Association of caffeine and related analytes with resistance to Parkinson disease among LRRK2 mutation carriers: A metabolomic study

To identify markers of resistance to developing Parkinson disease (PD) among mutation carriers ( +), we carried out metabolomic profiling in individuals with PD and unaffected controls (UC), with and without the mutation. Plasma from 368 patients with PD and UC in the LRRK2 Cohort Consortium (LCC), comprising 118 +/PD+, 115 +/UC, 70 -/PD+, and 65 /UC, and CSF available from 68 of them, were analyzed by liquid chromatography with mass spectrometry. For 282 analytes quantified in plasma and CSF, we assessed differences among the 4 groups and interactions between and PD status, using analysis of covariance models adjusted by age, study site cohort, and sex, with value corrections for multiple comparisons. Plasma caffeine concentration was lower in patients with PD vs UC ( < 0.001), more so among + carriers (by 76%) than among - participants (by 31%), with significant interaction between and PD status ( = 0.005). Similar results were found for caffeine metabolites (paraxanthine, theophylline, 1-methylxanthine) and a nonxanthine marker of coffee consumption (trigonelline) in plasma, and in the subset of corresponding CSF samples. Dietary caffeine was also lower in PD+ compared to UC with significant interaction effect with the mutation ( < 0.001). Metabolomic analyses of the LCC samples identified caffeine, its demethylation metabolites, and trigonelline as prominent markers of resistance to PD linked to pathogenic mutations, more so than to idiopathic PD. Because these analytes are known both as correlates of coffee consumption and as neuroprotectants in animal PD models, the findings may reflect their avoidance by those predisposed to develop PD or their protective effects among mutation carriers.