Parkinson's disease (PD) is a complex progressive neurodegenerative disorder with a wide range of phenotypes like motor, cognitive and affective manifestations (1, 2), which is further entangled by heterogeneous age at onset (AAO) and symptom progression between individuals (3). The interplay of multiple factors like aging, genetics and environmental factors might contribute to such heterogeneity (4). Identifying risk factors for PD progression could help better understand the pathogenesis of the disease, and provide care and therapeutic strategies for patients and clinicians.

Green tea, a widely-consumed beverage, was suggested to have health benefits against cancer, cardiovascular diseases, diabetes and several neurodegenerative disorders including PD (5). Previous case-control designed studies have identified an inverse association between tea intake and risk of PD (6, 7). Pathologically, several potential mechanisms for the protective role of green tea against PD have also been proposed, like the antioxidant potential of green tea in combating oxidative stress and alleviating mitochondrial dysfunction (8). As for the progression of PD, a previous study among 278 patients with PD found that consumption of tea more than 3 cups per day could delay the onset age of motor symptoms (9). However, a recent prospective cohort study investigating lifestyle factors and the progression of PD found that caffeinated tea was associated with reduced mortality but not progression (10). Similarly, a systematic review of prospective longitudinal studies found evidence for a protective role of tea intake against the risk for PD, but not progression of PD (11). Therefore, whether green tea intake has a beneficial role in the progression of PD is still unknown. Meanwhile, the observational studies might be biased by unavoidable confounding factors and relatively small sample size, and cannot determine causation.

In this context, we performed a two-sample Mendelian randomization (MR) analysis to explore the causal role of green tea intake in the progression of PD (Supplementary Figure 1). The MR approach is not susceptible to reverse causation or confounding factors which may distort interpretations of conventional observational studies. As a result, we found that green tea intake was causally associated with a lower risk of dementia in PD.

We analyzed the role of green tea intake in the progression of PD using the two-sample MR approach. Results showed that each standard deviation increase in green tea intake was significantly associated with slower progression to dementia (OR: 0.87, 95% CI: 0.81–0.94, P: 3.48E−04) after the Bonferroni correction (Figure 1). Such association was further verified using the other three MR methods (Figure 2). Consistently, green tea intake was nominally associated with a lower risk of dementia at baseline, suggesting a protective role of green tea against cognitive impairment in PD. In addition, nominal association was observed between green tea intake and slower progression to depression, and lower risk of depression, hyposmia and insomnia at baseline (Figure 1).

Next, we performed sensitivity analyses to validate the causal association between green tea intake and the progression of PD. No heterogeneity of effects was detected by Cochran's Q test (Table 1). The F statistics of all the instrumental variables were above 10 (ranging from 30 to 44), indicating absence of weakness in the selected instrumental variables. No apparent horizontal pleiotropy was observed as the intercept of MR-Egger was not significantly deviated from zero (Table 1). Meanwhile, no potential instrumental outlier was detected at the nominal significance level of 0.05 by the MR-PRESSO analysis (Table 1). The leave-one-out results suggested that the causal effect was not driven by a single instrumental variable (Supplementary Figures 3–7). Lastly, we used the PhenoScanner tool to check if the SNPs used in the MR analysis were associated with other phenotypes. As a result, no instrumental variable was associated with other phenotypes which might affect the progression of PD independent of green tea intake (Supplementary Table 1).

Previous epidemiological studies have suggested green tea intake has a protective effect against risk of PD, but whether it could slow down the progression of PD is less explored. Meanwhile, unmeasured confounding factors in clinical studies might potentially bias the association evidence, as is a common criticism inherent to observational studies. Therefore, we investigated the role of green tea intake in the progression of PD using the MR approach. The results demonstrated a protective role of great tea intake against the risk of dementia and depression in PD. Meanwhile, green tea intake was nominally associated with a lower risk of hyposmia and insomnia for patients with PD at baseline. These findings provided a better understanding of the role of green tea intake in the progression of PD, and provided novel targets to explore the pathogenesis of PD.

Previous observational studies have suggested that green tea intake might reduce the risk of dementia, Alzheimer's disease, and cognitive impairment in the elderly (19). However, whether the effect applies to dementia in other disorders was less explored. From a genetic perspective, our results demonstrated the protective role of green tea intake applied to dementia in PD as well, suggesting a universal favorable role of green tea against cognitive impairment. Though how green tea exerts this effect is still unknown, several potential mechanisms have been proposed (19). The first mechanism is the antioxidant activity of green tea catechins in the brain. Oxidative stress has been demonstrated to be involved in the pathogenesis of dementia, while catechins in green tea could chelate bivalent metal ions and prevent oxidation caused by reactive hydroxyl radicals (20). Secondly, several brain inflammatory markers are associated with the risk of all-cause dementia (21), while the anti-inflammatory effects of green tea polyphenols through the inhibition of nuclear factor kappa-beta activation could reduce brain inflammation. Thirdly, epigallocatechin gallate (EGCG), the main component of green tea catechins, has neuroprotective effects due to its inhibition of amyloid-beta aggregation which is closely related to the pathogenesis of dementia (22). Meanwhile, in vitro experiments suggested that green tea polyphenols (GTP) could protect dopamine neurons and thus might be beneficial to cognitive function (23). And EGCG was suggested to reduce neuronal cell death and induce nitric oxide synthase (NOS) expression in an MPTP mouse model of PD, which provided further evidence for the neuroprotective role of green tea (24). Additionally, our results also suggested a nominal protective role of green tea intake against depression of PD. Depression is closely related to dementia, and depressive symptoms are considered as the first glimpse of the brain failure that will lead to dementia. The role of green tea against depression in the elderly has been reported by previous observational studies (25). Our results further strengthened this protective effect and broadened the spectrum of this effect to PD. Though the exact mechanism remains elusive, the main components of green tea, namely L-theanine and EGCG might play a role (26, 27). Future clinical or functional studies could attach importance to this in exploring how green tea intake protects against dementia and depression in PD.

Besides, we noticed a nominal protective role of green tea against hyposmia and insomnia at baseline. A previous cohort study found that lower lifetime caffeine consumption was associated with abnormal olfaction in relatives of patients with PD (28). Since caffeine was a major component of green tea, green tea might protect against hyposmia as well. Additionally, daily ingestion of low-caffeine green tea might be beneficial for improving the sleep quality of the elderly via the suppression of stress (29). However, contradictory results have also been reported. For example, one study found that caffeine administration had little or no effect on hyposmia in a group of 76 hyposmic individuals (30). Meanwhile, the caffeine within green tea might also increase the risk of insomnia. Since only nominal association was detected in the current study, further exploration was still necessary to explore the role of green tea intake in hyposmia and insomnia.

In addition, we also noticed an association with borderline significance between green tea intake and progression to HY-3 stage (OR = 0.94, 95 % CI: 0.89–1.00, P = 0.054), which described the overall motor symptom progression of PD. Green tea might exert this effect by modulating microglia activation and decreasing the production of inflammatory mediators (31). Similarly, a previous clinical study found that drinking green tea could improve antioxidant status and reduce oxidative damage (32), suggesting the potential beneficial role of green tea in the progression of PD. Pathologically, a previous study has shown that EGCG strongly inhibited the aggregation of α-synuclein and prevented toxicity in PC12 cells (33). Meanwhile, EGCG could also bind to the native unfolded α-synuclein polypeptide chain and prevent the formation of toxic β structures by mediating the formation of the unstructured oligomer. Previous study has shown that EGCG could reduce interaction between α-synuclein oligomers and cell membranes and thus protect rat neuronal cells from toxicity (34). However, a previous epidemiological study did not find an association between tea intake and the time to reach the HY-3 stage of PD (35). Therefore, more evidence was necessary to better understand whether and how green tea was involved in the overall progression of PD.

In contrast, for other symptoms like the Unified Parkinson's Disease Rating Scale (UPDRS) which was shown to benefit from green tea intake, we did not identify a significant association in the current study. This might be due to the different pathogenesis of various symptoms in PD. However, we cannot exclude the possibility that we failed to detect the association due to the insufficiency of the sample sizes. The moderate variance explained by the instrumental variables of the exposure limited the power to detect weaker causal associations. Further validations in larger cohorts were still necessary.

In conclusion, based on results from the MR analysis, we demonstrated a protective effect of green tea intake against dementia and depression of PD. These results could help better understand the role of green tea in the progression of PD, will facilitate therapeutic drugs in the future clinical trials, and also provide some lifestyle recommendation for the patients with PD.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

CL: research project—conception and execution, statistical analysis—design, execution, review and critique, and manuscript—writing of the first draft. JL: statistical analysis—execution, manuscript—writing of the first draft, and review and critique. TY: manuscript—review and critique. HS: research project—organization, statistical analysis—review and critique, and manuscript—review and critique. All authors contributed to the article and approved the submitted version.

This research was supported by the funding of the National Key Research and Development Program of China (Grant Nos. 2021YFC2501203, and 2021YFC2501205), the Sichuan Science and Technology Program (Grant Nos. 2022ZDZX0023 and 2021YJ0415), and the National Natural Science Foundation of China (Grant Nos. 81901294 and 81871000). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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