Coffee and Alzheimer’s Disease

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Background

Alzheimer’s Disease (AD) is the most frequent cause of dementia. It is estimated that between 50-70% of people with dementia suffer from AD84-87. In addition, approximately one person out of 20 over the age of 65 suffers from AD, as opposed to less than one person in a thousand under the age of 6585. Approximately 44 million people globally suffer from AD86.  The 2015 World Alzheimer’s Report suggested that approximately 10.5 million people in Europe suffer with AD and the number is predicted to increase to 13.4 million by 2030 and to 18.7 million by 205087.

In 2014 Alzheimer Europe published an updated systematic review of papers reporting the prevalence of dementia.  The authors concluded that that for the majority of age groups, dementia prevalence has not changed significantly over the last few decades.  However, they did report a higher prevalence in older females than was previously thought88.

AD, a neurodegenerative disease, leads to progressive cognitive decline and the accumulation of β-amyloïd peptide (Aβ) in the brain. Some forms of AD are due to the mutation of genes coding for the precursor of Aβ, presenilin 1 and 2. Genetic factors interact with surrounding environmental factors and the influence of these additional factors, deleterious or protective, remains largely unknown89.

Coffee, caffeine and risk of Alzheimer’s disease

The majority of studies suggest that regular coffee/caffeine consumption over a lifetime reduces the risk of developing AD, particularly in the elderly, however some studies show varying results.  It seems that coffee/caffeine consumption may be particularly beneficial before the occurrence of the disease i.e. during the pre-morbid phase.

A number of meta-analyses and reviews have been undertaken which together support the view that coffee consumption is associated with a reduced risk of AD.

  • A 2007 review of observational studies suggested that coffee consumption was associated with a reduced risk of AD by approximately by 30% as compared to non-coffee consumers29. Four studies carried out between 1990 and 2002 were included in this review (2 case-control and 2 cohort studies) 25-28. Overall, the results suggested a protective effect of coffee consumption, however, there was a large heterogeneity across the studies.
  • A further meta-analysis of the relation between coffee/caffeine intake and the risk of AD, suggested that the summary risk ratio reached 0.80-0.83 for Alzheimer’s disease after adjustment for smoking and hypertension10.
  • A 2010 review also suggested that daily intake of 3-5 cups of coffee in middle age may lower the risk of the dementia and AD by about 65% as compared to lower amounts of coffee. However, the author also highlighted the fact that some findings are inconsistent30.
  • A 2017 review concluded that reports indicate that moderate coffee consumption may in fact lower the risk for common neurodegenerative conditions including AD. However, the authors concluded that methodological differences in studies mean comparisons and conclusions can be difficult to reach and further well constructed research is required31.
  • A 2017 theoretical review suggested an association between genetically predicted higher coffee consumption and higher odds of AD. The role of genetic polymorphisms in diet and disease warrants further investigation32.
  • A further 2018 meta- analysis of prospective studies that focused on Alzheimer’s disease revealed no association between coffee consumption and Alzheimer’s disease and no deviations from a linear trend. The relative risk of Alzheimer’s disease per 1 cup/day increment of coffee consumption was 1.0112.

Larger studies that have also considered associations between coffee consumption and AD.

  • A study of 4,615 subjects followed over 5 years (194 AD cases, 3,894 cognitively ‘normal’ controls, and 527 exclusions) found that the use of non-steroidal anti-inflammatory drugs, wine consumption, coffee consumption, and regular physical activity were associated with a reduced risk of AD (risk ratio of 0.69 for coffee). Interestingly, there was no protection for tea consumers in this study26.
  • A further study of 1,409 individuals aged 65 to 79 were examined after 21 years’ follow-up. Coffee consumption in midlife decreased the risk of AD and dementia in the elderly, with the lowest risk (65% decrease) found in people who drank 3-5 cups/day33.

However, other studies have not shown an association between coffee consumption and a reduced risk of AD. Both a Finnish study34 and the Honolulu-Asia Aging Study35, found no link between coffee consumption and dementia or cognitive impairment.

Mechanism of action for caffeine

A number of animal studies point to possible mechanisms of action behind coffee/caffeine’s effects on AD risk.

In one study, caffeine in drinking water, given to transgenic mice that develop AD-like symptoms around 8 months of age, improved learning and memory and reduced the concentration of Aβ peptide and presenilin in the hippocampus, the main brain structure involved in memory36.

Moreover, these effects were also found when caffeine treatment was started late i.e. once the mice had already developed cognitive deficits. Caffeine seemed to act by reducing the mediators of inflammation37,38.

Caffeinated coffee increased plasma levels of granulocyte-colony stimulating factor (GCSF), which seemed to improve the cognitive performance of AD transgenic mice with the recruitment of bone marrow cells, enhanced synaptogenesis, and increased neurogenesis. Neither a caffeine solution alone, nor decaffeinated coffee, provided this effect. The authors hypothesize that caffeine might interact with another component in coffee to selectively elevate GCSF39.

Caffeine may also be active at a different level. In an animal study, the long-term consumption of caffeine in drinking water by rats increased cerebrospinal fluid (CSF) production and cerebral blood flow, which directly affects the production of CSF35. Defective CSF production and turnover, with diminished clearance of Aβ, may be one mechanism implicated in the pathogenesis of AD36. This may partly explain the caffeine-induced reduction of brain levels of Aβ peptide although it is not yet known whether this effect also occurs in humans40,41.

A further hypothesis suggests that the modulation of adenosine receptors, namely, the A2Areceptor, affords neuroprotection through the control of microglia reactivity and neuroinflammation. Again, further work is required to explore this hypothesis42.

A role for other coffee constituents

Other coffee constituents, which may be involved in coffee’s beneficial effect on AD risk, besides caffeine, have also been studied.

Several animal studies suggest that trigonelline may have neuro-protective properties and improve memory retention43-45.

The polyphenol antioxidant ferulic acid found in coffee, given to mice in drinking water, has been found to protect against cognitive deficits, mainly spatial and working memory, suppress inflammation and prevent the loss of acetylcholine from the cerebral cortex – all factors that characterize the disease46.

There is an increasing number of experimental and human scientific studies suggesting a potentially protective role for caffeine – and potentially also for other coffee compounds e.g. anti-oxidants or anti-inflammatory agents – in the development of AD. However, further studies aimed at identifying the different coffee compounds that appear to be active against the disease, and the mechanism of action, are needed before any firm conclusions can be drawn.

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