Background: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown. Objectives: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD. Methods: Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups. Results: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21–0.57) and in both pathogenic and risk variant carriers (ORPathogenic, 0.38; 95% CI, 0.21–0.67 and ORRiskVariant, 0.19; 95% CI, 0.04–0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen, 0.19; 95% CI, 0.07–0.50 and ORAspirin, 0.51; 95% CI, 0.28–0.91). Conclusions: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association.

Original languageEnglish
Pages (from-to)1755-1764
Number of pages10
JournalMovement Disorders
Issue number10
StatePublished - 1 Oct 2020


FundersFunder number
Adamas Therapeutics
Amici Foundation
Bigglesworth Family Foundation
Fundacao MSD
NHMRC Australia
National Institute of Neurological Disorders and Stroke K23NS0099441-O1A
National Institute of Neurological Disorders and Stroke K23NS0099441‐O1A
Parkinson's Fonds Deutschland gGmbH
Parkinson’s Foundation
Singapore Translational ResearchNMRC/STaR/0030/2018
Spanish Network for Research on Neurodegenerative Disorders
National Institutes of Health
U.S. Department of Defense
National Institute of Neurological Disorders and StrokeK23NS099441, K23NS0099441‐O1A
Michael J. Fox Foundation for Parkinson's Research
Boehringer Ingelheim
California Department of Fish and Game
Agency for Toxic Substances and Disease Registry
Teva Pharmaceutical Industries
Meso Scale Diagnostics
International Parkinson and Movement Disorder Society
Janssen Pharmaceuticals
Ontario Brain Institute
Fondation Brain Canada
Smart Family Foundation
Aegis Foundation
Parkinson's Foundation
Neurocrine Biosciences
UCB Pharma
European Parkinson’s Disease Association
Farmer Family Foundation
Johns Hopkins University Press
Canadian Institutes of Health Research
W. Garfield Weston Foundation
Parkinson Society Canada
National Medical Research CouncilMOH‐OFLCG18May‐0002
Ministry of Health -Singapore
Deutsche ForschungsgemeinschaftFOR2488
Bundesministerium für Bildung und Forschung
Edmond J. Safra Philanthropic Foundation
Instituto de Salud Carlos III
Bundesministerium für Wirtschaft und Energie
Damp Stiftung
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas


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