Coffee’s link to Parkinson’s risk may depend on how your body handles caffeine

In a recent study published in the journal npj Parkinson’s disease, researchers investigated whether the cytochrome P450 1A2 (CYP1A2) genotype and sex modify the association between Parkinson’s disease (PD) and coffee consumption.

PD is a progressive neurodegenerative condition that manifests with non-motor and motor symptoms, which impair the quality of life. While the etiology of PD is elusive, most cases (> 90%) result from the interplay between environmental exposures and genetic susceptibility. Organic solvents, heavy metals, and pesticides have been linked to a higher risk of PD, whereas caffeine intake has been associated with reduced risk.

Sex differences are also well recognized, with males exhibiting two-fold higher PD incidence than females, and females showing faster disease progression and higher mortality. Epidemiological studies consistently indicate an association between coffee intake and lower PD incidence, an association thought to be driven largely by caffeine, as decaffeinated coffee has not shown comparable benefits. However, not all people benefit equally from caffeine intake, suggesting inter-individual differences.

CYP1A2 is the main enzyme involved in caffeine metabolism. A genetic variant of CYP1A2, rs762551, alters inducibility: AA carriers are classified as fast metabolizers, AC carriers as intermediate metabolizers, and CC carriers as slow metabolizers, with slower metabolism resulting in prolonged systemic exposure to caffeine. Nevertheless, studies have yielded inconsistent results regarding caffeine–gene interactions, with some finding inverse associations in slow metabolizers and others reporting none.

About the study

In the present study, researchers evaluated how sex and the CYP1A2 genotype modify the association between PD and coffee consumption. They used data from the United Kingdom Biobank (UKB), a prospective cohort study of over half a million participants aged 37–73 years. At baseline, subjects completed questionnaires, underwent physical examinations, and provided blood, urine, and saliva samples.

Coffee consumption was determined from baseline questionnaires. Genotyping was performed using two genome-wide arrays. The primary exposure was the CYP1A2 rs762551 polymorphism. Participants were classified by genotype: AA carriers (fast metabolizers), AC carriers (intermediate metabolizers), and CC carriers (slow metabolizers). The primary outcome was PD incidence, determined from linked hospital and healthcare records.

Kaplan-Meier survival curves were used to illustrate the cumulative incidence of PD across CYP1A2 genotypes and coffee intake categories (0 cups/day, <5 cups/day, and ≥5 cups/day). Cox proportional hazards regression was used to assess the association between coffee intake and PD risk. Effect modification by CYP1A2 genotype and sex was investigated. Restricted cubic spline analyses examined potential non-linear dose-response relationships.

Findings

The study included 435,551 UKB participants free of PD at baseline. Most participants were White (>94%), and CYP1A2 genotypes were similarly distributed across coffee intake categories. Among these, 3,319 individuals developed PD during a median of 15.7 years of follow-up. Individuals with higher coffee intake (≥ five cups/day) had more frequent alcohol consumption, higher rates of current smoking, and lower tea intake. In the overall analysis, no significant associations were observed between the CYP1A2 genotype or coffee intake and PD risk.

Survival curves also revealed no significant differences in PD incidence across CYP1A2 genotypes or coffee intake categories. Nevertheless, there was a significant interaction between the CYP1A2 genotype and coffee consumption, indicating that the association varied by genotype. That is, AA carriers had a significantly reduced PD risk with low-to-moderate coffee consumption, an effect not observed at high intake levels.

AC carriers had a significant increase in PD risk with higher coffee intake; CC carriers also showed an increased risk. AA carriers exhibited a non-linear association, with the lowest risk of PD at about three cups/day of coffee intake. CC or AC carriers showed no significant non-linearity. Furthermore, stratified analyses by genotype and sex revealed that female AA carriers consuming < five cups/day had a lower PD risk, whereas male AC or CC carriers had an increased risk with high intake. However, formal interaction tests involving sex were not statistically significant, so these sex-specific patterns should be interpreted cautiously.

The genotype-specific patterns were broadly maintained across sensitivity analyses that excluded early PD cases, used alternative coffee-intake categories, adjusted more extensively for smoking, and tested different genotype groupings.

Conclusions

In summary, the association between coffee intake and PD risk varied by CYP1A2 genotype. There was a lower risk of PD among AA carriers who reported low-to-moderate coffee consumption, with the pattern most evident in females, but an increased risk among CC or AC carriers, particularly in males, with higher intake. However, coffee consumption was self-reported only at baseline and included both caffeinated and decaffeinated coffee, meaning the findings cannot be interpreted as evidence of a caffeine-specific effect.

The predominantly White European cohort and relatively small numbers of PD cases in some genotype–intake groups, particularly CC carriers, also limit the precision and generalizability of the subgroup findings. As an observational study, the research does not establish causality or support changing coffee consumption based on CYP1A2 genotype; instead, it provides hypotheses for future genotype-informed epidemiological and interventional studies.