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This biomarker characterization study explored within\u2010 and between\u2010subject variability of multiple LRRK2 pathway biomarkers (total LRRK2 [tLRRK2], phosphorylation of the serine 935 (Ser935) residue on LRRK2 [pS935], phosphorylation of Rab10 [pRab10], and total Rab10 [tRab10]) in different biological sources (whole blood, peripheral blood mononuclear cells [PBMCs], neutrophils) as candidate human target engagement and pharmacodynamic biomarkers for implementation in phase I\/II pharmacological studies of LRRK2 inhibitors. PD patients with a LRRK2 mutation (<jats:italic>n<\/jats:italic>\u2009=\u20096), idiopathic PD patients (<jats:italic>n<\/jats:italic>\u2009=\u20096), and healthy matched control subjects (<jats:italic>n<\/jats:italic>\u2009=\u200910) were recruited for repeated blood and cerebrospinal fluid (CSF) sampling split over 2\u2009days. Within\u2010subject variability (geometric coefficient of variation [CV], %) of these biomarkers was lowest in whole blood and neutrophils (range: 12.64%\u201351.32%) and considerably higher in PBMCs (range: 34.81%\u2013273.88%). Between\u2010subject variability displayed a similar pattern, with relatively lower variability in neutrophils (range: 61.30%\u201366.26%) and whole blood (range: 44.94%\u2013123.11%), and considerably higher variability in PBMCs (range: 189.60%\u2013415.19%). Group\u2010level differences were observed with elevated mean pRab10 levels in neutrophils and a reduced mean pS935\/tLRRK2 ratio in PBMCs in PD LRRK2\u2010mutation carriers compared to healthy controls. These findings suggest that the evaluated biomarkers and assays could be used to verify pharmacological mechanisms of action and help explore the dose\u2013response of LRRK2 inhibitors in early\u2010phase clinical studies. In addition, comparable \u03b1\u2010synuclein aggregation in CSF was observed in LRRK2\u2010mutation carriers compared to idiopathic PD patients.<\/jats:p>","DOI":"10.1111\/cts.13541","type":"journal-article","created":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T05:51:21Z","timestamp":1683957081000},"page":"1408-1420","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["A <scp>leucine\u2010rich<\/scp> repeat kinase 2 (<scp>LRRK2<\/scp>) pathway biomarker characterization study in patients with Parkinson's disease with and without <scp>LRRK2<\/scp> mutations and healthy controls"],"prefix":"10.1111","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7199-7301","authenticated-orcid":false,"given":"Maurits F. J. 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