, South Korea.