In the only large, population-based study of the effects of habitual coffee consumption on cognition, Jarvis 17 surveyed 9, British adults. A significant, positive trend between coffee intake and cognitive performance was found.

Additionally, an age-by-coffee interaction indicated that greater improvement in cognitive performance occurred among the oldest men and women.

On the basis of the research by Jarvis 17 , Reidel and Jolles 18 hypothesized that caffeine has a supplementary effect, improving memory only when cholinergic function is impaired by aging or disease. Cognitive decline is age related.

Reaction time, perceptual speed, and processing speed remain relatively stable from age 20 to age 60, while a general slowing in cognitive function occurs between the ages of 60 and 80 years It is therefore plausible that caffeine intake may have a protective effect on the cognitive decline associated with aging 13 , The present study investigates the relation of lifetime coffee consumption and current caffeinated and current decaffeinated coffee consumption with performance on several cognitive function tests in a community-based sample of men and women aged 50 years or older.

Between and , 82 percent of the residents of Rancho Bernardo, a middle-class, predominantly Caucasian, southern California community, were enrolled in a study of heart disease risk factors. This report includes all men and women aged 50 or more years at the — follow-up visit for whom interview data, measures of cognitive function, and coffee-drinking history were available.

All were ambulatory and gave written, informed consent. The study was approved by the Committee on Investigations Involving Human Subjects at the University of California at San Diego. At the — follow-up visit, participants came into the clinic after an overnight fast of 12—16 hours.

Medication use, including estrogen replacement therapy, was validated by examination of prescriptions or pills brought to the clinic for that purpose. Diet was assessed with a self-administered food frequency questionnaire. Finally, 12 measures of cognitive function were administered individually by trained personnel.

All cognitive tests had demonstrated adequate reliability and validity 21 , The Buschke-Fuld Selective Reminding Test 23 assesses short- and long-term storage and retrieval of spoken words.

Ten unrelated words are read to participants at a rate of one every 2 seconds. Immediately after, the participant is asked to recall the entire list.

This procedure is followed for six trials. Measures of long- and short-term memory and of total recall are obtained. Higher scores on the short-term memory test indicate poorer performance.

The Heaton Visual Reproduction Test 24 , adapted from the Wechsler Memory Scale 25 , assesses memory for geometric forms. Three stimuli of increasing complexity are presented one at a time, for 10 seconds each. The participant is asked to reproduce the figures immediately to assess short-term memory and after 30 minutes of unrelated testing to assess long-term memory for geometric forms.

After both memory trials are completed, the participant copies the stimulus figures to account for any existing visuospatial impairments. Three scores are obtained: immediate recall, delayed recall, and copying. The Mini-Mental State Examination 26 , 27 assesses orientation, registration, attention, calculation, language, and recall.

Total Mini-Mental State Examination scores range from 0 to For either item, the maximum possible score is 5. Two items from the information-memory-concentration test of Blessed et al. The maximum possible score across the two items is 7. The Trail-Making Test, part B, from the Halstead-Reitan Neuropsychological Test Battery 28 , tests visuomotor tracking and attention.

The participant scans a page continuously to identify numbers and letters in a specified sequence while shifting from number to letter sets. A maximum of seconds is given; scoring is the time taken to finish the test.

A higher score indicates a poorer test performance. Category fluency 29 is assessed by naming as many animals as possible in 1 minute.

The score is the number of animals named correctly. The Willett Semiquantitative Food Frequency Questionnaire 20 is self-administered and was used to assess dietary intake.

It contains two items assessing caffeinated and decaffeinated coffee intake during the past year and served as the measure of current coffee intake. A 1-cup ml quantity was specified on the questionnaire, and participants marked one of nine responses to indicate their frequency of consumption.

Each of the nine responses, along with the associated cups per day, was as follows: never or less than once per month, 0; 1—3 per month, 0. Values for the cups per day were converted to cups per week by multiplying by 7 and were then divided into quintiles.

Regular, current drinkers of caffeinated and decaffeinated coffee were defined as those drinking at least 1 cup of coffee per month. Consumptions of tea, cola, and chocolate were also queried on the questionnaire and analyzed as additional sources of caffeine for current coffee consumption.

The Willett Semiquantitative Food Frequency Questionnaire has demonstrated reliability and validity The mailed survey in assessed lifetime coffee intake in terms of years of use and usual number of cups per day of caffeinated and decaffeinated coffee intake. Cup-years were then divided into quintiles of cup-years; those who reported never drinking caffeinated coffee were included in the lowest quintile.

Regular lifetime drinkers of caffeinated coffee were defined as having drunk at least 1 cup of caffeinated coffee for at least 1 year. Men and women were examined in separate analyses because they differed in both coffee consumption patterns and cognitive abilities.

Analyses of current coffee consumption were based on exclusive drinkers of decaffeinated or caffeinated coffee as appropriate. All cognitive function tests were scaled so that higher scores indicated better cognitive performance.

The Buschke-Fuld Selective Reminding Short-Term Recall Test and the Trail-Making Test, part B, were reverse scored. In these analyses, cognitive function was linearly transformed to z scores.

For current coffee consumption, analyses were performed by coffee intake alone and by coffee with additional sources of caffeine, including tea, cola, and chocolate. Age-adjusted comparisons of covariates by quintiles of lifetime and current caffeinated coffee intake were performed with analysis of covariance.

Because cognitive function may be positively related to intelligence 30 , education 1 year of college vs. less than 1 year of college served as an indicator of intelligence and was assessed as a potential confounder along with age in regression models.

A variable was identified as a confounder if its removal from the regression model resulted in a change in the beta weight of 10 percent or greater for coffee consumption.

Using this criterion, a third confounder for men was the use of antihypertensive or diuretic medications, and for women, a third confounder was ever use of estrogen replacement therapy.

no , most recent job status professional vs. nonprofessional , alcohol use at least 3—4 drinks per week vs. no , current use of estrogen replacement therapy yes vs. no , and history of heart attack or stroke yes vs. Lifetime and current coffee consumptions were entered as continuous variables in regression analyses.

It was not possible to determine whether lifetime consumption of decaffeinated coffee was associated with cognitive performance, because only 23 men and 29 women reported drinking decaffeinated coffee exclusively during their lifetime.

The Statistical Analysis System, version 6. An alpha level of 0. Because analyses were exploratory, no adjustment was made for multiple comparisons, and p values between 0.

At the — clinic visit, men were aged 52—94 years with an average age of Most men 82 percent and women 65 percent had completed at least 1 year of college. Thirty-seven percent of men reported the use of antihypertensive or diuretic medications, and 76 percent of women reported ever use of estrogen replacement therapy.

Most men 90 percent and women 86 percent reported regular use of caffeinated coffee at some time in their lives. The average number of cup-years of caffeinated coffee consumed by men was significantly greater than the amount consumed by women means, The number of years that men and women drank coffee on a regular basis increased with age and ranged from 38 to 51 years in men and from 29 to 51 years in women.

Men started drinking coffee at about 20 years of age and drank an average of 3. Differences in the pattern of coffee consumption by birth cohort were also observed in men and women. Men in the oldest birth cohort, who were born about , reported drinking only 2. By contrast, men aged 50—59 years, who were born about , reported drinking 5.

The difference in cups per day among women by birth cohort was less striking, and cup-years did not differ across age groups for women. There were men and women who were current, exclusive drinkers of caffeinated coffee and men and women who were current, exclusive drinkers of decaffeinated coffee.

Current consumption among exclusive drinkers of caffeinated coffee decreased as a function of age for both men and women.

Women, but not men, also decreased their consumption of decaffeinated coffee with age. The age-adjusted distributions of covariates by quintile of lifetime and current caffeinated coffee consumption of women and men are shown in table 2.

The proportion of women who reported ever use of estrogen replacement therapy decreased with increasing lifetime coffee intake.

For men, use of antihypertensive drugs decreased with increasing quintile of current coffee intake. There was no association between current intake of decaffeinated coffee and any cognitive function test among women.

No other tests were significantly associated with current or lifetime caffeinated or decaffeinated coffee intake among men data not shown. To minimize fluctuations due to small sample sizes, only z scores at the lowest and highest quintile levels are graphed, with lines interpolated between the two graphed points.

On all tests but the Heaton Visual Reproduction Copying Test, there was a nonsignificant increase in cognitive function among the eldest members of the cohort as a function of lifetime coffee quintile. In this community-based sample, men drank more coffee across their lifetimes than did women, based on all the indices: years of coffee drinking, cups per day, and cup-years.

Nevertheless, higher levels of lifetime and current caffeinated coffee intake were associated with better scores on several tests of cognitive performance in women but not in men. The trend was strongest for lifetime, as compared with current, coffee intake and among women aged 80 or more years.

This observed coffee-cognitive function association was not explained by age, education, or estrogen replacement therapy in women. No effect for decaffeinated coffee intake was found. These findings are partially consistent with those of the population-based study of 9, British adults aged 18 years or more, conducted by Jarvis 17 , which found a positive effect of caffeine on cognitive performance in both women and men.

In the present study, caffeine was positively associated with cognitive performance in the oldest women. These results are consistent with those of the Jarvis study 17 ; when participants were stratified into three age groups 16—34, 35—54, and 55 or more years , the association of coffee intake with verbal memory, visuospatial reasoning, and reaction time increased with age.

The results of this study indicate that lifetime coffee intake among women may have differential effects, depending on the type of cognitive process involved. The majority of the cognitive function tests positively associated with coffee intake involved a verbal component Although the cognitive function tests were interrelated, the tests shared less than 30 percent of their variance.

Correlations between the tests, not including between subtests, ranged between 0. Additionally, differential effects of coffee on various cognitive tests may be due at least in part to differences in the psychometric properties of the tests. The limited score variance decreased the likelihood of observing a coffee-cognition association.

The remaining tests with adequate test score variance demonstrated at least marginally significant positive associations with lifetime coffee intake among women. The two tests Heaton Visual Reproduction Copying Test and Trail-Making Test, part B not significantly associated with lifetime caffeinated coffee intake involve, at least in part, visuomotor tracking It is biologically plausible that caffeine lessens age-related cognitive decline, in that a stronger effect of caffeine among older adults as compared with younger adults has been demonstrated previously 17 , 32 , Molchan et al.

Riedel et al. Riedel and Jolles 18 suggested that caffeine may have a supplementary effect on cholinergic stimulation: Caffeine does not affect memory in younger adults when cholinergic function is optimal, but it may exert a positive effect on memory when cholinergic dysfunction is induced experimentally or occurs naturally because of aging.

The present study found stronger effects for lifetime as compared with current coffee intake. The pharmacologic effects of caffeine in the body are complex Caffeine is a nonselective A 1 and A 2A adenosine receptor antagonist While adenosine has sedative effects within the body, the antagonist properties of caffeine result in central nervous stimulation, and an effect of adenosine on memory and learning has been demonstrated The chronic effects of caffeine, however, often differ markedly from its acute effects 36 , although much of the cognitive-based research on the effect of caffeine has been oriented toward acute administration.

Although many of the physiologic effects of acute caffeine administration are detrimental, chronic administration of caffeine is often protective For example, chronic treatment with caffeine decreased susceptibility to ischemic brain damage in gerbils, while acute administration increased damage Similar findings for the positive effect of chronic versus the negative effect of acute administration of caffeine on spatial memory and seizures in mice have also been demonstrated Therefore, although caffeine ingested as coffee is readily and essentially completely absorbed from the gastrointestinal tract and peak levels of caffeine in body fluids are reached about an hour after ingestion, long-term intake of caffeine may result in significant adaptive changes in the brain That lifetime coffee intake was more strongly associated with cognitive function than was current coffee intake in the present study may also suggest that it is the cumulative exposure to caffeine that is protective against losses in cognitive function.

The differences found between men and women may be due to unmeasured confounding or the somewhat smaller sample size of men, or they may be real. Unmeasured confounding may mask a true effect among men or create an illusory finding among women.

If the effect of chronic administration of caffeine on cognitive function is weak or if measurement of caffeine intake is poor, then the smaller sample size among men may result in nonsignificant findings. A real finding may indicate that women are more vulnerable to the effects of chronic administration of caffeine than are men.

The elimination half-life of caffeine ranges between 3 and 7 hours; however, among women, elimination is 20—30 percent shorter because of more rapid biotransformation 1. Despite the differences in clearance, the levels of metabolites among men and women do not differ, however 1. Research by Carrillo and Benitez 43 indicates that, in healthy participants, women were more likely than men to experience acute toxic reactions, such as restlessness, palpitation, muscle tremor, and dizziness, after administration of high doses of caffeine compared with men.

Thus, gender differences may be due to pharmacodynamic differences in sensitivity to caffeine effects between men and women. In another study, Relling et al. That coffee-cognition effects were found for women but not for men in the present study may also suggest that women are more susceptible to the cholinergic properties of caffeine than men are in older populations.

A meta-analysis indicated that women are at 1. Several limitations of the present study were considered. This study is an observational field study; therefore, conclusions about the causal effect of caffeine on cognitive function are limited. Self-reported lifetime coffee intake may be inaccurate, and the resulting nondifferential misclassification bias 1 would obscure a true association.

Because current coffee drinkers may have better cognitive function, they may have better recall on retrospective recalls, thus strengthening the results for current coffee intake.

Lifetime assessment of coffee intake has unknown reliability and validity. Caffeine may be protective against neurodegenerative diseases like Alzheimers. There is increasing evidence that moderate caffeine intake e. Caffeine can help analgese headaches. Whilst caffeine withdrawal can cause headaches, caffeine itself can improve headaches, especially when combined with popular pain relievers like aspirin, paracetamol and ibuprofen.

Caffeine narrows the blood vessels that feed the brain — supposedly that is the mechanism of action. However, because the withdrawal from caffeine can increase headaches, those who experience them regularly including migraines are sometimes recommended to abstain from too much caffeine.

Caffeine can improve your mood. Supposedly a coffee every 4 hours can sustain a measurable improvement in mood. In lower doses, caffeine induces a sense of calmness and interest. Increased intake is associated with a lower risk of depression. It seems that outside of having a few too many leading to anxiety, nervousness , moderate coffee consumption is, on average, beneficial for mood.

e judgements, decision making, problem-solving. Caffeine can help you in passive or low complexity situations. But turn up the heat in terms of the complexity of the task, and caffeine is not really going to help you much. Have a complex essay to write? Caffeine will help you stay awake, but not make you any better at essay writing.

Individuals with ADHD are commonly given stimulant medications yes, it does seem a bit contradictory, but it works. As caffeine is a stimulant, it does provide some benefit to individuals with ADHD, but in no way better than prescribed medications.

Caffeine is less helpful to regular consumers of it. If you already consume a significant amount of caffeine, you will unlikely get much benefit from additional amounts.

You are more likely to experience the effects of mild overdose anxiety, jitters, etc. In fact, you are more likely to experience performance decrements if your caffeine intake falls.

My reading of an admittedly small number of review articles suggests there are positive reasons to be a regular consumer of caffeine within guidelines. This is particularly the case if you have unavoidable fatigue or tiredness arising from insufficient or irregular sleep patterns.

For increasing alertness, concentration and focus, mood and learning caffeine seems to be an effective and safe method. Most of its effects are achieved through a general increase in arousal level, not an increase in intelligence or ability to work with and process information.

The positive impacts of caffeine intake on preserving abilities during periods of high fatigue should be treated cautiously. Caffeine is not an excuse to maintain or even celebrate poor lifestyle habits e. Whilst late nights and busyness are often unavoidable, When such , as the cognitive enhancing properties of good quality, regular sleep are well documented also.

International journal of epidemiology 44 , — Burgess, S. Sample size and power calculations in Mendelian randomization with a single instrumental variable and a binary outcome.

International journal of epidemiology 43 , — Cole, S. Illustrating bias due to conditioning on a collider. International journal of epidemiology 39 , — Ye, Z. Association between circulating hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study. The lancet.

Holmes, M. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.

Nehlig, A. Is caffeine a cognitive enhancer? Levy, D. Genome-wide association study of blood pressure and hypertension. Nature genetics 41 , — MacArthur, J. The new NHGRI-EBI Catalog of published genome-wide association studies GWAS Catalog.

Nucleic acids research 45 , D—d Hamza, T. Taylor, A. Investigating the possible causal role of coffee consumption with prostate cancer risk and progression using Mendelian randomization analysis. International journal of cancer , — Cowen, P. The role of serotonin in cognitive function: evidence from recent studies and implications for understanding depression.

Journal of psychopharmacology Oxford, England 27 , — Guessous, I. Caffeine intake and CYP1A2 variants associated with high caffeine intake protect non-smokers from hypertension.

Human molecular genetics 21 , — Associations of coffee genetic risk scores with consumption of coffee, tea and other beverages in the UK Biobank.

Addiction Abingdon, England Hernan, M. Epidemiology Cambridge, Mass. A review of instrumental variable estimators for Mendelian randomization. Statistical methods in medical research Download references.

This study was financially supported by J. Mason and H. Williams Memorial Foundation CT For full acknowledgement and study specific funding information, see the supplementary materials. Australian Centre for Precision Health, University of South Australia, Adelaide, Australia. MRC Integrative Epidemiology Unit IEU at the University of Bristol, Bristol, UK.

UK Centre for Tobacco and Alcohol Studies UKCTAS and School of Experimental Psychology, University of Bristol, Bristol, UK. Center for Life Course Health Research, University of Oulu, Oulu, Finland.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

Helsinki Collegium for Advanced Studies, Helsinki, Finland. Department of Psychology and Logopedics, Faculty of medicine, University of Helsinki, Helsinki, Finland.

Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala University, Uppsala, Sweden. Department of Surgical Sciences, Orthopaedics, Uppsala University, Uppsala, Sweden.

Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland. Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.

Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland. Department of Pediatrics, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.

Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland. Wellcome Centre for Human Genetics, Nuffield Department of Medicine, Oxford, OX3 7BN, UK.

Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden. Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.

Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.

Department of Psychiatry, Research Unit of Clinical Neuroscience, University of Oulu, Oulu, Finland. Department of Psychiatry, University Hospital of Oulu, Oulu, Finland. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, , USA.

Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. Stanford Cardiovascular Institute, Stanford University, CA, , USA.

University of Exeter Medical School, Exeter, United Kingdom. South Australian Health and Medical Research Institute, Adelaide, Australia. You can also search for this author in PubMed Google Scholar. Wrote the manuscript: A. Study supervision: K.

Data analysis: A. Provision of administrative technical or material support: S. Data collection: S. Interpretation and manuscript revision: A. Correspondence to Elina Hyppönen. receives grant from Pfizer unrelated to present project.

is a scientific advisor for Precision Wellness, Cellink and Olink Proteomics for work unrelated to the present project. is supported by the UK National Institute for Health Research NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula PenCLAHRC.

The views expressed in this article are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health.

All other authors declare no competing interests. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. Zhou, A. Habitual coffee consumption and cognitive function: a Mendelian randomization meta-analysis in up to , participants.

Sci Rep 8 , Download citation. Received : 18 September Accepted : 24 April Published : 14 May Anyone you share the following link with will be able to read this content:.

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nature scientific reports articles article. Download PDF. Subjects Epidemiology Risk factors. Introduction Coffee is one of the most widely consumed beverages worldwide 1. Methods Study population Data came from 10 European cohorts including the British birth cohort BC , UK Biobank, Mothers of Avon Longitudinal Study of Parents and Children ALSPAC-M , Northern Finland Birth Cohorts NFBC , Cardiovascular Risk in Young Finns Study YFS , Helsinki Birth Cohort Study HBCS , Prospective Investigation of the Vasculature in Uppsala Seniors PIVUS , Uppsala Longitudinal Study of Adult Men ULSAM , Swedish twin registry STR and TwinGene studies.

Genetic variants Genome-wide association studies to date have identified eight loci influencing habitual coffee intake patterns 21 , Habitual coffee, tea and caffeine consumption Coffee intake was the primary exposure of interest, with tea and caffeine consumption only used in the secondary analyses.

Global cognition and memory scores Cognitive measures included in the cohorts ranged from tests of global cognition such as the Mini-Mental State Examination MMSE to domain specific tests such as the Trail Making Tests, Digit Symbol Coding and the Paired Associates Learning test Supplementary Table S3.

Statistical analyses Three primary association analyses were performed, including 1 the phenotypic associations between the habitual coffee intake patterns and global cognition and memory function, 2 genetic associations between the genetic score indexing higher coffee intakes and global and memory cognition, and 3 instrument validation assessing the association between the genetic instruments and coffee intake patterns.

Results Information for coffee intake was available for , participants from 10 European cohorts, including , coffee consumers. Table 1 Characteristics of the participating cohorts. Full size table. Table 2 Phenotypic and genetic associations of habitual coffee intake with cognition. Figure 1.

Full size image. Figure 2. Figure 3. Discussion Our large-scale genetic analyses including over , coffee drinkers did not find any evidence to support beneficial or adverse long-term effects of coffee intake on global cognition or memory. References Fredholm, B.

Association of Coffee Consumption with MRI Markers and Cognitive Function: A Population-Based Study. Inconsistency of Association between Coffee Consumption and Cognitive Function in Adults and Elderly in a Cross-Sectional Study ELSA-Brasil.

Nutrients 7 , — Soroko, S. Reasons for changing caffeinated coffee consumption: the Rancho Bernardo Study. Journal of the American College of Nutrition 15 , 97— Davey, S. What can mendelian randomisation tell us about modifiable behavioural and environmental exposures? BMJ , — Lawlor, D.

Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Article MathSciNet PubMed Google Scholar. Davey Smith, G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies.

Human molecular genetics 23 , R89—98 Haller, S. Acute caffeine administration effect on brain activation patterns in mild cognitive impairment. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.

Molecular psychiatry 20 , — Genome-wide meta-analysis identifies regions on 7p21 AHR and 15q24 CYP1A2 as determinants of habitual caffeine consumption. PLoS genetics 7 , e McMahon, G.

Phenotype refinement strengthens the association of AHR and CYP1A1 genotype with caffeine consumption. PloS one 9 , e Article PubMed PubMed Central ADS Google Scholar. Josse, A. Associations between polymorphisms in the AHR and CYP1A1-CYP1A2 gene regions and habitual caffeine consumption.

The American journal of clinical nutrition 96 , — Genome-wide association study of caffeine metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior.

Human molecular genetics 25 , — Llewellyn, D. Exposure to secondhand smoke and cognitive impairment in non-smokers: national cross sectional study with cotinine measurement. BMJ Clinical research ed. Bowden, J.

Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. International journal of epidemiology 44 , — Burgess, S. Sample size and power calculations in Mendelian randomization with a single instrumental variable and a binary outcome.

International journal of epidemiology 43 , — Cole, S. Illustrating bias due to conditioning on a collider. International journal of epidemiology 39 , — Ye, Z.

Association between circulating hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study. The lancet. Holmes, M. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. Nehlig, A.

Is caffeine a cognitive enhancer? Levy, D. Genome-wide association study of blood pressure and hypertension. Nature genetics 41 , — MacArthur, J. The new NHGRI-EBI Catalog of published genome-wide association studies GWAS Catalog.

Nucleic acids research 45 , D—d Hamza, T. Taylor, A. Investigating the possible causal role of coffee consumption with prostate cancer risk and progression using Mendelian randomization analysis.

International journal of cancer , — Cowen, P. The role of serotonin in cognitive function: evidence from recent studies and implications for understanding depression. Journal of psychopharmacology Oxford, England 27 , — Guessous, I.

Caffeine intake and CYP1A2 variants associated with high caffeine intake protect non-smokers from hypertension. Human molecular genetics 21 , — Associations of coffee genetic risk scores with consumption of coffee, tea and other beverages in the UK Biobank.

Addiction Abingdon, England Hernan, M. Epidemiology Cambridge, Mass. A review of instrumental variable estimators for Mendelian randomization. Statistical methods in medical research Download references. This study was financially supported by J. Mason and H. Williams Memorial Foundation CT For full acknowledgement and study specific funding information, see the supplementary materials.

Australian Centre for Precision Health, University of South Australia, Adelaide, Australia. MRC Integrative Epidemiology Unit IEU at the University of Bristol, Bristol, UK. UK Centre for Tobacco and Alcohol Studies UKCTAS and School of Experimental Psychology, University of Bristol, Bristol, UK.

Center for Life Course Health Research, University of Oulu, Oulu, Finland. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. Helsinki Collegium for Advanced Studies, Helsinki, Finland.

Department of Psychology and Logopedics, Faculty of medicine, University of Helsinki, Helsinki, Finland. Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.

Uppsala University, Uppsala, Sweden. Department of Surgical Sciences, Orthopaedics, Uppsala University, Uppsala, Sweden.

Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland. Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.

Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland. Department of Pediatrics, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.

Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland. Wellcome Centre for Human Genetics, Nuffield Department of Medicine, Oxford, OX3 7BN, UK. Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.

Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK. Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland. Department of Psychiatry, Research Unit of Clinical Neuroscience, University of Oulu, Oulu, Finland.

Department of Psychiatry, University Hospital of Oulu, Oulu, Finland. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, , USA. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Stanford Cardiovascular Institute, Stanford University, CA, , USA. University of Exeter Medical School, Exeter, United Kingdom. South Australian Health and Medical Research Institute, Adelaide, Australia. You can also search for this author in PubMed Google Scholar.

Wrote the manuscript: A. Study supervision: K. Data analysis: A. Provision of administrative technical or material support: S. Data collection: S. Interpretation and manuscript revision: A.

Correspondence to Elina Hyppönen. receives grant from Pfizer unrelated to present project. is a scientific advisor for Precision Wellness, Cellink and Olink Proteomics for work unrelated to the present project.

is supported by the UK National Institute for Health Research NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula PenCLAHRC. The views expressed in this article are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health.

All other authors declare no competing interests. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. Zhou, A. Habitual coffee consumption and cognitive function: a Mendelian randomization meta-analysis in up to , participants. Sci Rep 8 , Download citation.

Received : 18 September Accepted : 24 April Published : 14 May Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative. By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Skip to main content Thank you for visiting nature. nature scientific reports articles article. Download PDF. Subjects Epidemiology Risk factors. Introduction Coffee is one of the most widely consumed beverages worldwide 1.

Methods Study population Data came from 10 European cohorts including the British birth cohort BC , UK Biobank, Mothers of Avon Longitudinal Study of Parents and Children ALSPAC-M , Northern Finland Birth Cohorts NFBC , Cardiovascular Risk in Young Finns Study YFS , Helsinki Birth Cohort Study HBCS , Prospective Investigation of the Vasculature in Uppsala Seniors PIVUS , Uppsala Longitudinal Study of Adult Men ULSAM , Swedish twin registry STR and TwinGene studies.

Genetic variants Genome-wide association studies to date have identified eight loci influencing habitual coffee intake patterns 21 , Habitual coffee, tea and caffeine consumption Coffee intake was the primary exposure of interest, with tea and caffeine consumption only used in the secondary analyses.

Global cognition and memory scores Cognitive measures included in the cohorts ranged from tests of global cognition such as the Mini-Mental State Examination MMSE to domain specific tests such as the Trail Making Tests, Digit Symbol Coding and the Paired Associates Learning test Supplementary Table S3.

Statistical analyses Three primary association analyses were performed, including 1 the phenotypic associations between the habitual coffee intake patterns and global cognition and memory function, 2 genetic associations between the genetic score indexing higher coffee intakes and global and memory cognition, and 3 instrument validation assessing the association between the genetic instruments and coffee intake patterns.

Results Information for coffee intake was available for , participants from 10 European cohorts, including , coffee consumers. Table 1 Characteristics of the participating cohorts. Full size table. Table 2 Phenotypic and genetic associations of habitual coffee intake with cognition.

Figure 1. Full size image. Figure 2. Figure 3. Discussion Our large-scale genetic analyses including over , coffee drinkers did not find any evidence to support beneficial or adverse long-term effects of coffee intake on global cognition or memory.

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Abstract This study examined the association of caffeinated and decaffeinated coffee intake with cognitive function in a community-based sample of older adults in — aged, 80 and over; aging; caffeine; coffee; cognition; sex. Open in new tab Download slide. TABLE 1.

Drinkers of caffeinated coffee exclusively. Open in new tab. TABLE 2. TABLE 3. J Psychol. Psychopharmacology Berl. Physiol Behav. Hum Psychopharmacol.

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Received for publication November 19, ; accepted for publication June 20, Caffeine is the most widely used psychoactive drug worldwide 1. Coffee is the main source of caffeine in the Western diet; most US adults regularly consume coffee 1 , 2.

As a mild stimulant, caffeine increases the activity of the central nervous system, resulting in heightened alertness and arousal 1. Results from previous studies of the effect of caffeine on cognition have been inconsistent 3 — 15 , indicating that caffeine may have either a facilitative or a detrimental effect on cognition 16 and that the effect of caffeine may be task specific.

In some studies, caffeine has been shown to improve performance on cognitive tasks requiring speed or vigilance 3 , 4. It has also been shown to improve complex, higher cognitive functions, including memory 5 , 8 — Caffeine is a methylxanthine, blocking adenosine receptors in the brain, resulting in cholinergic stimulation.

It is hypothesized that cholinergic stimulation improves memory In one study, caffeine reversed the memory-impairing effects of scopolamine, a drug that blocks the neurotransmitter acetylcholine Performance on memory tasks improved but reaction time did not, suggesting that caffeine acted as a cognition enhancer in the presence of cholinergic dysfunction and not merely as a central nervous system stimulant.

In the only large, population-based study of the effects of habitual coffee consumption on cognition, Jarvis 17 surveyed 9, British adults. A significant, positive trend between coffee intake and cognitive performance was found.

Additionally, an age-by-coffee interaction indicated that greater improvement in cognitive performance occurred among the oldest men and women. On the basis of the research by Jarvis 17 , Reidel and Jolles 18 hypothesized that caffeine has a supplementary effect, improving memory only when cholinergic function is impaired by aging or disease.

Cognitive decline is age related. Reaction time, perceptual speed, and processing speed remain relatively stable from age 20 to age 60, while a general slowing in cognitive function occurs between the ages of 60 and 80 years It is therefore plausible that caffeine intake may have a protective effect on the cognitive decline associated with aging 13 , The present study investigates the relation of lifetime coffee consumption and current caffeinated and current decaffeinated coffee consumption with performance on several cognitive function tests in a community-based sample of men and women aged 50 years or older.

Between and , 82 percent of the residents of Rancho Bernardo, a middle-class, predominantly Caucasian, southern California community, were enrolled in a study of heart disease risk factors.

This report includes all men and women aged 50 or more years at the — follow-up visit for whom interview data, measures of cognitive function, and coffee-drinking history were available.

All were ambulatory and gave written, informed consent. The study was approved by the Committee on Investigations Involving Human Subjects at the University of California at San Diego.

At the — follow-up visit, participants came into the clinic after an overnight fast of 12—16 hours. Medication use, including estrogen replacement therapy, was validated by examination of prescriptions or pills brought to the clinic for that purpose.

Diet was assessed with a self-administered food frequency questionnaire. Finally, 12 measures of cognitive function were administered individually by trained personnel. All cognitive tests had demonstrated adequate reliability and validity 21 , The Buschke-Fuld Selective Reminding Test 23 assesses short- and long-term storage and retrieval of spoken words.

Ten unrelated words are read to participants at a rate of one every 2 seconds. Immediately after, the participant is asked to recall the entire list. This procedure is followed for six trials.

Measures of long- and short-term memory and of total recall are obtained. Higher scores on the short-term memory test indicate poorer performance. The Heaton Visual Reproduction Test 24 , adapted from the Wechsler Memory Scale 25 , assesses memory for geometric forms.

Three stimuli of increasing complexity are presented one at a time, for 10 seconds each. The participant is asked to reproduce the figures immediately to assess short-term memory and after 30 minutes of unrelated testing to assess long-term memory for geometric forms.

After both memory trials are completed, the participant copies the stimulus figures to account for any existing visuospatial impairments.

Three scores are obtained: immediate recall, delayed recall, and copying. The Mini-Mental State Examination 26 , 27 assesses orientation, registration, attention, calculation, language, and recall.

Total Mini-Mental State Examination scores range from 0 to For either item, the maximum possible score is 5. Two items from the information-memory-concentration test of Blessed et al.

The maximum possible score across the two items is 7. The Trail-Making Test, part B, from the Halstead-Reitan Neuropsychological Test Battery 28 , tests visuomotor tracking and attention. The participant scans a page continuously to identify numbers and letters in a specified sequence while shifting from number to letter sets.

A maximum of seconds is given; scoring is the time taken to finish the test. A higher score indicates a poorer test performance. Category fluency 29 is assessed by naming as many animals as possible in 1 minute. The score is the number of animals named correctly.

The Willett Semiquantitative Food Frequency Questionnaire 20 is self-administered and was used to assess dietary intake. It contains two items assessing caffeinated and decaffeinated coffee intake during the past year and served as the measure of current coffee intake.

A 1-cup ml quantity was specified on the questionnaire, and participants marked one of nine responses to indicate their frequency of consumption. Each of the nine responses, along with the associated cups per day, was as follows: never or less than once per month, 0; 1—3 per month, 0. Values for the cups per day were converted to cups per week by multiplying by 7 and were then divided into quintiles.

Regular, current drinkers of caffeinated and decaffeinated coffee were defined as those drinking at least 1 cup of coffee per month. Consumptions of tea, cola, and chocolate were also queried on the questionnaire and analyzed as additional sources of caffeine for current coffee consumption.

The Willett Semiquantitative Food Frequency Questionnaire has demonstrated reliability and validity The mailed survey in assessed lifetime coffee intake in terms of years of use and usual number of cups per day of caffeinated and decaffeinated coffee intake.

Cup-years were then divided into quintiles of cup-years; those who reported never drinking caffeinated coffee were included in the lowest quintile. Regular lifetime drinkers of caffeinated coffee were defined as having drunk at least 1 cup of caffeinated coffee for at least 1 year.

Men and women were examined in separate analyses because they differed in both coffee consumption patterns and cognitive abilities. Analyses of current coffee consumption were based on exclusive drinkers of decaffeinated or caffeinated coffee as appropriate.

All cognitive function tests were scaled so that higher scores indicated better cognitive performance. The Buschke-Fuld Selective Reminding Short-Term Recall Test and the Trail-Making Test, part B, were reverse scored.

In these analyses, cognitive function was linearly transformed to z scores. For current coffee consumption, analyses were performed by coffee intake alone and by coffee with additional sources of caffeine, including tea, cola, and chocolate.

Age-adjusted comparisons of covariates by quintiles of lifetime and current caffeinated coffee intake were performed with analysis of covariance.

Because cognitive function may be positively related to intelligence 30 , education 1 year of college vs. less than 1 year of college served as an indicator of intelligence and was assessed as a potential confounder along with age in regression models.

A variable was identified as a confounder if its removal from the regression model resulted in a change in the beta weight of 10 percent or greater for coffee consumption. Using this criterion, a third confounder for men was the use of antihypertensive or diuretic medications, and for women, a third confounder was ever use of estrogen replacement therapy.

no , most recent job status professional vs. nonprofessional , alcohol use at least 3—4 drinks per week vs. no , current use of estrogen replacement therapy yes vs. no , and history of heart attack or stroke yes vs.

Lifetime and current coffee consumptions were entered as continuous variables in regression analyses. It was not possible to determine whether lifetime consumption of decaffeinated coffee was associated with cognitive performance, because only 23 men and 29 women reported drinking decaffeinated coffee exclusively during their lifetime.

The Statistical Analysis System, version 6. An alpha level of 0. Because analyses were exploratory, no adjustment was made for multiple comparisons, and p values between 0. At the — clinic visit, men were aged 52—94 years with an average age of Most men 82 percent and women 65 percent had completed at least 1 year of college.

Thirty-seven percent of men reported the use of antihypertensive or diuretic medications, and 76 percent of women reported ever use of estrogen replacement therapy. Most men 90 percent and women 86 percent reported regular use of caffeinated coffee at some time in their lives.

The average number of cup-years of caffeinated coffee consumed by men was significantly greater than the amount consumed by women means, The number of years that men and women drank coffee on a regular basis increased with age and ranged from 38 to 51 years in men and from 29 to 51 years in women.

Men started drinking coffee at about 20 years of age and drank an average of 3. Differences in the pattern of coffee consumption by birth cohort were also observed in men and women. Men in the oldest birth cohort, who were born about , reported drinking only 2.

By contrast, men aged 50—59 years, who were born about , reported drinking 5. The difference in cups per day among women by birth cohort was less striking, and cup-years did not differ across age groups for women.

There were men and women who were current, exclusive drinkers of caffeinated coffee and men and women who were current, exclusive drinkers of decaffeinated coffee.

Current consumption among exclusive drinkers of caffeinated coffee decreased as a function of age for both men and women. Women, but not men, also decreased their consumption of decaffeinated coffee with age.

The age-adjusted distributions of covariates by quintile of lifetime and current caffeinated coffee consumption of women and men are shown in table 2. The proportion of women who reported ever use of estrogen replacement therapy decreased with increasing lifetime coffee intake.

For men, use of antihypertensive drugs decreased with increasing quintile of current coffee intake. There was no association between current intake of decaffeinated coffee and any cognitive function test among women.

No other tests were significantly associated with current or lifetime caffeinated or decaffeinated coffee intake among men data not shown. To minimize fluctuations due to small sample sizes, only z scores at the lowest and highest quintile levels are graphed, with lines interpolated between the two graphed points.

On all tests but the Heaton Visual Reproduction Copying Test, there was a nonsignificant increase in cognitive function among the eldest members of the cohort as a function of lifetime coffee quintile. In this community-based sample, men drank more coffee across their lifetimes than did women, based on all the indices: years of coffee drinking, cups per day, and cup-years.

Nevertheless, higher levels of lifetime and current caffeinated coffee intake were associated with better scores on several tests of cognitive performance in women but not in men. The trend was strongest for lifetime, as compared with current, coffee intake and among women aged 80 or more years.

This observed coffee-cognitive function association was not explained by age, education, or estrogen replacement therapy in women. No effect for decaffeinated coffee intake was found. These findings are partially consistent with those of the population-based study of 9, British adults aged 18 years or more, conducted by Jarvis 17 , which found a positive effect of caffeine on cognitive performance in both women and men.

In the present study, caffeine was positively associated with cognitive performance in the oldest women. These results are consistent with those of the Jarvis study 17 ; when participants were stratified into three age groups 16—34, 35—54, and 55 or more years , the association of coffee intake with verbal memory, visuospatial reasoning, and reaction time increased with age.

The results of this study indicate that lifetime coffee intake among women may have differential effects, depending on the type of cognitive process involved.

The majority of the cognitive function tests positively associated with coffee intake involved a verbal component Although the cognitive function tests were interrelated, the tests shared less than 30 percent of their variance.

Correlations between the tests, not including between subtests, ranged between 0. Additionally, differential effects of coffee on various cognitive tests may be due at least in part to differences in the psychometric properties of the tests. The limited score variance decreased the likelihood of observing a coffee-cognition association.

The remaining tests with adequate test score variance demonstrated at least marginally significant positive associations with lifetime coffee intake among women. The two tests Heaton Visual Reproduction Copying Test and Trail-Making Test, part B not significantly associated with lifetime caffeinated coffee intake involve, at least in part, visuomotor tracking It is biologically plausible that caffeine lessens age-related cognitive decline, in that a stronger effect of caffeine among older adults as compared with younger adults has been demonstrated previously 17 , 32 , Molchan et al.

Riedel et al. Riedel and Jolles 18 suggested that caffeine may have a supplementary effect on cholinergic stimulation: Caffeine does not affect memory in younger adults when cholinergic function is optimal, but it may exert a positive effect on memory when cholinergic dysfunction is induced experimentally or occurs naturally because of aging.

The present study found stronger effects for lifetime as compared with current coffee intake. The pharmacologic effects of caffeine in the body are complex Caffeine is a nonselective A 1 and A 2A adenosine receptor antagonist While adenosine has sedative effects within the body, the antagonist properties of caffeine result in central nervous stimulation, and an effect of adenosine on memory and learning has been demonstrated The chronic effects of caffeine, however, often differ markedly from its acute effects 36 , although much of the cognitive-based research on the effect of caffeine has been oriented toward acute administration.

Although many of the physiologic effects of acute caffeine administration are detrimental, chronic administration of caffeine is often protective For example, chronic treatment with caffeine decreased susceptibility to ischemic brain damage in gerbils, while acute administration increased damage Similar findings for the positive effect of chronic versus the negative effect of acute administration of caffeine on spatial memory and seizures in mice have also been demonstrated Therefore, although caffeine ingested as coffee is readily and essentially completely absorbed from the gastrointestinal tract and peak levels of caffeine in body fluids are reached about an hour after ingestion, long-term intake of caffeine may result in significant adaptive changes in the brain That lifetime coffee intake was more strongly associated with cognitive function than was current coffee intake in the present study may also suggest that it is the cumulative exposure to caffeine that is protective against losses in cognitive function.

The differences found between men and women may be due to unmeasured confounding or the somewhat smaller sample size of men, or they may be real. Unmeasured confounding may mask a true effect among men or create an illusory finding among women. If the effect of chronic administration of caffeine on cognitive function is weak or if measurement of caffeine intake is poor, then the smaller sample size among men may result in nonsignificant findings.

A real finding may indicate that women are more vulnerable to the effects of chronic administration of caffeine than are men. The elimination half-life of caffeine ranges between 3 and 7 hours; however, among women, elimination is 20—30 percent shorter because of more rapid biotransformation 1.

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Print This Page Click to Print. Related Content. Yuko Hara, PhD, is Director of Aging and Alzheimer's Prevention at the Alzheimer's Drug Discovery Foundation. Hara was previously an Assistant Professor in Neuroscience at the Icahn School of Medicine at Mount Sinai, where she remains an adjunct faculty member.

Her research focused on brain aging, specifically how estrogens and reproductive aging influence the aging brain's synapses and mitochondria.

She earned a doctorate in neurology and neuroscience at Weill Graduate School of Medical Sciences of Cornell University and a bachelor's degree in biology from Cornell University, with additional study at Keio University in Japan.

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