Importance LRRK2 kinase inhibition is one of the most promising therapeutic strategies in Parkinson’s disease (PD), yet understanding of kinase activity in the Asian-prevalent p.G2385R and p.R1628P variants, each affecting 5–10% of PD patients, remains limited. Development of patient stratification and target engagement markers applicable across global cohorts is an urgent priority.

Objective To investigate pRab10^Thr73 phosphorylation and pLRRK2^Ser935 dephosphorylation as markers of in vivo LRRK2 activation status in human monocytes from manifesting carriers of p.G2385R and p.R1628P, and idiopathic PD (iPD), with clinical correlations.

Design Cross-sectional, observational study conducted between 2021 to 2024.

Setting Multi-ethnic Asian cohort from two quaternary hospitals in Malaysia.

Participants This study included 242 participants, consisting of PD-G2385R (n=57), PD-R1628P (n=61), PD-G2385R+R1628P (n=5), as well as age- and sex-matched iPD (n=61) and healthy controls (HC; n=58) who were negative for p.G2385R and p.R1628P. Exclusion criteria included recent acute infections and inability to complete assessments.

Exposure PD with and without LRRK2 p.G2385R/p.R1628P risk variants.

Main Outcomes and Measures pRab10^Thr73 and pLRRK2^Ser935 phosphorylation were measured using multiplexed quantitative immunoblotting. Clinical severity was evaluated using standardized MDS-UPDRS, CISI-PD, and MoCA ratings.

Results Compared to HC, pRab10^Thr73 phosphorylation was significantly elevated in PD-G2385R (∼1.2-fold, p=0.011) and markedly higher in double-variant carriers (∼2.8-fold, p=0.008), but not in PD-R1628P or iPD. In parallel, pLRRK2^Ser935 phosphorylation was reduced in all PD subgroups (lowest in double-variant carriers) vs. HC, and inversely correlated with pRab10^Thr73 (rs=-0.611, p<0.001). All double-variant carriers, the majority of single-variant carriers, and one-third of iPD exceeded the HC median in pRab10^Thr73 phosphorylation. Higher pRab10^Thr73 levels correlated with better cognition, but motor or disability associations were not significant after covariate adjustment.

Conclusions and Relevance LRRK2 kinase activity is enhanced in PD patients with LRRK2 p.G2385R, with more pronounced effects in those who carry concomitant p.R1628P variant. Elevated kinase activity in a considerable subset of iPD underscores the broader relevance of LRRK2 signaling and therapeutics beyond coding variants. The observed inter-individual variability highlights the role of additional genetic and environmental modifiers and supports biochemical stratification beyond genotyping in future LRRK2 trials.