Can coffee consumption lower the risk of Alzheimer's disease and Parkinson's disease? A literature review.

In light of the fact that the number of elderly citizens in society is steadily increasing, the search for dietary factors which might prolong mental agility is growing in significance. Coffee, together with its main ingredient, caffeine, has been the focus of much attention from various researchers, as data on its beneficial effects on human health continue to accumulate. Most reports indicate that moderate coffee consumption may in fact lower the risk for common neurodegenerative conditions, i.e. Alzheimer's and Parkinson's diseases. Regardless, due to their complex pathogenesis as well as methodology of scientific research, the exact impact of coffee consumption remains to be fully elucidated. At present, it seems safe to inform the general public that coffee drinkers need not fear for their health. Possibly, in the future experts will recommend drinking coffee not only to satisfy individual taste preferences but also to decrease age-related mental deterioration.

Introduction

According to demographic statistics, numerous populations in various regions of the world have noted a steadily increasing lifespan over the last decades. In Poland, average life expectancy has risen by 17 years for males and 19 for females as compared to the 1950s (from 56 to 73 years and from 62 to 81 years, respectively) [1]. The data are undoubtedly optimistic, but it is important to bear in mind that increased lifespan and aging of society will result in higher rates of age-related disorders, including neurodegenerative diseases, e.g. Alzheimer’s disease (AD) and Parkinson’s disease (PD) [2-5]. Dementia, which develops in brain-degenerative diseases, has been estimated to affect approximately 10% of people > 65 years of age, but the prevalence index doubles every 5 years. Also, experts emphasize that epidemiological data may be inconsistent due to variability in the diagnostic criteria [4]. Population aging is the reason why healthcare systems all over the world face the need to change and to increase their expenditures on elderly citizens [2, 5]. At present, due to a lack of effective therapies for neurodegenerative diseases, attempts are being made to discover their pathogenesis, including the impact of genetic and numerous environmental factors [6-12]. Their role might be proven by significant differences in the incidence of dementia in various regions of the world, e.g. only 17% in China but 43% in Germany among people ≥ 85 years of age [13].

The etiology of neurodegenerative diseases remains to be fully elucidated with respect to both genetic and environmental factors [8, 14]. The literature emphasizes the need to expand the knowledge about dietary factors which might slow down the development of dementia [10, 15–17]. The 2012 Nutritional Prevention of Cognitive Decline Congress enumerated coffee, tea, B group vitamins, omega-3 acids, and vitamin D among the beneficial factors. However, their postulated preventive effects require extensive studies [2, 18–20]. In the case of AD and PD, fish, antioxidants, including polyphenols (especially regular consumption of wine) and curcumin are believed to be beneficial, while saturated fatty acids, high intake of cholesterol and calories promote disease development [11, 15, 17, 21–25]. The literature suggests that the significantly lower prevalence of neurodegenerative diseases in Asian countries may be the result of a better diet, i.e. large quantities of fruit and vegetables, as well as spices [23].

The article summarizes current literature reports about the effect of coffee consumption on the risk of some neurodegenerative disorders.

Coffee and the risk of dementia

Caffeine – a psychoactive and neurostimulating substance – is one of the main ingredients of coffee and is hypothesized to help maintain cognitive functions in the elderly [2, 26–29]. Regardless, studies on the correlation between the effect of natural sources of caffeine – coffee and tea – and the changes in age-related mental agility have reported conflicting results.

As far as a beneficial effect of coffee is concerned, a large multicenter cohort study from three European countries (Holland, Finland, Italy) in elderly men demonstrated that coffee consumption was associated with slower progression of dementia, measured over the course of 10 years. The most beneficial effect (4-fold lower decrease in cognitive functions) was observed in the group with moderate coffee intake (3 cups a day), and the least beneficial in the group with low and high coffee consumption [29]. Also, a positive impact of moderate (3–5 cups a day) coffee consumption in middle-aged people, resulting in a significant decrease (by 65%) of dementia risk in the elderly, was reported by Finnish researchers after a 21-year-long period of observation, contrary to low consumption of coffee in that group [30]. In turn, a 4-year-long observational French study in women > 65 years of age, who consumed > 3 cups of coffee a day, revealed a significantly lower deterioration of speech and memory function as compared to women who consumed 1 cup of coffee a day or abstained. However, no such findings were reported in the group of men [31]. A randomized study on the applicability of caffeine to treat somnolence in PD patients also generated interesting results [32]. Apart from motor symptoms, sleep disorders are among the symptoms of the disease, and daytime somnolence is often the cause of patient exclusion from social life [32, 33]. In a study by Postuma et al. Parkinson patients with excessive daytime somnolence received 200–400 mg of caffeine for the course of 6 weeks. Although no cases of decreased sleepiness were observed, significant improvement in motor skills was noted in the study group receiving caffeine as compared to placebo controls [32].

Coffee consumption may also affect brain vascular dementia. The vascular system has a significant impact on maintenance of cognitive function [34]. Vascular dementia can be caused by two events that can occur in blood vessels. The first is stroke and the second is small vessel disease, although many people may have a mixture of causes. Stroke refers to brain damage that is permanent and results from interrupted blood supply to a specific part of the brain. Small vessel disease results from damage to blood vessels. The pathophysiology of small vessel disease is complex. The thickening of the blood vessel walls, atherosclerosis, is accompanied by hardening of vessel walls, which result in narrowing of the lumen of the vessel. These two events (stroke and small vessel disease) impair cerebral blood flow and contribute to neurodegenerative disorders [35, 36].

A study by Nakaguchi et al. conducted in Japan demonstrated that people who drink at least 3 cups of coffee per day had a lower incidence of silent brain infarction in middle age, which can prevent vascular dementia in older age [37]. A meta-analysis of prospective studies found that habitual coffee consumption may be weakly inversely associated with risk of stroke. The strongest significant association (17% lower risk) was noted in the case of moderate coffee consumption (3–4 cups/day). The authors of that report also pointed out that in four studies the association between coffee consumption and stroke was similar for ischemic stroke and hemorrhagic stroke, but the results were statistically significant only for ischemic stroke [38].

In contrast to the abovementioned studies, numerous authors report a lack of beneficial effects of coffee consumption on lucidity. Long-term cohort studies by Mirza et al., in a group of over 4000 elderly people in Holland, found no correlation between coffee intake and the development of dementia [39]. Identical results were reported by yet another observational study in Holland, and those authors questioned the validity of encouraging consumption of caffeinated drinks to decrease age-related mental deterioration [40]. Other data questioning the link between coffee intake and dementia come from Finland, where a 28-year-long study on twins found no correlation between coffee consumption in middle age and the development of dementia in older age [9]. Finally, two recently published reports from a cohort study in China [41] and Japan [28] also detected no correlation between coffee intake and decreased cognitive function. Interestingly, these studies concluded that tea lowered the risk of deteriorated mental agility in the elderly by 70% due to daily consumption of green tea [28], and by 30% for black and red tea [41]. Interestingly, also Italian prospective studies generated important data and showed that mild changes in cognitive functions were less frequently observed in elderly people who consumed a small amount of coffee (1–2 cups a day), consumption of > 2 cups of coffee had no effect, whereas increased coffee intake over the course of the study resulted in deterioration of cognitive functions [42].

In light of the conflicting data of single studies, it seems prudent to focus on the results of meta-analyses. Santos et al., in their meta-analysis of cohort and case-control studies, found a slightly beneficial trend between coffee intake and decreased risk for dementia. However, these authors emphasize that the number of well-designed studies is very low, not permitting unequivocal conclusions [43]. Also Arab et al. are of the opinion that coffee or tea consumption may limit the decrease in cognitive functions but, similarly to other authors, they also emphasize methodological limitations of the available studies [44]. Contrary to the abovementioned sources, Kim et al., in the latest meta-analysis of observational studies, concluded that they found no correlation between caffeine intake, in tea or coffee, and dementia [8]. Discrepancies in methodology between various studies include, among other things, different diagnostic criteria, e.g. Mini-Mental State Examination, Diagnostic and Statistical Manual of Mental Disorders – Third Edition, or only a telephone interview, which might have affected the results.

Coffee versus Alzheimer’s disease

Alzheimer’s disease is the most prevalent neurodegenerative disease [8, 17, 43]. It has been estimated to constitute 50–70% of all cases of degenerative brain diseases [4, 12]. According to Wyka, it affects 5–10% of people > 65 years of age and almost 50% of patients > 80 [17]. Przysławski and Stelmach estimate that in Poland AD is diagnosed in 2.3–3.5% of individuals between 65 and 84 years of age, with higher incidence among women than men [22]. Accumulation of β-amyloid, a protein which surrounds neurons and impairs absorption of nutrients and oxygen from blood vessels, plays a key role in the pathogenesis of the disease [4, 7, 45]. Thus, AD therapy aims to lower the level of that protein by inhibition of the enzyme activity generating amyloid production [7, 45]. In the future, the assay of β-amyloid in cerebrospinal fluid may be used in standard management to diagnose preclinical stages of the disease, i.e. the phase of mild cognitive impairment [46].

According to the literature, coffee consumption is hypothesized to be one of the possible preventive measures, which is based on the promising results of studies on animal models [33, 44]. Arendash and Cao demonstrated that caffeine intake in mice – from young to old age – lowers the concentration of this neurotoxic peptide [47]. Thus, these authors concluded that caffeine consumed in moderation (the human equivalent of 500 mg of caffeine or 5 cups of coffee a day) may protect against the development of AD or may be used in its therapy [47].

A 2007 quantitative review of observational studies demonstrated a new, positive effect of coffee consumption on lowering the risk for AD – approximately by 30% as compared to non-coffee consumers [48]. A 2010 review of longitudinal epidemiological studies suggested that daily intake of 3–5 cups of coffee in middle age may lower the risk of the disease by 64% as compared to lower amounts of coffee [6]. Two meta-analyses of cohort and case-control studies, from 2010 and 2015, also reported an inverse correlation between disease incidence and coffee/caffeine consumption [43, 49]. Furthermore, a review of the literature on the effects of various environmental reasons for the development of AD indicated a beneficial influence of coffee intake [14]. However, most authors emphasize a great number of methodological differences, which renders unequivocal conclusions difficult. One of the main limitations is a lack of accurate data on the duration of coffee intake among the studied populations. As a result, it is challenging to establish at what age coffee might start to exhibit its positive effect [43, 48]. The amounts of coffee, described as ‘low’, ‘moderate’, or ‘high’ in various sources [39, 42], and of caffeine in a cup, which might be anything between 36 and 220 mg, constitute yet another difference [8, 50].

Coffee versus Parkinson’s disease

The incidence of PD in the general population has been estimated at 0.15–0.3% [7, 51], increasing dramatically with age (1.7–2.2% in people over 65 [52], and 4% in the oldest age group [51]). According to Gaweł and Potulska-Chromik, mean age at onset is 58 years [7]. The etiology of PD remains to be fully elucidated. As in the case of AD, genetic as well as environmental factors are taken into consideration [25].

The first reports about coffee consumption and the risk of PD were published in the 1970s [53]. Since then, numerous authors have investigated coffee as a potentially protective factor. Ascherio et al. demonstrated that men who drink at least 1 cup of coffee a day are at a lower risk for PD mortality as compared to non-coffee consumers. No such correlation was found in females, possibly as the result of hormone replacement therapy, which inhibits caffeine metabolism. Nevertheless, other prospective cohort studies of these authors reported an effect in women as well. The lowest risk for disease was associated with daily consumption of 1–3 cups of coffee [54]. Ross et al. conducted an observational study exclusively among men and demonstrated a dose-dependent positive effect of coffee consumption. Male non-coffee drinkers were at a 3–5-fold higher risk of developing PD as compared to men who consumed at least 800 ml of coffee daily [55]. A correlation between coffee intake and disease development was also confirmed by studies in Parkinson patients only. Coffee drinkers developed the disease 8 years later than did non-coffee drinkers (mean age at onset 72 and 64 years, respectively) [56]. Despite the confirmed link, these authors suggest that coffee may be indirectly correlated with disease development, and that a complex interplay of numerous factors plays the decisive role. A cohort study from Finland in a population aged 50–79, conducted over a period of 22 years, demonstrated that the highest consumption of coffee was associated with the lowest risk of the disease (74% lower than for non-drinkers) [25]. However, a positive link between coffee intake and PD has not been confirmed by many clinical control trials, including the studies by Morano et al. [57], Checkoway et al. [58], and Jiménez-Jiménez et al. [59]. Also, no correlation was found between coffee consumption and mild changes typical for PD (i.e. tremor, abnormal posture and gait) in elderly people without diagnosed neurological diseases [60].

Joint studies offer more valid and general conclusions. A meta-analysis of cohort and case-control studies by Hernán et al., including reports published between 1966 and 2002, revealed a strong correlation between coffee consumption and the incidence of PD. Coffee drinkers were at a 30% lower risk of the disease as compared to non-drinkers [61], which is consistent with the latest meta-analysis from 2014 and the conclusion that the strongest positive effect (28% lower risk) was observed for the daily intake of 3 cups of coffee [52]. Additionally, that analysis demonstrates a linearly dependent correlation between caffeine dose and risk for disease. Daily increase of caffeine consumption by 200 mg resulted in a 17% lower risk for disease. Regardless, many authors emphasize the possibility that other factors might interfere with the correlation, e.g. smoking, which is associated with lower risk of the disease, whereas smokers tend to drink more coffee than non-smokers [9, 52, 62, 63]. Also, a meta-analysis of epidemiological studies by Costa et al. generated optimistic conclusions. According to these authors, caffeine lowered the risk of PD in a linear, dose-dependent manner. Moderate coffee consumption (300 mg a day) lowers the risk of PD disease by 24% [64].

Coffee: a possible mechanism of action

Explaining the widely reported link between coffee intake and the incidence of neurodegenerative diseases remains a considerable challenge. So far, none of the numerous hypotheses has been confirmed or rejected. Coffee contains many different components, mostly caffeine, polyphenol, trigonelline, niacin, potassium, diterpenes, and acrylamide [6, 8, 62, 65, 66]. Figure 1 presents a possible mechanism of the impact of coffee on the risk for neurodegenerative diseases [6, 66–79].

Figure 1

The possible mechanism of the impact of coffee on the risk for neurodegenerative diseases [6, 66–79]

Most researchers focus their attention on caffeine, whose role in the pathogenesis of the disease might be supported by data confirming beneficial effects of caffeine from other sources, e.g. tea or cola drinks [61]. It is believed that caffeine exhibits neuroprotective effects by blocking adenosine receptors. This in turn results in higher concentrations of serotonin and acetylcholine – neurotransmitters in the central nervous system [6, 53, 62, 67, 80]. A clinical study on Parkinson’s patients demonstrated that administration of adenosine receptor antagonists alleviates disease symptoms [81]. Experimental studies on animal models revealed that caffeine stabilizes blood-brain barrier (BBB) integrity, which contributes to brain homeostasis. The BBB disruption has been implicated in the pathogenesis of a number of neurodegenerative disorders, including dementia, AD, and PD. However, the detailed molecular mechanism of caffeine’s action on BBB remains poorly understood [68]. Some studies have revealed that also the main metabolites of this substance, i.e. paraxanthine and theophylline, have similar neuroprotective properties as caffeine [69].

Also, individual conditioning, including the metabolic rate, is taken into account when analyzing the role of caffeine in the mechanism of the disease. The cytochrome P450 (CYP 1A2) enzyme is responsible for caffeine degradation, and its genotype-conditioned activity determines the metabolic rate. Carriers of the AA genotype metabolize caffeine much faster than do carriers of the AC or CC genotype [82-84]. At present, it is difficult to precisely determine the effect of that factor. In a study by Popat et al., a positive correlation between coffee intake and the risk of PD was stronger in slow metabolizers of caffeine [85], whereas Tan et al. found no association with metabolic rate [84]. As for the role of caffeine in the process of slowing down the development of neurodegenerative diseases, the potentially beneficial dose has not been determined, and the abovementioned studies lack more detailed data on its exact amount in the particular brews. Moreover, the dose is typically cup-dependent. A typical portion of coffee in the USA is 250 ml, whereas in Europe it is much smaller (125–150 ml). On the other hand, American brews are weaker than those in European countries [86].

Another positive effect of coffee may be related to an improved oxidative system due to polyphenols. Oxidative stress is considered to be a promoting factor for PD [25, 68]. Chlorogenic acid, one of the most important polyphenols to be found in coffee, has well-documented antioxidant properties and thus may inhibit the destructive effects of free radicals on neurons. The literature has suggested that neuroprotective activity of chlorogenic acid is the basis for further research on its use for therapeutic purposes [70, 75]. The amount of polyphenols in coffee depends on numerous factors, including their content in coffee beans and the method of brewing. The authors of various meta-analyses emphasize the lack of precise data about the method of brewing in the available publications, which may explain the inconsistent results [25, 52]. Also, the method of brewing coffee affects the content of cholesterol-raising diterpenes – cafestol and kahweol. Unfiltered, boiled coffee is rich in diterpenes, whereas filtered coffee has far lower concentrations of these compounds because of their retention by the filter paper [76]. Two meta-analyses of randomized controlled trials indicated that consumption of unfiltered coffee increases serum lipid levels [77, 78]. Some experts believe that coffee brewed without filters in fact increases the risk of dementia due to a higher serum concentration of cholesterol [39].

Coffee also contains the alkaloid trigonelline and products of its partial degradation during the roasting process – nicotinic acid and N-methylpyridinium. All of them are bioactive constituents and have been investigated as potential neuroprotective agents. However, similarly to other coffee compounds, their exact action remains to be fully elucidated. Trigonelline is believed to have the ability to induce axonal extension in human neuroblastoma and thus enhance synapse formation. Moreover, it may increase the activity of the antioxidant enzymes and decrease lipid peroxidation [66, 71, 79]. Niacin (vitamin B3) is involved in a multitude of intracellular processes. It plays an important role as an antioxidant in brain mitochondria, and it is considered to be a protective factor against cognitive decline. Coffee can be a source of a considerable part of the daily niacin supply for coffee drinkers [87, 88].

Positive effects of coffee consumption on the decreased risk of AD may be related to lower incidence of type 2 diabetes due to the fact that insulin resistance is considered in the etiology of that disease [8]. Other factors must also be taken into account, chief among them smoking. Smokers process caffeine at a much higher rate, and that might hinder the attempts to establish a link between coffee intake and the state of cognitive functions [2, 43].

Conclusions

The cumulative body of evidence about lower incidence of PD and AD among coffee drinkers is substantial but not conclusive enough to prove a positive effect of coffee consumption on the development of these diseases. The current state of knowledge permits the conclusion that coffee intake does not constitute a health risk. Taking into account the fact that most people drink coffee for pleasure, because of its taste, the additional and unexpected health benefit would be an added value.

Of note, in 2015, a cup of coffee and of tea were included in the new graphic food pyramid designed by the National Food and Nutrition Institute in Warsaw [89]. The American experts are also of the opinion that moderate coffee intake may in fact become an element of a rational and healthy diet [90].