The chemical components of coffee and an examination of the relationship between consumption and possible cognitive protective effects

JP Slovack NTR 402/502 Paper Rewrite: December 3rd, 2013

2 Introduction Coffee is one of the most popular drinks in the world, consumed by millions of people daily (Cropley et al., 2011). Everyday, more than 2 billion cups of coffee are consumed (International Coffee Organization [ICO], n.d.). Finland, Norway and the Netherlands consume the most coffee at 9+ kg coffee/person/year with the United States consuming 4.2 kg coffee/person/year (ICO, n.d.). Due to this popularity, the health effects of coffee are of the upmost interest. One of the single most well studied compounds found in coffee is caffeine. Past studies have demonstrated a positive relationship between coffee and improvements in alertness, reaction time, and reduction in fatigue (Cropley et al., 2011). Caffeine is not the only compound of interest in coffee though. Other molecules that have become important research components include cholorogenic acids (CGAs), caffeic acid and ferulic acid, to name a few (Cropley et al., 2011). The effects of coffee on cognition have demonstrated mixed results (Van Gelder et al., 2007). Few large scale, well-organized studies investigating long-term effects of coffee on agerelated cognitive decline (ARCD) and Alzheimers Disease (AD) exist (Arab et al., 2013). The purpose of this paper is to investigate current research involving the role of coffee as either a preventative agent or treatment option for ARCD and AD. This paper will also attempt to identify possible levels of coffee consumption that may have a therapeutic effect, if one exists. Age-Related Cognitive Decline ARCD is a large area interest due to the rapidly aging population around the world (Deary et al., 2009). It is important to understand what ARCD is and how it differs from abnormal cognitive diseases such as dementia and AD. A natural decline in cognitive function is expected during the aging process. This decline is believed to occur due to oxidative stress,

3 shortening of teleomeres during DNA replication, hormonal changes and a reduction in the activity of the immune system (Deary et al., 2009). The effects of normal cognitive decline can begin as early as age 30 (Deary et al., 2009). Many areas show little to no change during aging such as verbal ability, certain numerical functions and general knowledge (Deary et al., 2009). Other areas may show signs of impairment such as memory, reasoning and the speed at which one can process incoming information (Deary et al., 2009). While a reduction in the quality of life can sometimes occur in ARCD, the individual can, for the most part, still live and function independently. Diseases such as dementia and AD can be seen as the far side of the aging spectrum where abnormal changes in the brain, such as the deposition of amyloid plaque, can cause such a steep decline in various mental processes that the individual can no longer live on his or her own (Center for Disease Control [CDC], n.d.). The cost of caring for those who are unable to care for themselves due to diseases like AD is estimated to cost programs such as Medicare and Medicaid approximately $130 billion dollars, with an estimated 5.4 million Americans being affected (CDC, n.d.). This number has doubled since 1980, and may reach as many as 13.8 million by the year 2050 (Alzheimers Association, n.d.). As of 2009, 1 out of every 8 Americans is over the age of 65, constituting 12.9 % of the population (39.6 million) (NIH, n.d.) Important lifestyle factors that may contribute to the changes seen in ARCD, dementia and AD include genetics and heredity, diet and lifestyle, physical activity and chronic inflammation (Deary et al., 2009)). Limited treatment options currently exist and no cognitive enhancers are currently known (Arab et al., 2013). Therefore, preventing or slowing the effects of cognitive decline are currently the main focus of public health (CDC, n.d.). Caffeine and effects on cognition, dementia and AD

4 As previously mentioned, coffee contains multiple components of interest. The chemical of most interest is caffeine. Caffeine acts as both a metabolic and central nervous system stimulant. It is the most widely used psychoactive substance in the world (Santos et al., 2010). Caffeine has demonstrated an affinity for several types of receptors located at the synaptic membrane (Santos et al., 2010). Its stimulatory effects are believed to be caused by its actions as an antagonist to adenosine in the brain and effects on other neurotransmitters such as dopamine, serotonin, acetylcholine (Santos et al., 2010). While coffee has shown a negative correlation with mental decline, caffeine on its own has shown mixed results. A prospective, case-control study of 3,734 men of Japanese ancestry followed since 1965, found that caffeine intake was not associated with dementia, AD or cognitive impairment/decline with caffeine intake estimated from coffee, tea and cola. After adjustments for age, physical activity, smoking, education and heart disease data showed caffeine had a slightly protective effect on AD (odds ratio (OR) = 0.95, 95% confidence interval (CI) 0.46-1.95) although this was not statistically significant. The men in the highest quartile of caffeine intake (greater than 411 mg/day) had a lower risk than those in the lowest quartile of caffeine intake (<137 mg/day) for any type of neuropathologic lesions (OR= 0.45, 95% CI 0.230.89 p=0.04) (Gelber et al., 2011). This particular study looked at caffeine ingestion during midlife (mean age = 52 years old). An epidemiologic review of caffeine ingestion between coffee and tea found that many studies have been unable to shown a specific correlation between caffeine ingestion and a reduction in mental decline in men, but have been able to show a protective benefit in women, suggesting that the effects of caffeine may benefit women more so than men (Arab et al., 2013). A population study investigating the effects of caffeine on the presence of white matter

5 lesions in the brain of 641 elderly adults (mean age = 74.2 for men and 74.4 for women) found similar results in terms of gender and caffeine protection. Women with the highest caffeine intake, greater than 300 mg/day, (~ 3 cups coffee/day) had the lowest white matter lesions/cranial volume ratio when compared to those consuming less than 300 mg/day (reduction of 35% p=0.04) with this significance holding after adjustments for age, alcohol and disability (p=0.046) (Ritchie et al, 2010). High caffeine in take in men (more than 300 mg/day) had no protective effect on men when compared to those consuming 100 mg (~1 cup of coffee/day) or less caffeine/day (p=0.88). This particular study was of interest for the authors controlled for possible confounding factors such as other health effects (depression, heart disease, cholesterol and diabetes) as well as education levels, BMI, disability and alcohol ingestion (Ritchie et al, 2010). Controlling for such factors allows for greater evidence of a direct relationship between caffeine ingestion rather than an indirect or spurious relationship. Caffeine is difficult to study independently in population studies due to the difficulty in obtaining accurate caffeine ingestion numbers. For example, caffeine is found in many beverages and foods (coffee, cola, tea, chocolate, supplements, etc) and therefore an all-inclusive questionnaire must be presented to account for all the various forms of caffeine that may be ingested. Additional, having participants recall their consumption can cause participants to misremember how much they consume on average (e.g reall bias). Also, many studies, such as the Japanese ancestry study, ask for beverage consumption at the time of the survey as opposed to life-long, historical consumption (Gelber et al., 2011). Caffeine ingestion can change over time and due to environmental factors, always posing a challenge in assigning causal order to caffeine and its possible cognitive protective effects. It has been shown that the cognitive effects of caffeine may be altered based upon the

6 individuals history of caffeine consumption (Cropley et al., 2012). Specifically, habitual users of caffeine may benefit the most by the cognitive effects of caffeine when compared to non-habitual users. A relatively small study (n=39 partipants) investigating the effects of caffeinated coffee versus decaffeinated coffee enriched with chlorogenic acids utilized individuals consuming less than 8-cups of coffee per week (Cropley et al., 2012). Participants consumed one cup of coffee and one-hour later were performed 70 minutes worth of cognitive tests. They found that, while the chlorogenic acid-enriched coffee did elicit some cognitive-enhancing effects, caffeinated coffee had the most prominent impact despite only acute administration of coffee (Cropley et al., 2012). Caffeine improved rapid visual information processing by score of 3.03 (p<0.001), increase alertness by a score of 2.04 (p =0.013) and increased CRVAS mood scores in the categories of relaxation (change =2.76 p=.002), alertness (change =2.16 p=.010) and mood (change =3.70 p=<.001). Caffeine also tended to decrease feeling tired (change =1.86 p=.021), tense (change =1.72 p=.028), headaches (change =2.33 p=.007) and fatigue (changed =3.43 p<0.001). This also shows demonstrates that simply drinking a cup of coffee is enough to elicit various cognitive enhancements, regardless of long term use or high-consumption. Other components of coffee affecting cognitive decline, AD and dementia Caffeine is not the only component of interest in coffee. On the contrary several other chemical components have contributed to the high anti-oxidant content found in coffee. In fact, coffee per serving amount of anti-oxidants is among the highest in the America and diet, making it the primary source of anti-oxidants consumed in America (Cao et al., 2011). Two antioxidants of interest are the polyphenols chlorogenic acid and caffeic acid (Cao et al., 2011). The previously mentioned work of Cropley et al. (2012) demonstrated that cognitive enhancement was observed in previously low coffee consumption group who then began to consume

7 caffeinated coffee enriched with CGAs. Participants who consumed decaffeinated coffee enriched with 521 mg CGAs (regular decaffeinated coffee = 224 mg CGAs) scored higher on alertness test (score difference = 2.98 p=0.003), had decreased inspection time scores (score difference = 1.69 p=0.099) and responded quicker to change in faces presented (score difference = 6.08 p =0.018). While this effect was not as great as seen in the group who consumed regular caffeinated coffee (saw broader improvements in areas of mood, fatigue, alertness and accuracy), the results do show that the other bioactive compounds found in coffee may be beneficial (Cropley et al., 2012). One suggestion is that the non-caffeine components of coffee may have a synergistic effect when combined with caffeine (Cao et al., 2011). One particular study of interest compared the effects of caffeine, caffeinated coffee and decaffeinated coffee on amyloid-beta transgenic mice who experienced cognitive decline at an enhanced rate due to this genetic mutation. The study looked at the effects the equivalence of five 8-oz cups of coffee consumed twice a week would have on the ability of the mice to navigate to the center of a circular maze. The researchers measured the number of errors the mice made, as well as their escape latency, comparing the experimental groups to the non-transgenic mice who had their scores indexed to 100% for comparison. The transgenic mice treated with caffeinated coffee for 3-months performed just as well as the non-transgenic control group with no statistical difference (p<0.05) when comparing the percent latency (125% +/- 15%) and percent errors (145% +/- 20%) (Cao et al., 2011). The group treated with decaffeinated coffee (percent errors = 200% +/- 20% and percent latency = 158% +/- 20% ) performed statistically similar to the transgenic group given no treatment (percent error = 250% +/- 38 % and percent latency = 176% +/- 14% p >0.05) (Cao et al., 2011).

8 Other studies have looked solely at the ingestion of coffee, and were more concerned with the protective effects the entire drink may have as opposed to the protective effects of a single compound or group of compounds. A relatively large study that looked at coffee consumption of 676 elderly men from Italy, the Netherlands and Denmark (areas of high coffee consumption) and followed for 10 years, found an inverse, j-shaped curve in regards to the relationship between coffee consumption and overall cognitive decline (Van Gelder et al., 2007). Cognition was measured by the Mini-Mental State Exam (MMSE) and at baseline, the sample groups mean score was 25.7. Those who consumed any coffee at all had a mean decline of 1.2 points (as measured again by the MMSE) after 10 years, while non-consumers had a mean 2.6 point decline (p < 0.001) (Van Gelder et al., 2007). The protective benefit of coffee increase with each additional cup, with 3 cups providing the greatest protection (mean decline =- .6 points over 10 years) while consuming more than 4 cups of coffee was observed to have a cognitive decline not significantly different from those who did not consume coffee ( -1.6 points, p > 0.05) (Van Gelder et al., 2007). This study looked at men who did not have any initial symptoms of cognitive decline, removed those who developed diabetes, had a myocardial infraction, stroke or cancer, since they felt that these diseases may have caused the men to alter their coffee intake (Van Gelder et al., 2007). Coffee consumption and assessing its effects on cognitive decline, AD While many studies have demonstrated a link between coffee consumption and a reduction in cognitive decline and other neurodegenerative diseases such as AD, some studies have shown little correlation. A large-scale study of Finnish twins looked at coffee consumption over several decades, with a median follow-up time of 28 years (Laitala et al., 2009). In this particular study, cognition was measured by a postal questionnaire at baseline, with a telephone

9 interview follow-up. Contrary to many other longitudinal studies, no correlation was found between coffee consumption and cognitive decline. Odds ratios found 3.5-8 cups of coffee as well as 8+ cups of coffee to be slightly protective towards cognitive impairment (OR= 0.83 and 0.79 respectively) but these values were not statistically significant (p= 0.39 and 0.54 respectively) (Laitala et al., 2009). Odds ratios for all levels of coffee consumption (0-3 cups/day, 3.5 -8 cups/day and 8+ cups/day) in regards to dementia were found to be greater than 1.00 (Laitala et al., 2009). This particular study is of interest due to its high number of participants (2556), length of time between initial assessment and follow-up (median = 28 years) and the low reported intake of other drinks such as soda (cola specifically) and tea (Laitala et al., 2009). One main difficulty in the assessment of coffee intake in many studies is that the mean coffee intake varies greatly. For example, it is relatively unknown what the therapeutic level of coffee intake might be for observed physiological affect (Santos et al., 2010). The Finnish twin study which found no correlation between coffee intake and decreased cognitive decline had a mean coffee intake of ~2 cups per day with women drinking ~0.5 cups/day more than men (Laitala et al., 2009). Trangenic mice who were observed to have experience less errors and latency in navigating a circular maze were given the equivalent of 5 cups per day, twice a week (Cao et al., 2011). The Honolulu study only found a reduction in cognitive decline in subjects who reported 4 or more cups per day (Gelber et al., 2011), while a study testing the effects of cholorogenic acid, saw cognitive improvement in subjects who only consumed ~ 1 cup per day (Cropley et al., 2011). Along the same lines some studies looked only total caffeine consumption while others looked at total coffee consumption. Some studies looked at coffee intake only in men (Gelber et al., 2011 and Van Gelder et al. 2007) and other studies saw an improvement in

10 cognition only in women (Ritchie et al., 2010). Some studies looked only at coffee consumption and cognition at the time of the survey (Gelber et al., 2011), while others had follow-up sessions of varying lengths (Laitala e al., 2009). Also, it is important to note that all the population studies reviewed for this report looked at coffee intake as a preventative measure and looked at older populations (middle age and up). Conclusion Coffee is a complex beverage with multiple biologically relevant chemicals (Cao et al., 2011). Due to this, it is difficult to isolate what compound(s) may have the most significant effect on reducing the effects of cognitive decline and diseases like AD and dementia. Caffeine has been the most studied, but some studies have shown other biologically relevant compounds such as CGAs to also have a protective effect (Cropley et al., 2012), while other studies have demonstrated a synergistic effect between caffeine and some other, possibly unidentified, compound(s) (Cao et al., 2011). It is also difficult to determine the amount that may be protective, as studies have utilized varying amounts of coffee as well as utilized multiple populations of people with varying histories of coffee consumption. At the very least coffee consumption has not shown negative effects in terms of increasing the risk of cognitive decline. Due to this, drinking two to three cups, of regular, caffeinated coffee on a relatively consistent basis (daily) may constitute some protection against cognitive decline and AD. If you are currently not drinking coffee though, there doesnt appear to be enough evidence that would encourage one to begin. Increasing other factors such as physical activity and consumption of fruits and vegetables, would probably constituent a greater increase in protection.

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