Gene, Caffeine, Creatine: Link to Parkinson Disease

Researchers studied the complicated relationship between GRIN2A, caffeine consumption, creatine, and progression of Parkinson disease.

A new study has found that Parkinson disease (PD) may progress more rapidly in people who possessed a certain gene element called the GRIN2A T allele, and who also took creatine and consumed high levels of caffeine.1   

Findings were published in the Journal of Neurological Sciences.

“These data provide a rare example of a gene-environment-environment interaction, with GRIN2A genotype interacting with level of caffeine intake, creatine, and rate of progression of PD, and highlight the complexity of the factors that contribute to PD progression,” wrote first author David Simon, MD, PhD, of Harvard Medical School (Boston, MA), and colleagues.

GRIN2A codes for the A2a receptor, a subunit of the NMDA receptor involved in movement and behavior control. As an A2a receptor antagonist, caffeine may modify PD risk and progression. Animal experiments and human epidemiological studies have pointed to a protective role for caffeine in PD. One past study has suggested that heavy coffee drinkers who possess the GRIN2A gene had lower risk of PD progression than light coffee drinkers with the gene,2 although a later study failed to confirm the findings.3

However, the relationship may not be so simple. Results from a past phase 3, placebo-controlled study by this same group of researchers found no link between increasing caffeine consumption and the rate of clinical progression of PD.4 An exception was among individuals who took creatine, for whom higher levels of caffeine intake were linked to faster progression of PD.5

To tease out these relationships, researchers evaluated a subset of 420 participants with available DNA samples and data on caffeine consumption from the previous study. In the earlier study, 1741 participants with early PD diagnosed within the past five years were randomized to 5 g creatine twice daily or placebo for five years. The study was ended early due to futility (median follow-up 4 years).

Researchers genotyped the subset, and categorized the GRIN2a genotype into a C allele group (more common) and a T allele group (less common).

Key Results:

• GRIN2a T and creatine consumption: high caffeine intake linked to faster progression of PD than low caffeine intake (P=0.03)

♦ No significant relationship among those with the C allele (P=0.13)

• Creatine consumption and low caffeine intake: No link between rate of PD progression and GRIN2A genotype (P=0.75)

• GRIN2a genotype and no creatine: No link between caffeine intake and rate of PD progression (P=0.62)

The authors say that it is unclear why the GRIN2a T allele may be associated with faster progression of PD among heavy coffee drinkers who take creatine. However, they speculated that caffeine may oppose the effects of creatine on muscle contraction, a hypothesis for which other studies have provided evidence.6,7

The authors mentioned several limitations. The study contained mostly white participants and did not adjust for race. Also, the study could not adjust for smoking, factors that change over time as PD progresses, and other constituents in coffee may have played a role.

Finally, participants were not randomized according to high vs low caffeine intake, so the results do not prove that high caffeine intake causes faster progression of PD in patients with the GRIN2a T allele who take creatine.   

They also noted that these results need to be confirmed other studies.

“[S]uch a study would require another large population of PD patients with extensive longitudinal clinical data as well as data on caffeine intake and availability of DNA samples. Given the potential importance of complex gene-environment interactions in PD risk and progression, it should be a priority to generate additional clinical and biospecimen resources to allow these types of studies in the future,” they concluded.

Take-home Points

• A study suggests that PD may progress more rapidly in people who possess the GRIN2A T allele, and who also take creatine and consume high levels of caffeine.

• The relationship between creatine, heavy caffeine consumption, and faster PD progression was not associated with the GRIN2a C allele.

• There was no link between rate of PD progression and GRIN2a genotype in those who took creatine and had low caffeine consumption.

• There was no link between caffeine intake and PD progression in people with the GRIN2a genotype who did not take creatine.

The parent study was funded by the National Institute of Neurological Disorders and Stroke.


1. Simon DK, et al. Caffeine, creatine, GRIN2A and Parkinson's disease progression. J Neurol Sci. 2017 Apr 15;375:355-359.

2. Hamza TH, et al. Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. PLoS Genet. 2011;7: e1002237.

3. Ahmed I, et al. Lack of replication of the GRIN2A-by-coffee interaction in Parkinson disease. PLoS Genet. 2014;10: e1004788.

4. Simon DK, et al. Caffeine and progression of Parkinson disease. Clin Neuropharmacol. 2008;31:189-196.

5. Simon DK, et al. Caffeine and progression of Parkinson disease: a deleterious interaction with creatine. Clin Neuropharmacol. 2015;38:163-169.

6. Hespel P, et al. Opposite actions of caffeine and creatine on muscle relaxation time in humans. J Appl Physiol. 2002;92:513-518.

7. Vandenberghe K, et al. Caffeine counteracts the ergogenic action of muscle creatine loading. J Appl Physiol. 1996;80:452-457.

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