Coffee and Parkinson’s disease
Parkinson’s Disease (PD) is a debilitating neurodegenerative disorder. In 2016, 6.1 million people were estimated to have PD globally90. The age of onset of PD is usually over 60, but it is estimated that one in 10 cases are diagnosed before the age of 50, with slightly more men than women affected91.
The cardinal features of PD are the slowing down of motor function, resting tremor, muscular rigidity, gait disturbances, and postural reflex impairment. The underlying pathological lesion is the progressive destruction of dopaminergic neurons in the midbrain. There is currently no available treatment to either prevent or slow down this neuronal loss and the resulting dopamine decrease in the midbrain.
Experimental and epidemiological research has focused on lifestyle, dietary and environmental risk factors, including coffee consumption.
Coffee, caffeine and risk of Parkinson’s disease
A large number of epidemiological studies report an inverse, dose-responsive relationship between coffee/caffeine consumption and the risk of developing PD. Coffee consumption appears to reduce or delay the development of PD and caffeine is most likely the causal factor. In women, however, the interaction between caffeine and hormonal therapy still needs further clarification.
As early as 1968, a study reported a higher percentage of non-coffee consumers in the control compared to the affected group47. Subsequent studies performed in Spain48, Sweden49 and Germany50 found an inverse relationship between coffee consumption and PD, and a lower coffee consumption before disease onset.
The first prospective study on 8,004 Japanese American men living in Hawaii (the Honolulu Heart Program), carried out over a median duration of 27 years, reported an inverse association between PD incidence with a five-fold reduced risk for those drinking more than 4 cups of coffee per day when compared to non-consumers. The same inverse relationship was shown for caffeine from non-coffee sources51. A smaller case control study published in 2014 suggested only a weak inverse association between coffee intake and the risk of PD52.
A number of meta-analyses and reviews have been undertaken which together support the view that coffee consumption is associated with a reduced risk of Parkinson’s Disease.
- A 2002 meta-analysis of 20 studies reported that the global risk of developing PD decreased by 31% (relative risk 0.69)53 in coffee drinkers compared to non-coffee drinkers. Some of the individual studies found very strong risk reductions, up to 80% with the consumption of over 4 cups of coffee per day.
- A further 2010 meta-analysis of 26 studies54 found that the overall risk of developing PD fell by 24-32% per 300 mg increase in caffeine intake (i.e. with every 3 cups of coffee, approximately).
- A 2012 review of 304,980 participants in the National Institutes of Health-AARP Diet and Health Study suggested that higher caffeine intake was associated with subsequent lower PD risk in both men and women. The authors conducted a meta-analysis of prospective studies and confirmed that caffeine intake was inversely associated with PD risk in both men and women and suggested that there was no gender difference in the relation between caffeine and PD55.
- A 2014 dose, response meta-analysis showed a linear relationship between risk reduction of PD with tea and caffeine consumption, however, the association with coffee intake reached a maximum at approximately 3 cups of coffee a day56.
- A 2018 literature review also confirmed that most reports indicate that moderate coffee consumption may in fact lower the risk for common neurodegenerative conditions, including PD31.
In women, the data are more equivocal. One study found a U-shaped relation, with moderate consumption of coffee/caffeine being the most protective57-59. Postmenopausal hormone use seems to affect the impact of coffee consumption on risk of PD.
A study performed on 77,713 women, followed up for 18 years, reported that in those not taking postmenopausal hormones (PMH), coffee was as protective against PD as in men. In women taking estrogens, the risk for PD was similar to men in case of low coffee consumption, but significantly increased four-fold in women drinking 6 or more cups of coffee a day when compared to non-coffee drinkers57. A case-control study, part of the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), did not find convincing evidence that variations in the genes coding for caffeine metabolism (CYP1A2 and NAT2) or estrogen receptors (ESR1 and ESR2) could predict the risk of PD linked to hormone replacement therapy use60.
Further analysis from the same data sets supported previous findings that increased caffeine intake may be associated with a decreased PD risk in men and also in women who have never used PMH61.
Additional work has considered the effect of coffee consumption on the symptoms associated with PD. A randomised control trial evaluated the effects of caffeine intake on the symptoms of PD, including daytime somnolence, motor severity and other non-motor features. The results showed improved objective motor measures, but only equivocal effects of caffeine on somnolence in PD; further evidence is required62. A further study of non-motor symptoms in patients with PD suggested that coffee drinking was significantly inversely associated with the prevalence of lack of motivation, anhedonia, and lack of pleasure, which were less frequent in coffee drinkers. In particular, coffee drinking was significantly associated with a reduced severity of the mood/cognition domain of non-motor symptoms63.
Mechanism of action
Experimental studies have identified a mechanism of action for caffeine’s preventative role in the development of PD.
Low doses of caffeine antagonize mainly adenosine A2A receptors, which are located with D2 dopaminergic receptors in the striatum, i.e. the cerebral region involved in the control of locomotion and movement and in which dopaminergic neurontransmission is dramatically impaired in patients with PD. In the striatum, the blockade of A2A receptors increases motor activity and improves motor deficits in models of PD, via the stimulation of D2 receptors64,65.
In animals, caffeine counteracts the symptoms of PD induced in rats and mice and enhances the effects of the classical treatment of PD, the precursor of dopamine, L-DOPA66,67.
Data obtained from several preclinical studies point to the beneficial effects of chronic A2A receptor antagonists (such as caffeine) on PD motor disability and on motor complications produced by long-term L-DOPA treatment, suggesting that they will be effective in the symptomatic treatment of PD5854,67.
Moreover, the A2A antagonists, including caffeine and D2 agonists, have neuroprotective properties and can attenuate the degeneration of dopaminergic cells in various animal models54,68.
The role of genetic polymorphisms has been considered in a number of areas. One assessment of PD incidence and prevalence with lifetime coffee consumption and polymorphisms in the ADORA2A and CYP1A2 suggested that associations with daily coffee consumption were strongest among carriers of variant alleles in both ADORA2A and CYP1A269. However, a further study of interactions between GRIN2A and CYP1A2 polymorphisms did not show an interaction with caffeine intake in determining PD risk70. Clearly further research on genetic polymorphisms is required to understand the associations in more detail.
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