coffee and brain

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‘Coffee and the brain’- Contents

Page

Introduction 5-6

1 Coffee, caffeine and headache

Headache 7

Caffeine and headache 8-9

Caffeine withdrawal, fasting and weekend headache 9-13

Headache and fl uid balance 13

References 14

2 Coffee, caffeine en cognition

Cognitive function 15-16

Caffeine and the brain 16-17

Coffee and alertness 17-19

Coffee and attention, concentration and memory 20-21

Coffee and qualifi cation caffeine effect 21-22

Coffee and mood 23-24

Coffee and sleep 24

References 26-27

3 Coffee and cognitive aging

Cognitive aging, MCI and dementia 29

Coffee and acute effects on cognitive aging 29-30

Coffee and long term effects on cognitive aging 30-31

Coffee and Alzheimer’s disease 31-32

Coffee and Parkinson’s disease 32-33

References 34

Study of coffee and health 35

Coffee and the brain | 3


Introduction

Coffee is not only appreciated for its taste and aroma, but also for its effect on

the mental performance. It’s widely known that coffee can help to stay alert, but

how much coffee do you have to drink before you notice any effect and what is

known about the mechanism? What is the effect of coffee on headache, does it

alleviate the symptoms or not? Coffee adds to cognition, but could coffee coun-

teract age-related cognitive decline? This brochure deals with common ques-

tions about coffee in relation to the effect on the brain and provides a summary

of results of innumerable scientifi c studies.

The Coffee and Health Information Bureau (Voorlichtingsbureau voor Koffi e

en Gezondheid) sought assistance from scientists who are well known for their

knowledge and experience in this research area. We would like to take this op-

portunity to thank them for their excellent contribution and cooperation in the

preparation of this brochure.

- Dr. Astrid Nehlig (research director, Faculté de Médécine, French National

Institute for Health and Medical Research, INSERM, Strasbourg, France)

- Dr. Monicque Lorist (associate professor, Faculteit der Gedrags- en

Maatschappijwetenschappen, Rijksuniversiteit Groningen, The Netherlands)

- Dr. Jan Snel (associate professor UHD psychofysiology, Universiteit van

Amsterdam, The Netherlands)

6 |

Research on the effects of coffee and/or caffeine on cognitive aging is highly

relevant and very timely due to the aging of the population. Some topics do not

have yet an unequivocal answer, because the amount of research is currently

insuffi cient. The Information Bureau will continue to closely monitor scientifi c

developments and inform you on new studies in our email newsletter and on

our website www.koffi eengezondheid.nl.

If after reading of this brochure you still have questions or comments, we will be

pleased to hear from you. You can also order Dutch copies of the brochure free

of charge or download the Dutch or English version at www.koffi eengezond-

heid.nl.


(Voorlichtingsbureau voor Koffi e en Gezondheid)


1 Coffee, caffeine and headache

1 What is headache?

Headaches occur as a response to daily life situations like stress, fatigue, lack

of sleep, hunger or weather changes. Despite the fact that headaches are

extremely common, almost 90% of men and 95% of women have at least one

headache a year, they are not fully understood. Neither the skull nor the brain is

sensitive to pain, however, both are surrounded by pain-sensitive membranes.

Abnormalities in these membranes or nearby muscles, blood vessels, or nerves,

either alone or in combination, are thought to be the source of most headache

pain. Also changes in estrogen level can make headaches worse (Harvard Health

Publications, 2010)

2 What are the common types of headache?

The International Classifi cation of Headache Disorders (ICHD) separates primary

headache disorders from the secondary headache disorders. The former include,

most importantly, migraine, tension type headache and cluster headache. The

latter is attributed to causative disorders like a head or neck trauma, a vascular

disorder, a substance (e.g. medication overuse), substance withdrawal (e.g.

caffeine) or a disorder of homeostasis (e.g. fasting) (IHS, 2004; Olesen, 2004).

Tension type headache and migraine are the most common types of headache;

however, mixed headaches do occur.

8 |

3 Can caffeine consumption relief headache symptoms?

Caffeine may act as analgesic for headache and the use of caffeine as constitu-

ent of analgesics dates back to 1875. Nowadays caffeine is an essential com-

ponent of numerous widely consumed medications for the relief of headache

symptoms (Shapiro, 2008; Nehlig, 2004). A meta-analysis of 30 clinical trials

indicates that adding caffeine to an analgesic agent reduces the dosage needed

of that analgesic agent by 40% to achieve equivalent analgesia (Laska, 1984).

A further meta-analysis of randomized controlled trials of simple analgesics

taken with or without caffeine indicates that addition of caffeine promotes a

signifi cant headache relief (Zhang, 2001). Studies on the effi cacy and safety

of over the counter (OTC) headache combination analgesics were reviewed in

2010 (Anneken, 2010). Treatment of migraine and tension-type headache,

was shown more effective using a combination of acetylsalicyclic acid (ASA),

acetaminophen and caffeine (100-150 mg) than monotherapy with either of

these substances. Adding caffeine was associated with an increased analgesic

effect, which is often unachievable via increased dosages of mono-analgesics

because of their fl at dose-effect relationships. Moreover, mixed analgesics co-

formulated with caffeine provide the same effi cacy using a lower analgesic dose,

thus potentially reducing dose dependent adverse effects.

4 Can you get a headache of too much caffeine?

Confl icting results have been found in population studies evaluating the

association between high caffeine consumption and the prevalence of headache

and chronic frequent headache (CFH), in particular. CFH is the collective term

for primary headaches occurring on more than 14 days per month for at least

3 months. In a general population study in the Netherlands, CHF was associated

with overuse of analgesics, psychiatric disorders, smoking, sleeping problems,

a history of head and neck trauma and low educational level, but not with


caffeine use (Wiendels, 2006). In this study, the average intake of caffeine was

7 consumptions a day, including coffee, tea, ice tea and cola. However, in a

large cross sectional study in Norway, high caffeine consumption (> 540 mg/d)

was associated with increased prevalence of infrequent headache, whereas

chronic headache was less likely among individuals with high caffeine consump-

tion (Hagen, 2009). According to the authors these results may indicate that

high caffeine consumption changes chronic headache into infrequent headache

due to the analgesic properties of caffeine, or that chronic headache sufferers

tend to avoid the intake of caffeine. This is in line with the conclusion of the

review by Shapiro (2008), stating that caffeine can exert potent pharmacologic

effects that can generate or alleviate headache, depending on the site of action,

dosage and timing of exposure.

5 Can you get a headache if you stop drinking coffee?

Abrupt cessation of regular caffeine consumption may result in headache

among sensitive individuals. The headache generally resolves within a few days

or at most one week after consumption stopped. In addition, the headache

disappears when caffeine consumption is resumed (Nehlig, 2004; Scher, 2004).

Caffeine withdrawal headache are not experienced by all individuals; prevalence

fi gures vary between 0.4% and 50% (Shapiro, 2008). Caffeine withdrawal head-

ache can be easily prevented by reducing caffeine consumption gradually in the

days before cessation of consumption, for instance in case of (religious) fasting

or a surgical procedure.

10 |

6 Are fasting headaches related to caffeine consumption?

Fasting of food is an important precipitating factor of headache and the

probability of onset increases directly with the duration of fasting. Fasting

headache is one of the most common forms of secondary headache, but much

remains to be explained about the underlying patho-physiological mechanisms.

Hypoglycemia (low blood glucose level) and caffeine withdrawal are suggested

as potential triggers, although fasting headache may occur even when there

is no hypoglycemia and in individuals who do not normally consume caffeine

(Torelli, 2009).

Headaches after fasting before and after surgical procedures are found to be

related to habitual caffeine consumption (Nehlig, 2004). A study of prolonged

fasting suggests that other factors like abstinence from water or foods, genetic

background or cultural factors may contribute more strongly to fasting induced

headache, but not fully exclude caffeine as a factor (Shapiro, 2008).

7 What is meant by 'weekend headache'?

Some people experience headaches in particularly on weekend mornings.

Different explanations are proposed for this so called weekend headache

(Couturier, 1992; Nehlig, 2004; Shapiro, 2004). It might be related to the

change in stress level, or sudden disappearance of stress during the weekend.

Change in the pattern of sleep, often longer than usual, has also been suggest-

ed as an important cause. Other possible causes are increased consumption of

alcohol at the beginning of the weekend, or missing breakfast because of sleep-

ing late. Weekend headaches are also linked to a delay (sleep later) or avoidance

of caffeine consumption during weekend mornings (see also question 5).


Coffee intake

Caffeine is naturally present in coffee, tea and cocoa, and added in small quanti-

ties to some soft drinks. Consumption of coffee varies largely between countries.

In Europe the consumption of coffee ranges from 1.5 to 11.9 kg coffee per

person per year. The highest consumption occurs in Scandinavia (Finland 11.9

kg coffee/person/year), and the lowest consumption in Poland (1.5 kg coffee/

person/year) (International Coffee Organization, 2010).

The amount of caffeine per cup of coffee varies with the type of coffee used

(Arabica or Robusta), the brewing method (e.g. drip fi lter, instant, espresso,

boiled) and the brewing strength (in the Netherlands on average 7 grams per

cup). The table on page 12 summarizes average values of caffeine per product.

8 Can weekend headache be prevented and if yes how?

If someone is prone to weekend headache, there are several steps to prevent

or diminish the headaches.

• Identify triggers (see question 6 and 7) so these can be avoided.

• In case of habitual caffeine consumption, include a cup of coffee for

breakfast during the weekends.

• Keep a regular schedule that includes a full night’s rest, balanced meals

and exercise during the weekends (Harvard Health Publications, 2010).

References

• American Psychiatric Association (1994, 2000). Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) APA Press, Washington DC.

• Anneken K e.a. (2010). Efficacy of fixed combinations of acetylsalicyclic acid, acetaminophen and caffeine in the treatment of idiopathic headache: a review. Eur J Neurol, 17: 534-540.

• Armstrong LE e.a. (2007). Fluid, Electrolyte, and Renal Indices of Hydration During 11 Days of Controlled Caffeine Consumption. Int J Sport Nutr Exerc Met, 15: 252-265.

• Couturier EGM (1992). Weekend attacks in migraine patients: caused by caffeine withdrawal? Cephalalgia, 12: 99-100.

• Dutch Nutrition Center (2011), www.voedingscentrum.nl.• Hagen K e.a. (2009). High dietary caffeine consumption is associated with a modest increase in

headache prevalence: results from the Head-HUNT Study. J Headache Pain, 10: 153-159.• Harvard Health Publications (2010). A Harvard Medical School Special Health Report. Headaches

Relieving and preventing migraine and other headaches.• IHS - Headache Classification Subcommittee of the International Headache Society (2004). The

International Classification of Headache Disorders. Cephalalgia, 24, S1: 1-160.• Institute of Medicine of National Academies; Food and Nutrition Board. Dietary Reference Intake for

Water, Potassium, Sodium, Chloride and Sulfate. The National Academic Press (2004). www.nap.edu.• International Coffee Organization (2010). Monthly Coffee Market Report, Oct. 2010. www.ico.org.• Kolasa KM e.a. (2009). Hydration and Health Promotion. Nutrition Today, 44: 190-201.• Laska EM e.a. (1984). Caffeine as an analgesic adjuvant. JAMA 251: 1711-1718.• Nehlig A (2004). Caffeine and Headache: Relationship with the effects of caffeine on cerebral

blood flow. In Nehlig A (ed) Coffee, Tea, Chocolate and the Brain; CRC Press LLC, Boca Raton, Florida: 175-186.

• Nehlig A e.a. (2010). SPECT assessment of brain activation induced by caffeine: no effect on areas involved in dependence. Dialogues Clin Neurosci, 12: 255-263.

• Olesen J and Steiner TJ (2004). The international classification of headache disorders, 2nd edn (ICDH-II). J Neurol Neurosurg Psychiatry, 75: 807-808.

• Ruxton CHS (2008). The impact of caffeine on mood, cognitive function, performance and hydration: a review of benefits and risks. Nutr Bull, 33: 15-25.

• Satel S (2006). Is caffeine addictive? A review of the literature. Am J Drug Alcohol Abuse, 32: 493-502.

• Scher AI e.a. (2004). Caffeine as a risk factor for chronic daily headache. A population based study. Neurology, 63: 2022-2027.

• Shapiro RE (2008). Caffeine and Headaches. Current Pain Headache Rep, 12: 311-315.• Torelli P e.a. (2009). Fasting Headache: A review of the literature and new hypotheses. Headache,

49: 744-752.• Wiendels NJ e.a. (2006). Chronic frequent headache in the general population: prevalence and

associated factors. Cephalalgia, 26: 1434-1442.• World Health Organization (WHO, 1994). The ICD-10 classification of mental and behavioral

disorders. WHO, Geneva.• Zhang WY e.a. (2001). A benefit-risk assessment of caffeine as an analgesic adjuvant. Drug Saf,

24: 1127-1142.

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2 Coffee, caffeine and cognition

1 What is cognitive function?

The word ‘cognition’ comes from the Latin word ‘cognoscere’ which means

‘to know’ or ‘to recognize’ (Nehlig, 2010). Cognitive function is a general term

that is used to describe a great variety of different brain mediated functions and

processes. These brain functions allow us to perceive, evaluate, store, manipulate

and use information from external sources, like our environment, and internal

sources, like experience, memory and thoughts, and respond to that informa-

tion (Schmitt, 2005). Cognitive functions can be clustered in six main domains:

executive functions, memory functions, attention functions, perceptual functions,

psychomotor functions and language skills (see schematic representation on

page 16). These distinct functions often act together to produce actual cogni-

tive performance output. For example, effi cient storage of new information in

the long-term memory cannot occur without proper attention for the relevant

information, adequate perceptual processing, and the executive learning strate-

gies. Besides, cognitive functioning is mediated by a number of other factors

which are not considered to be cognitive functions themselves. A key mediator is

the level of central arousal, which can be roughly described as the level of mental

energy. Mood state (sad, happy) is also known to modulate cognitive function, as

well as motivation and physical well-being.


In doses normally consumed, caffeine blocks inhibitory A1 and A2A receptors,

and hence increases central nervous system activity (Nehlig, 1992; Fredholm,

1999; Daly, 2004; Fisone, 2004; Tieges, 2007).

3 What is the effect of coffee or caffeine on alertness?

It is well-known that caffeine ingestion leads to dose dependent increased

energetic arousal, which refl ects alertness and mental energy (Nehlig, 2010).

However, the relationship between the level of arousal and task performance is

not a linear one, but follows an inverted U-curve: performance decrements can

occur due to under- and over-arousal (Schmitt, 2005). Furthermore, the optimal

arousal level is thought to vary between different cognitive tasks (Van Boxtel,

2004).

Some of the most sensitive functions for increased arousal are reaction time and

vigilance. There is a large number of scientifi c studies showing that consump-

tion of caffeinated foods and beverages is associated with increased alertness,

improvements of reaction time and vigilance performance. Most of this research

includes computer tests which have the advantage of a standardized presenta-

tion and accurate and detailed response capture. The level of performance is

usually measured in terms of speed (e.g. simple reaction time) and accuracy

(the amount of correct information), free recall of information or selective visual

tasks. The stimulating effect of caffeine consumption on alertness and perform-

ance effi ciency was demonstrated for a variety of tasks (Lorist, 1994, 1996;

Ruijter, 1999, 2000; Smit, 2000, 2005a; Smith, 2005b; Haskell, 2005; Hewlett,

2007; Olson, 2010). EEG data support the stimulating effect of caffeine on the

brain (Lorist, 2003).

18 |

4 When is the effect of caffeine most noticeable?

The impact of caffeine on increased alertness is more marked for individuals

with low arousal levels. However, improved performance has also been observed

when reduced alertness is not involved (Smith, 2002; Snel, 2004). Sleepiness

leads to deterioration in performance and is associated with an increased risk

of error and injury. For instance shift work is a major cause of sleepiness as it

requires being awake at times which are different from those dictated by our

body-clock. A review of 13 trials shows that caffeine can reduce the number of

errors and improve cognitive performance in shift workers and also in persons

suffering from jet lag (Ker, 2010). In addition, caffeine or coffee consump-

tion has been shown to counter-act fatigue induced by a night with sleep-

deprivation (Lorist, 1994), and to reduce the post lunch dip (Robelin, 1998),

to improve nocturnal driving performance whereas napping did not (Sagaspe,

2007) and is associated with improved alertness and reduced risk for accidents

at work (Smith, 2005a).

How is caffeine metabolized in the body?

After drinking a cup of coffee, caffeine is rapidly and effi ciently absorbed from

the gastro intestinal tract and peak plasma concentrations are reached between

15 and 120 minutes. Caffeine is distributed throughout the body and easily

enters the brain. The half life of caffeine amounts 2.5 to 4.5 hours but can vary

considerably depending on endogenous factors such as physiology and genet-

ics, and exogenous factors such as lifestyle. For example, caffeine half-life can

be reduced by about 50% in smokers compared to non-smokers. Caffeine is

metabolized in the liver and its break down products are excreted through the

kidney (Nehlig, 1992; Fredholm, 1999).


In the same way, for short stopovers (1-2 days) during trips with time zone

differences, judicious naps combined with caffeine and short-term hypnotics

appear to be the best way to maintain alertness and sleep (Arendt, 2009).

5 How much coffee do I have to drink to become more alert and achieve a better performance?

The benefi t of caffeine in typical servings of coffee (60-100 mg of caffeine) on

alertness was demonstrated in several studies. Even lower doses have been

demonstrated to increase alertness, such as 40 mg caffeine per serving (Smit,

2000), 32 mg per serving (Lieberman, 2001) or doses as low as 12.5 mg

caffeine (Smit, 2000). However, the effect of low doses of caffeine was observed

predominantly in those people who are not accustomed to taking caffeine.

Higher caffeine intakes, as those found in more than one or two cups of

coffee do not necessarily result in additional increases in alertness (Smit, 2000;

Quinlan, 2000). It is thought that the relationship between the level of arousal

and task performance follows an inverted U-curve: performance decrements

can occur due to under- and over-arousal (Schmitt, 2005). In general, benefi cial

behavioral effects of caffeine are found with doses comparable to those found in

habitual coffee consumption levels (Smith, 2002).

20 |

6 How can drinking coffee contribute to attention and concentration?

Concentration is usually related with improved selective attention, meaning

that the mind is focusing narrowly on the task at hand. Focusing of attention

can be improved by caffeine as shown in several selective attention task studies.

Subjects had to focus on the task and neglect distracters. The results suggested

an increased performance in selection of relevant information (Smith, 1999;

Ruijter, 2000; Lorist, 2003; Snel, 2004). Recently caffeine was shown to improve

participant’s ability to effi ciently use stored information and inhibit the infl uence

of action-irrelevant information (Brunyé, 2010).

7 What is the effect of coffee or caffeine on memory?

Memory is one aspect of cognition which includes encoding, consolidation and

retrieval of information. Memory can be divided according to the duration of

memory: short-term memory, which is transient and limited in capacity and

long-term memory, which includes the vast store of knowledge and the record

of prior events, for potentially unlimited duration. Working-memory refers to

short-term memory and other processing mechanisms that are assumed to be

necessary in order to keep things in mind while performing complex tasks such

as reasoning, comprehension and learning. Memory is not located in a single

part of the brain, but involves a widely distributed network located in different

brain structures (Cowan, 2008; Baddeley, 2010).

Low doses of caffeine enhance working memory performance, while higher

doses are found to decrease it, possibly due to over-stimulation. Comparable

results are shown in a study with low-load memory tasks versus high load

memory tasks (Nehlig, 2010). Caffeine was shown to facilitate low-diffi culty

performance in low load memory tasks. High-load and complicated tasks


induced increased arousal by itself, and caffeine could lead to over-arousal.

Thus caffeine appears to rather improve working memory performance under

conditions that otherwise produce low arousal. There are not many studies

on the effects of caffeine on long-term memory. In elderly caffeine could help

attenuating age-related arousal decrements to reduce the decline in memory

performance during the day (Ryan, 2002; Nehlig, 2010). However, the effects of

caffeine on memory are inconsistent. Discrepancies between studies may be due

to the memory assessment method (recall or recognition), time frame (immedi-

ate versus delayed), sex and age of the subjects.

8 Does caffeine have a real impact on cognitive functioning, or does it just alleviate withdrawal symptoms, in other words, restore cognitive functioning to baseline levels?

It has been suggested that the positive effects of caffeine really refl ect removal

or negative effects of caffeine withdrawal (James, 2005). However, this view

cannot account for effects observed in non-consumers or deprived individuals

(Smith, 2002). Several studies suggested a real impact of caffeine on mood and

performance, irrespective of an overnight caffeine withdrawal. No difference in

mood and performance has been shown between habitual caffeine consumers

after an overnight caffeine withdrawal and non-caffeine consumers. Moreover,

caffeine challenge enhanced mood and performance and the effects increased

with the caffeine dose (Haskell, 2005; Smith, 2005b, 2006). Further, a study

of the effects of caffeine following a day of normal consumption showed that

caffeine had similar effects in those who had abstained from caffeine for more

than 6 hours and those who had consumed caffeine up to the time of testing

(Hewlett, 2007).

22 |

9 Can a cup of coffee affect my mood?

Enjoying a cup of coffee for its taste and smell, talking with family, friends or

colleagues during a coffee break might be part of the benefi t coffee can have on

our mood.

Mood states are generally assessed using validated self-rating scales with a vari-

ety of mood terms like happy, sad, depressed, pleasant, calm and contented.


Despite the variability in mood defi nitions, research has provided a fairly consist-

ent picture of effects of caffeine on mood state. In low to moderate dosages

(20-200 mg), caffeine has been quite constantly shown to improve mood state

(Smith, 2004; Casas, 2004; Smith, 2005b; Olson, 2010). People report that

they feel energetic, imaginative, effi cient, self confi dent and alert after caffeine

consumption. They feel more able to concentrate and motivated to work but

also more willing to socialize (Fredholm, 1999). In a recent prospective follow

up study coffee consumption was associated with a decreased risk of depression

(Ruusunen, 2010).

10 Can caffeine consumption cause anxiety?

In general it appears that low doses of caffeine tend to improve the mood states

and that high caffeine doses are associated with negative affective change, like

restlessness and jitteriness. Individual differences in caffeine sensitivity very likely

play a substantial role in determining the mental and physical response to

caffeine (Smith, 2004). In addition, a genetic variation on the adenosine

receptor A2A is associated with sensitivity to caffeine effects on anxiety (Alsene,

2003).

Anxiety is rarely seen with the average range of caffeine consumption, but

the literature suggests that extremely high doses of caffeine may increase

anxiety (Smith, 2002). Moreover, caffeine is a substance that is normally

considered as ‘self-regulating’, meaning that most people know when they took

enough coffee and usually stop drinking before negative effects will emerge

(Tieges, 2007).

24 |

11 Can caffeine/coffee consumption interfere with sleep?

Caffeine can increase wakefulness and has been shown to counter-act fatigue

induced by a night with sleep-deprivation (see also question 4). In a French

study on sleep duration and caffeine consumption in a middle aged working

population no effect on sleep duration was found up to a habitual use of 7 cups

of coffee or 600 mg of caffeine equivalent (Sanchez-Ortuno, 2005). Regular

consumption of caffeine can result in some degree of tolerance, reducing

the effects on sleep (Bonnet, 2005). Other research indicated that drinking

caffeinated beverages in the evening may interfere with the onset of sleep in

caffeine sensitive subjects. Differences in caffeine pharmacokinetics have been

reported for sleep sensitive and non-sensitive subjects (Bchir, 2006). Caffeine

elimination was slower in subjects with sleep disturbances; they had half lives for

caffeine between 6.5 and 8 hours. The average half life for caffeine amounts 2.5

to 4.5 hours (see frame on page 18). Signifi cant plasma caffeine concentrations

may persist during the night when caffeine is consumed in the late afternoon.

In addition, a genetic variation on the adenosine receptor A2A is associated with

caffeine sleep sensitivity and a habitual caffeine consumption (Cornelis, 2007;

Retey, 2007). In case of insomnia caffeine abstinence or avoiding caffeine

consumption in the afternoon and evening might be one of the factors to

consider, next to regular exercise, sleeping in a quiet and comfortable

environment and avoiding TV watching in the bedroom and strenuous activities

shortly before going to bed.

Is it safe to consume caffeine?

Caffeine is one of the most investigated components in our diet. Based on

extensive reviews of scientifi c literature there is general consensus that 400

mg caffeine per day (about 4-5 cups of coffee) are not associated with adverse

health effects in adults. Women who are pregnant, lactating or planning to

become pregnant are recommended to limit their caffeine consumption to

200-300 mg per day (about 2-3 cups of coffee). Caffeine intake in children

should be limited to 2.5 mg caffeine per kg bodyweight per day (Nawrot,

2003; Higdon, 2006; Fredholm, 1999).


References

• Alsene K e.a. (2003). Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology, 28(9): 1694-702.

• Arendt (2009). Managing jet lag: Some of the problems and possible new solutions. Sleep Med Rev, 13(4): 249-56.

• Baddeley A (2010). Working memory. Curr Biol, 20(4): R136-140.• Bchir F e.a. (2006). Differences in pharmacokinetics and electroencephalographic responses to

caffeine in sleep-sensitive and non-sensitive subjects. CR Biologies, 329: 512-519.• Bonnet MH e.a. (2005). The use of stimulants to modify performance during sleep loss: A review by

the Sleep Deprivation and Stimulant Task Force of the American Academy of Sleep Medicine. Sleep, 28(9): 1163-1187.

• Brunyé TT e.a. (2010). Caffeine modulates attention network function. Brain and Cognition, 72(2): 181-189.

• Casas M (2004). Effects of Coffee and Caffeine on Mood and Mood Disorders. In Nehlig A (ed) Coffee, Tea, Chocolate and the Brain; CRC Press LLC, Boca Raton, Florida: 73-83.

• Cornelis MC e.a. (2007). Genetic polymorphism of the adenosine A2A receptor is associated with habitual caffeine consumption. Am J Clin Nutr, 86: 240–244.

• Cowan N (2008). What are the differences between long-term, short-term, and working memory? Prog Brain Res, 169: 323-338.

• Daly JW e.a. (2004). Mechanism of Action of Caffeine on the Nervous System. In Nehlig A (ed) Coffee, Tea, Chocolate and the Brain; CRC Press LLC, Boca Raton, Florida: 1-11.

• Fisone G e.a. (2004). Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci, 61(7-8): 857-872.

• Fredholm B e.a. (1999). Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacology Rev, 51(1): 83-133.

• Haskell CF e.a. (2005). Cognitive and mood improvements of caffeine in habitual consumers and habitual non-consumers of caffeine. Psychopharmacology, 179: 813-825.

• Hewlett P and Smith A (2007). Effects of repeated doses of caffeine on performance and alertness: new data and secondary analyses. Hum Psychopharmacology, 21: 167-180.

• Higdon JV and Frei B (2006). Coffee and health: a review of recent human research. Critical Reviews in Foods Science and Nutrition, 56(2): 101-123.

• James JE and Rogers PJ (2005). Effects of caffeine on performance and mood: withdrawal reversal is most plausible explanation. Psychopharmacology, 182: 1-8.

• Ker K e.a. (2010). Caffeine for the prevention of injuries and errors in shift workers (Review). The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. www.thecochranelibrary.

• Lieberman HR (2001). The effects of Ginseng, Ephedrine, and Caffeine on cognitive performance, mood and energy. Nutrition Reviews, 59: 91-102.

• Lorist MM and Tops M (2003). Caffeine, fatigue and cognition. Brain and Cognition, 53: 82-84.• Lorist MM e.a. (1994). Infl uence of caffeine on information processing stages in well rested and

fatigued subjects. Psychopharmacology, 113: 411–421.• Lorist MM e.a. (1996). Acute effects of caffeine on selective attention and visual search processes.

Psychophysiology, 33: 354-361. • Nawrot P e.a. (2003). Effects of caffeine on health. Food Additives and Contaminants, 20(1): 1-30.• Nehlig A e.a. (1992). Caffeine and the central nervous system: Mechanisms of action, biochemical,

metabolic, and psycho stimulant effects. Brain Research Reviews, 17: 139-170.• Nehlig A (2010). Is Caffeine a Cognitive Enhancer? J Alzheimers Dis, 20, S1: 85-94.

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• Olson CA e.a. (2010). Effects of Adenosine Antagonists, Quercetin and Caffeine, on Vigilance and Mood. J Clin Psychopharmacology, 30(5): 537-578.

• Quinlan PT e.a. (2000). The acute physiological and mood effects of tea and coffee: the role of caf-feine level. Pharmacol Biochem Behav, 66(1): 19-28.

• Retey JV e.a. (2007). A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep. Clin Pharmacol Ther, 81: 692–698.

• Robelin M and Rogers PJ (1998). Mood and psychomotor performance effects of the fi rst, but not of subsequent, cup of coffee equivalent doses of caffeine consumed after overnight caffeine abstinence. Behav Pharmacol, 9(7): 611-618.

• Ruijter J (1999). The infl uence of different doses of caffeine on visual task performance. Journal of Psychophysiology, 13: 37-48.

• Ruijter J e.a. (2000). The effects of caffeine on visual selective attention to color: An ERP study. Psychophysiology, 37: 427-439.

• Ruusunen A e.a. (2010). Coffee, tea and caffeine intake and the risk of severe depression in middle-aged Finnish men: the Kuopio Ischaemic Heart Disease Risk Factor Study. Public Health Nutrition, 1-6.

• Ryan L e.a. (2002). Caffeine reduces time-of-day effects on memory performance in older adults. Psychological Science, 13: 68-71.

• Sagaspe P (2007). Aging and nocturnal driving: better with coffee or a nap? A randomized study. Sleep, 30(12): 1808-1813.

• Sanchez-Ortuno M e.a. (2005). Sleep duration and caffeine consumption in a French middle-aged working population. Sleep Medicine, 6: 247-251.

• Schmitt JAJ e.a. (2005). General methodological considerations for the assessment of nutritional infl uences on human cognitive functions. Eur J Nutr, 44: 459-464.

• Smit HR and Rogers PJ (2000). Effects of low doses of caffeine on cognitive performance, mood and thirst in low and higher caffeine consumers. Psychophymacology, 152: 167-173.

• Smith A (2002). Effects of caffeine on human behaviour. Food and Chemical Toxicology, 40:1243-1255.

• Smith AP e.a. (1993). Investigation of the Effects of Coffee on Alertness and Performance during the day and night. Neuropsychobiology, 27: 217-223.

• Smith AP e.a. (1999). Effects of low dose of caffeine given in different drinks on mood and performance. Human Psychopharm Clin Exp, 14: 473-482.

• Smith AP (2005a). Caffeine at work. Hum Psychopharmacol. 20(6): 441-445. • Smith AP e.a. (2005b). Effects of repeated doses of caffeine and mood and performance of alert and

fatigued volunteers. J Psychopharmacol, 19(6): 620-626.• Smith AP e.a. (2006). Effects of caffeine in overnight withdrawn consumers and non-consumers.

Nutritional Neuroscience, 9: 63-71.• Smith BD e.a. (2004). Arousal and behaviour: Biopsychological Effects of Caffeine. In A. Nehlig (ed).

Coffee, Tea, Chocolate, and the Brain; CRC Press LLC, Boca Raton, Florida: 35-52.• Snel J e.a. (2004). Coffee, Caffeine, and Cognitive Performance. In A. Nehlig (Ed.). Coffee, Tea,

Chocolate, and the Brain. Boca Raton, FL: CRC Press: 53-71.• Tieges Z (2007). Caffeine and cognitive control: Behavioural and electrophysiological studies.

Thesis: ISBN 987-90-9022340-7. • Van Boxtel MPJ and Schmitt JAJ (2004). Age-Related Changes in the Effects of Coffee on Memory

and Cognitive Performance. In Nehlig A (ed) Coffee, Tea, Chocolate and the Brain; CRC Press LLC, Boca Raton, Florida: 85-96.


3 Coffee and cognitive aging

1 What is the difference between normal cognitive decline, mild cognitive impairment (MCI) and dementia?

By late adulthood, people typically experience some deterioration in cogni-

tive abilities as part of the normal course of aging. Abilities, such as memory,

reasoning and processing speed, all seem to decline, on average, with age

(Corley, 2010). People with mild cognitive impairment (MCI) suffer from more

severe memory impairments beyond that would be expected according to age

(Roberts, 2009). People with MCI are at higher risk of progressing to dementia

and Alzheimer’s disease, which in turn is the leading cause of dementia. With

dementia, people lose their cognitive abilities to an extent that they are unable

to carry out normal activities and relationships. In addition to memory losses

also behavior and personality changes can occur.

2 What are the acute effects of coffee in elderly people?

It’s well known that caffeine ingestion leads to dose dependent increased ener-

getic arousal, which refl ects alertness and mental energy (Nehlig, 2010). Caffeine

is a mild stimulant and its cognitive enhancing effects are more pronounced in

individuals with low arousal levels, for instance due to sleep deprivation, fatigue or

prolonged mental activity (see chapter 2, questions 3 and 4). Since mental energy

and speed of information processing diminish with age, elderly in particular could

benefi t from the cognitive effects of caffeine. The vast majority of knowledge on

the acute behavioral effects of caffeine is based on experiments with young or

middle-aged subjects. Although caffeine appears to be metabolized similarly in

young and old individuals, only few studies have investigated the acute cognitive

effects of caffeine in elderly. The results indicate that caffeine may restore arousal

levels and hence facilitate cognitive functioning (Van Boxtel, 2004). This effect is

even more pronounced in situations of prolonged mental activity, since elderly

have less compensatory capacity (spare energy sources). Moreover, research

suggests that caffeine intake can ameliorate the decline in memory performance

during the day in older adults (Ryan, 2002). There is some, although very limited,

evidence suggesting that older people may benefi t more from relatively higher

dosage (Van Boxtel, 2004). It is suggested to be an interesting topic for further

research since caffeine intake typically increases in early adulthood and declines

with older age.

3 Could caffeine counteract age-related cognitive decline?

There is a growing number of epidemiological studies suggesting that

coffee consumption is associated with better cognitive performance later in life.

In a large cross- sectional study of 9,003 British adults a dose-response trend

between habitual coffee consumption and cognitive abilities was measured;

the oldest men and women seemed to benefi t most from a higher caffeine in-

take (Jarvis, 1993). Higher caffeine intake was not associated to better cognition

after 6 years in 1,376 individuals studied in the Netherlands (Van Boxtel, 2003).

In a prospective population study in France, higher caffeine consumption was

associated with less memory decline in women but not in men. The association

was stronger with increasing age and higher caffeine doses (> 300 mg per day)

(Ritchie, 2007). Similar results were found in a study by Johnson-Kozlow (2002).

In a longitudinal prospective cohort study with 676 older men in Finland, Italy

and the Netherlands, coffee intake was associated with lower levels of cognitive

decline 10 years later in life, with 4.3 times less decline in men consuming 3

cups a day in comparison with non-consumers (Van Gelder, 2007).

30 |


In a Scottish study, a general trend was shown for individuals who drink more

coffee and less tea to have better cognitive health at age 70 (Corley, 2010). So

far, results indicate that habitual coffee and or caffeine intake seems to be as-

sociated with less cognitive decline in elderly.

4 Does caffeine intake protect from dementia and Alzheimer’s disease?

There are currently no cures and only limited treatment options for Alzheimer’s

disease. Research focused on prevention of Alzheimer disease suggested that

coffee and caffeine might have a protective effect on the likelihood of develop-

ing Alzheimers’s disease (Rosso, 2008). In a meta-analysis of two case-control

studies and two cohort studies on coffee consumption and the risk of Alzhe-

imer’s disease a protective effect of coffee consumption was found (Barranco

Quintana, 2007). In the pooled estimate the risk was 0.73 (i.e. 27% lower) for

coffee-users versus non-coffee users. In a Finnish cohort study with an average

follow-up of 21 years, coffee drinking at midlife was associated with a decreased

risk of dementia and Alzheimer’s disease and dementia later in life. There are

several indications that caffeine, and perhaps other components in coffee as

well, play a neuroprotective role in the aging brain through a combination of

actions, including anti-infl ammatory effects by blockade of both A1 and A2A

receptors. Caffeine has been suggested to increase transcription factors which

enhance cell proliferation and prevent cell death. Moreover, caffeine has been

shown to reduce the negative effects of �-amyloid, whose accumulation is the

pathological signature of Alzheimer disease (Rosso, 2008). Caffeine consump-

tion was shown to be dose-dependently related with less white matter lesions in

elderly women, which is an indication of less �-amyloid accumulation (Ritchie,

2010). These biological fi ndings indicate that the relationship between caffeine

and cognitive decline found in epidemiological research is highly likely to be a

true causal relationship and not a spurious association (Ritchie, 2010).

Polyphenols in coffee have been hypothesized to neutralize free radicals that can

cause damage to neurons and other cells and have also anti-infl ammatory prop-

erties. There are still a lot of questions to be answered before a conclusion on

the potential protective effect of coffee and or caffeine can be drawn, however

the results so far are encouraging.

5 What causes Parkinson’s disease and what is the effect of coffee?

Parkinson’s disease is suggested to be a multifactorial disease, although the precise

cause for Parkinson’s disease remains still undetermined. Complex interactions

between neurotoxins and neuroprotective agents with genetic factors are thought

to be responsible for the development and progression of the disease (Morelli,

2010). Genetic factors seem to be important in early-onset cases of Parkinson’s

disease, while environmental and lifestyle factors are probably more relevant in

the development of Parkinson’s disease at older ages (Costa, 2010). Among these

lifestyle factors, coffee/caffeine is of particular interest in light of caffeine’s safety

and widespread consumption. Caffeine has been demonstrated to be neuropro-

tective in various experimental models of Parkinson’s disease (Xu, 2010; Morelli,

2010; Kachroo, 2010), probably via blocking A2A receptors in the brain. The

knowledge on the plausible biological mechanism based on the pharmacological

actions of caffeine strengthens the inverse association between coffee drinking and

Parkinson’s disease found in epidemiological research (Costa, 2010).

32 |


6 I s coffee consumption a protective factor for Parkinson’s disease?

The fi rst study to indicate the possible effects of drinking coffee and reducing

the risk of Parkinson disease was published as early as 1968 (Nefzger, 1968).

More than 30 years later, a meta-analysis including 8 case-control and 5 cohort

studies demonstrated that the relative risk of Parkinson’s disease was 30% lower

for coffee drinkers, in comparison to non-coffee drinkers (Hernan, 2002).

A recent systemic review and meta-analysis of 26 studies (7 cohorts, 2 nested

case-controls, 16 case-controls and 1 cross-sectional study) on caffeine and

the risk of Parkinson’s disease confi rmed the strength of the inverse association

(Costa, 2010). A 25% reduction in risk of Parkinson’s disease among caffeine

consumers was demonstrated. The results also indicate a linear dose-response

relation, with higher intakes of caffeine being associated with lower risk of

Parkinson’s disease. Moreover, coffee consumption is signifi cantly associated

with a reduced Parkinson’s disease mortality in men (Ascherio, 2004); the effect

in women was dependent on post menopausal estrogens use. In women

consuming 4 cups or more coffee per day compared to women not consum-

ing coffee the risk reduced by 53% among never users and increased by 30%

among users (Ascherio, 2004). These differences could partly refl ect a varia-

tion in the genetic expression of one enzyme metabolizing caffeine, CYP1A2

rs762551 (Palacios, 2010).

References

• Ascherio A e.a. (2004). Coffee consumption, Gender, and Parkinsons’s disease mortality in the Can-cer prevention Study II Cohort: The Modifying Effects of Estrogen. Am J Epidemiol 160(10): 977-984.

• Barranco Quintana JL e.a. (2007). Alzheimer’s disease and coffee: a quantitative review. Neurol Res, 29: 91-95.

• Corley J e.a. (2010). Caffeine consumption and cognitive function at age 70: The Lothian Birth Cohort 1936 Study. Psychosom Med, 72: 206-214.

• Costa J e.a. (2010). Caffeine Exposure and the Risk of Parkinson’s Disease: A Systemic Review and Meta-Analysis of Observational Studies, 20: S221-S238.

• Hernan MA (2002). A meta-analysis of Coffee Drinking, Cigarette Smoking, and the Risk of Parkinson’s Disease. Ann Neurol, 52: 276-284.

• Jarvis MJ (1993). Does caffeine intake enhance absolute levels of cognitive performance? Psychopharmacology, 110(1-2): 45-52.

• Johnson-Kozlow M e.a. (2002). Coffee consumption and cognitive function among older adults. Am J Epidemiol, 156: 842-850.

• Kachroo A e.a. (2010). Caffeine protects against combined paraquat and maneb-induced dopaminergic neuron degeneration. Exp Neurol, 223: 657-661.

• Morelli M and Simola N (2010). Can dietary substances protect against Parkinson’s disease? The case of caffeine. Exp Neurol, 225(2): 246-249.

• Nefzger MD e.a. (1968). A retrospective study of smoking in Parkinson’s disease. Am J Eidemiol, 88: 149-158.

• Nehlig A (2010). Is Caffeine a Cognitive Enhancer? J Alzheimer’s Disease 20, S1: 85-94.• Palacios N e.a. (2010). Polymorphisms of caffeine metabolism and estrogen receptor genes and risk

of Parkinson's disease in men and women. Parkinsonism Relat Disord, 16(6): 370-375.• Ritchie K e.a. (2007). The neuroprotective effects of caffeine. A prospective population study.

Neurology, 69: 536-545.• Ritchie K e.a. (2010). Caffeine, cognitive functioning, and white matter lesions in the elderly:

establishing causality from epidemiological evidence. J Alzheimers Dis, 20 S1: 161-166.• Roberts JL e.a. (2009). Subject memory Complaints and Awareness of Memory Functioning in Mild

Cognitive Impairment: A Systematic Review. Demet Geriatr Cogn Disord, 28: 95-109.• Rosso A e.a. (2008). Caffeine: Neuroprotective Functions in Cognition and Alzheimer’s Disease.

Am J Alzheimers Dis Other Dem, 23(5): 417-422.• Ryan L e.a. (2002). Caffeine reduces time-of-day effects on memory performance in older adults.

Psychological Science, 13(1): 68-71.• Van Boxtel MPJ e.a. (2003). The effects of habitual caffeine use on cognitive change:

a longitudinal perspective. Pharmacol Biochem Behav, 75: 921-927.• Van Boxtel MPJ and Schmitt JAJ (2004). Age-Related Changes in the Effects of Coffee on Memory

and Cognitive Performance. In Nehlig A (ed) Coffee, Tea, Chocolate and the Brain; CRC Press LLC, Boca Raton, Florida: 85-96.

• Van Gelder B e.a. (2007). Coffee consumption is inversely associated with cognitive decline in elderly European men: the FINE Study. Eur J Clin Nutr, 61(2): 226-232.

• Xu K e.a. (2010). Neuroprotection by caffeine: Time course and role of its metabolites in the MPTP model of Parkinson Disease. Neuroscience, 167(2): 475-481.

34 |


Study of coffee and health

Every type of research has its own evidential value and limitations.

Most of the studies reported in this brochure can be differentiated into:

1. Meta-analysis: A literature study of various studies (intervention studies, cohort

studies and/or patient control studies) of the relationship between coffee con-

sumption behaviour and a biomarker or (medical) condition, with the aim of

obtaining a more precise outcome.

2. Cohort study (prospective): In this brochure in the case of this type of study large

groups of people have been monitored (prospectively) over a longer period. In

this context at the start of the study differences in coffee consumption between

people who have and have not developed a (medical) condition during the

study are examined. The pattern of coffee consumption of the participants has

therefore not been infl uenced by the condition.

3. Cross-sectional study: This is a study in which one monitors simultaneously

(smaller) cohorts which follow each other in time. For example a group in the

age range 31-45 and a group in the age range 45-60 are then examined simul-

taneously. In this case at the start of the study differences in coffee consumption

have been examined between people who did and people who did not acquire

the (medical) condition during the study. In this manner a good picture can be

obtained of the association between for example coffee consumption and the

development of a condition between the ages of 30 and 60.

4. Patient-control study: In the case of this type of study the differences in coffee

consumption patterns are investigated in groups of people who have and have

not developed the (medical) condition. In this case therefore questions are

asked after the event about previous coffee consumption behaviour. A disad-

vantage of this type of study may be that the coffee consumption pattern of

the people who have that condition has been modifi ed or is assessed differently

than in the case of people who do not have the condition.

5. Intervention study: In the case of this type the effect of the substance to be

investigated on a group of people is measured and compared with a control

group, which is not given the substance. Intervention studies in the area of

coffee research are usually relatively short and the group size is limited.

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