This study finds elevated monocyte LRRK2 kinase activity (pRab10Thr73) in PD patients carrying the Asian-prevalent p.G2385R variant—markedly higher in rare double p.G2385R/p.R1628P carriers—and reduced pLRRK2Ser935 across PD groups, with a subset of idiopathic PD patients also showing increased…

Provides actionable blood-based LRRK2 activity biomarkers that support biochemical stratification and target-engagement monitoring to expand and refine LRRK2 inhibitor trials beyond genetically defined carriers.

BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) kinase inhibition is a promising therapeutic strategy for Parkinson's disease (PD), but the functional impact of Asian-prevalent LRRK2 p.G2385R and p.R1628P variants remains unclear. Robust patient stratification and target engagement markers are needed for global LRRK2-targeted trials. OBJECTIVE: The aim of this study was to characterize ex vivo LRRK2 activation status and its clinical correlates in patients with PD carrying LRRK2 p.G2385R and/or p.R1628P variants and in patients with idiopathic PD (iPD). METHODS: We recruited 242 participants: patients with PD carrying LRRK2 p.G2385R (PD-G2385R; n = 57), p.R1628P (PD-R1628P; n = 61), or both (n = 5); patients with iPD (n = 61); and healthy control subjects (HCs; n = 58). Monocyte LRRK2 activity markers (pRab10Thr73 and pLRRK2Ser935) were analyzed using multiplexed quantitative immunoblotting. Clinical severity was assessed using the International Parkinson and Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Clinical Impression of Severity Index for PD, and Montreal Cognitive Assessment. RESULTS: Compared with HCs, pRab10Thr73 was elevated (indicative of LRRK2 kinase hyperactivation) in PD-G2385R (~1.2-fold, P = 0.011) and in double-variant carriers (~2.8-fold, P = 0.008), but not in PD-R1628P or iPD. Inversely correlated with pRab10Thr73 (rs = -0.611, P < 0.001), pLRRK2Ser935 was reduced (indicative of a more active LRRK2 conformation) in all PD subgroups (lowest in double-variant carriers). All double-variant carriers, the majority of single-variant carriers, and one-third of participants with iPD had pRab10Thr73 greater than the control median. Higher pRab10Thr73 correlated with better cognition. CONCLUSIONS: LRRK2 kinase activity is enhanced in patients with PD carrying LRRK2 p.G2385R, with further elevation observed in a small group of double-variant carriers. Elevated kinase activity in a subset of iPD underscores the relevance of LRRK2 signaling and therapeutics beyond coding variants. The observed interindividual variability indicates additional genetic or environmental modifiers and highlights the need for biochemical stratification beyond genotyping in future LRRK2 trials. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.