{"doi":"10.1002/mds.28240","title":"If <scp>LRRK2</scp> Set the Fire, Can Nonsteroidal Anti‐inflammatory Drugs Wet the Flames?","abstract":"In recent years, the complex interplay between genes and the environment has gained increased attention in Parkinson's disease (PD), a progressive neurodegenerative disorder. Despite the identification of causal mutations in several genes (ie, LRRK2, GBA, SNCA, and others) and environmental or lifestyle factors linked to reduced risk (eg, smoking, caffeine) or increased risk (eg, dairy products, pesticides) for development of PD, our understanding of gene-environment interaction remains modest. Further exploration of how an individual's environmental exposures (“exposome”) and their genome may intertwine to influence the development and progression of PD is thus warranted. This increased knowledge could have both mechanistic and clinical implications, leading to trials of disease-modifying and preventive strategies. In this month's issue of Movement Disorders, Luciano et al1 carried out a case-control study in individuals with LRRK2 gene mutations pathogenic for PD. The G2019S mutation, which is the predominant LRRK2 variant in this cohort, demonstrates variable age-dependent penetrance, with PD developing in 25% to 42% of carriers by the age of 80 years.2 This incomplete penetrance suggests that other factors play a role in LRRK2 mutation-driven PD. Recently, several case-control studies of symptomatic (“LRRK2-PD”) and asymptomatic (“LRRK2-non-PD”) LRRK2 mutation carriers have sought to identify potential markers of its penetrance. Iwaki et al3 evaluated a polygenic risk score in mutation carriers from several large research databases and found that a higher polygenic risk score was associated with greater odds of development of PD (odds ratio [OR], 1.34; 95% confidence interval [CI]: 1.09–1.64) per 1 standard deviation of increase from the cohort mean. Bakshi et al4 investigated urate in LRRK2-PD and LRRK2-non-PD from the Parkinson's Progression Markers Initiative (PPMI) and LRRK2 Cohort Consortium (LCC) cohorts and discovered that the odds of having developed PD were approximately halved (OR, 0.46; 95% CI: 0.29–0.76) for each 2-mg/dL increment in plasma (or serum) urate. Caffeine, a well-studied, potential protectant in PD, has also been explored in mutation carriers, with both caffeine drinkers and those with higher levels of caffeine-linked plasma analytes observed to have lower odds of PD.5, 6 Other studies of LRRK2 mutation carriers include targeted and untargeted metabolomics profiling showing a different metabolomic profile in LRRK2-PD and LRRK2-non-PD groups,7 and assessment of urinary phospholipids observing marginally higher levels of urinary 2,2′-di-18:1-bis(monoacylglycerol)phosphate in LRRK2-PD compared with LRRK2-non-PD subjects (P = 0.045). Notably, urinary phospholipid concentrations were greater in both the LRRK2-PD and LRRK2-non-PD groups compared with those without LRRK2 mutation, and thus they may not be a useful marker for LRRK2 resistance.8 Although yet to be investigated in humans, another potential indicator of LRRK2 PD resistance is 5′-deoxyadenosylcobalamin (AdoCbl), a physiologically active form of vitamin B12. In cellular and animal models of LRRK2 PD, AdoCbl was found to be a mixed-type allosteric modulator of LRRK2 kinase, reduced dopaminergic neurodegeneration, or dopamine deficits.9 Luciano et al1 evaluated the association between regular nonsteroidal anti-inflammatory drug (NSAID) use, defined as two or more pills per week for 6 months or more, and the presence of PD in 259 LRRK2-PD and 318 LRRK2-non-PD participants from the LCC and the PD-Genetic and Environmental Modifiers cohorts. Their retrospective case-control study found that regular NSAID use was associated with lower odds of having PD for any NSAID (OR, 0.34; 95% CI: 0.21–0.57), and separately for ibuprofen and aspirin (OR, 0.19 and 0.51, respectively). They concluded that regular NSAID use may be associated with reduced penetrance in LRRK2 mutation carriers. Although NSAID exposure has been previously identified as an inverse risk f","journal":"Movement Disorders","year":2020,"id":111967,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":530541,"name":"Raymond Y. Lo","orcid":"0000-0001-6510-1935","position":1,"is_corresponding":false},{"id":263854,"name":"Michael A. Schwarzschild","orcid":"0000-0001-6019-8280","position":2,"is_corresponding":false},{"id":314161,"name":"Grace F. Crotty","orcid":"0000-0002-8106-7842","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-18T23:13:09.353152Z","pmid":"33068466","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}