Results from a metabolomic study published in Neurology identified caffeine and its metabolites as potential markers of resistance to Parkinson Disease (PD) in carriers of the leucine-rich repeat kinase 2 gene mutation (LRRK2+). Compared to healthy LRRK2+ carriers, carriers with PD had significantly lower plasma concentrations of caffeine and its demethylated metabolites, even after adjustments for dietary consumption levels. Notably, the same associations were not observed in individuals who did not carry the LRRK2 mutation (LRRK2-).

Prior studies have identified a potential link between caffeine intake and a reduced risk for PD. To further assess this association, investigators obtained plasma samples from participants enrolled in the LRRK2 Cohort Consortium (LCC). The LCC comprises 4 distinct groups of individuals: (1) patients with idiopathic PD (LRRK2-/PD+); pathogenic LRRK2 gene mutation carriers with PD (LRRK2+/PD+); LRRK2 gene mutation carriers without PD (LRRK2+/UC); and unaffected non-carrier controls (LRRK2-/UC-).

Patients provided detailed medical history and dietary intake information. Blood samples were obtained after a recommended 8-10 hour fasting interval. Plasma concentrations of 282 analytes were quantified using liquid chromatography–mass spectrometry. Mean differences in analyte concentrations between patients and controls were computed using a robust analysis of covariance. Concentrations were also compared between LRRK2+ and LRRK2- individuals.

Plasma samples were obtained from 368 individuals: 65 LRRK2-/UC; 70 LRRK2-/PD+; 115 LRRK2+/UC; and 118 LRRK2+/PD+. Of 282 quantified plasma metabolites, a cluster of 5 analytes emerged as significantly different between patients and controls, regardless of LRRK2 gene status. Compared to controls, patients with PD had lower plasma levels of caffeine (by 71%) and 3 of its partially demethylated xanthine-based metabolites: paraxanthine (by 57%), theophylline (by 56%), and 1-methylxanthine (by 49%) (all P ≤.001). Patients with PD also had 52% lower levels of trigonelline, a non-xanthine constituent of coffee (P <.001).

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Lower levels of caffeine-related metabolites were particularly pronounced among pathogenic LRRK2 mutation carriers. LRRK2+/PD+ plasma samples had caffeine levels 76% lower than in LRRK2+/UC samples. By contrast, caffeine levels were only 31% lower in LRRK2-/PD+ samples compared to LRRK2-/UC samples (P =.005 for LRRK2 x  PD status interaction). The differences between PD and controls remained greater in the LRRK2+ group compared to the LRRK2- group for paraxanthine (66% vs 21%), theophylline (67% vs 21%), 1-methylxanthine (62% vs 14%), and trigonelline (63% vs 15%). These trends persisted even after adjustments for dietary caffeine levels, which were lower in LRRK2+/PD+ individuals compared to LRRK2+/UC individuals.

Matching cerebrospinal fluid (CSF) samples were available for 68 patients who provided plasma samples. The CSF results mirrored that of the plasma analyses: caffeine levels were lower in LRRK2+/PD+ samples compared to LRRK2+/UC samples (by 74%; P <.02). Similarly, CSF levels of paraxanthine, theophylline, and trigonelline were lower in LRRK2+/PD+ samples vs LRRK2+/UC samples. By contrast, levels were not significantly different between patients and controls without the LRRK2 mutation.

These data identified caffeine and its metabolites as a significantly affected pathway in patients with PD compared to unaffected controls. This effect was even more pronounced among pathogenic LRRK2 mutation carriers with PD compared to LRRK2- controls. Regarding study limitations, investigators noted that while matching was attempted, demographic data varied somewhat between patient groups. Additionally, the cross-sectional design prevented direct assessment of analytes as predictors of PD risk and progression.

“The identification of caffeine and adenosine antagonists as potential markers of PD resistance among LRRK2 mutation carriers supports their potential for development as biomarkers contributing to phenoconversion risk assessment among carriers, and to progression rates among LRRK2 PD patients,” the investigators wrote. “In addition, identification of caffeine-related analytes as resistance markers [raises] the possibility of their development as candidate therapeutics.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry.

Please see the original reference for a full list of authors’ disclosures.


Crotty GF, Maciuca R, Macklin EA, et al. Association of caffeine and related analytes with resistance to Parkinson’s disease among LRRK2 mutation carriers: A metabolomic study [published online September 30, 2020]. Neurology. doi: 10.1212/WNL.0000000000010863