Caffeine is a central nervous system stimulant which stimulates the adrenal gland secretion of catecholamines, an excitatory neurotransmitter mediating the effects on cognition, emotion, and motor function. Hence, caffeine is known to have broad physiological influences, affecting sleep patterns, mood, motor activity, heart rate, body core temperature and oxygen consumption.
There are mechanisms which could mediate a potential role of coffee on brain morphology and the risk of dementia and stroke. For example, brain volume changes may be caused by the antagonist binding of caffeine to adenosine receptors, inducing morphological change in mossy-fibres or pyramidal cells and a reduction of information transmission. However, there are only a handful of studies looking into the associations between coffee intake and brain volume and they report inconsistent findings with positive, Ushaped or negative association conclusions.
A Mendelian randomisation study has provided evidence for a potential adverse effect of higher coffee consumption on the risk of Alzheimer’s disease, with each cup of coffee increasing the risk by 26%.
However, observational evidence is inconsistent, and of the 11 most recent longitudinal cohort studies on habitual coffee intake and dementia risk, five supported a possible protective effect, whereas six studies found no association.
Several recent studies on stroke have reported an inverse relationship with coffee consumption, while others have found no association. There is also some evidence for a U-shaped association with respect to both outcomes, where moderate drinkers were reported to have the lowest stroke risk.
In the current study, a global team of researchers used information from up to 398,646 participants in the UK Biobank to investigate the association between coffee consumption and brain neuroimaging biomarkers and the odds of dementia and stroke.
The UK Biobank recruited participants aged 37–73 years, in 2010. During baseline assessment, information was collected using questionnaires (including a question about daily coffee consumption), verbal interview, and physical examination, including a collection of blood, urine, and saliva samples. An imaging substudy
was incorporated in 2014 to conduct brain, heart and body MRI imaging on 100,000 participants.
The analyses on disease outcomes were conducted in up to 398,646 participants who had information on habitual coffee consumption, while the brain volume analyses conducted in up to 17,702 participants with valid data on brain imaging.
Information on incident dementia and stroke were collated by the UK Biobank using primary care data, hospital admission electronic health records (EHR), national death registers and self-reported medical conditions in the UK Biobank touchscreen questionnaire.
The resulting data indicates caffeinated coffee consumption has a linear inverse association with total brain volume, with consistent patterns for grey matter, white matter, and hippocampal volumes. Compared to the basic model adjusted for age, sex and assessment centre, further inclusion of anthropometric measures, dehydration indicators, and lifestyle factors, each attenuated the associations, but evidence for an inverse trend remained even after full adjustment.
There was non-linear association between coffee consumption and the odds of dementia, with slightly higher odds seen with non-coffee or decaf drinkers, and more notable increases for participants in the highest coffee consumption categories.
For stroke, the association between higher coffee consumption was explained by covariate adjustment. Association between high coffee consumption and dementia was less affected by adjustment, and odds remained elevated for participants drinking more than 6 cups/day even after accounting for socioeconomic, anthropometric, lifestyle, dehydration, sleep, and disease related covariates. No differences in estimates were found among men and women or among different age groups.
After full covariate adjustment, consumption of more than 6 cups/day was associated with 53% higher odds of dementia compared to consumption of 1–2 cups/day (fully adjusted OR 1.53, 95% CI 1.28, 1.83), with less evidence for an association with stroke (OR 1.17, 95% CI 1.00, 1.37, p = 0.055).
The authors conclude: "Our results and an earlier genetic study suggest increased odds of dementia by high coffee intakes. Furthermore, in line with a recent placebo controlled trial demonstrating a dose-dependent GMV lowering effect for caffeine administration, we also found evidence for linear inverse associations between higher habitual coffee consumption and total, grey matter, white matter, and hippocampal volumes, providing further support for effects of coffee on the brain.
"While our study cannot confirm underlying causality of association, these results warrant carefully controlled studies to clarify the beneficial and adverse effects of coffee on the brain."
Study background
The largest of the earlier studies looking at the effects of habitual coffee consumption on the brain was conducted in the Rotterdam cohort (n=2,914) which is similar to UK Biobank with respect to age (mean age 59 years). Compatible with the current findings, they reported an inverse linear association between habitual coffee consumption and total hippocampal
volume, and directionally consistent but non-significant associations for total and grey matter volumes.
Competitive binding of caffeine to adenosine receptors in the brain is a well-known physiological mechanism and has been implicated in coffee consumption studies as the cause of changes in brain morphology. Changes in brain volume are theorised to be caused by structural change in mossy-fibres and pyramidal cells, initiated by the antagonist binding of caffeine.
Other effects could be mediated through the cardiovascular system, with relevance for both vascular
dementia and AD. For example, the consumption of unfiltered coffee increases serum total cholesterol, LDL cholesterol and triglyceride levels. These lipid abnormalities are a leading risk factor for atherosclerosis, which has been associated with AD, independently of other brain pathologies.
Source: Nutritional Neuroscience
Pham. K., Mulugeta. A., Zhou. A., O’Brien. J. T., Llewellyn. D. J., and Hyppönen. E.
"High coffee consumption, brain volume and risk of dementia and stroke"
DOI: 10.1080/1028415X.2021.1945858