The effect of caffeine on memory
Data from the Women's Health Initiative Memory Study, involving 6,467 postmenopausal women (65+) who reported some level of caffeine consumption, has found that those who consumed above average amounts of coffee had a lower risk of developing dementia.
Caffeine intake was estimated from a questionnaire. The median intake was 172 mg per day (an 8-ounce cup of brewed coffee contains 95mg of caffeine, 8-ounces of brewed black tea contains 47mg, so slightly less than 2 cups of coffee or less than 4 cups of tea). The women were cognitively assessed annually.
Over ten years, 388 were diagnosed with probable dementia (209) or MCI (179). Those who consumed above the median amount of caffeine had a 36% reduction in risk. The average intake in this group was 261 mg (3 cups of coffee), while the average intake for those below the median was 64 mg per day (less than one cup).
Risk factors such as hormone therapy, age, race, education, body mass index, sleep quality, depression, hypertension, prior cardiovascular disease, diabetes, smoking, and alcohol consumption, were taken into account.
The findings are consistent with other research finding a benefit for older women. It should not be assumed that the findings apply to men. It also appears that there may be a difference depending on education level. This sample had a high proportion of college-educated women.
It should also be noted that there was no clear dose-response effect — we could put more weight on the results if there was a clear relationship between amount of caffeine and benefit. Part of the problem here, however, is that it’s difficult to accurately assess the amount of caffeine, given that it’s based on self-report intake of coffee and tea, and the amount of caffeine in different beverages varies significantly.
Moreover, we do have a couple of mechanisms for caffeine to help fight age-related cognitive decline.
A recent study using rats modified to have impaired receptors for the adenosine A2A produced rats showing typical characteristics of an aging brain. In humans, too, age-related cognitive decline has been associated with over-activation of these receptors and dysfunction in glucocorticoid receptors.
The rat study shows that over-activation of the adenosine A2A receptors reduces the levels of glucocorticoid receptors in the hippocampus, which in turn impairs synaptic plasticity and cognition. In other words, it is the over-activation of the adenosine receptors that triggers a process that ends with cognitive impairment.
The point of all this is that caffeine inhibits the adenosine A2A receptors, and when the rats were given a caffeine analogue, their memory deficits returned to normal.
Another more recent study has found that caffeine increases the production of an enzyme that helps prevent tau tangles.
Building on previous research finding that an enzyme called NMNAT2 not only protects neurons from stress, but also helps prevent misfolded tau proteins (linked to Alzheimer’s, and other neurodegenerative disorders), the study identified 24 compounds (out of 1,280 tested) as having potential to increase the production of NMNAT2. One of the most effective of these was caffeine.
When caffeine was given to mice modified to produce lower levels of NMNAT2, the mice began to produce the same levels of the enzyme as normal mice.
Consistent with earlier indications that moderate caffeine consumption may protect against memory decline, a study of genetically engineered mice has found that when the old mice began to show memory impairment, those given caffeine for 2 months performed as well as normal aged mice on cognitive tests, while those given plain drinking water continued to do poorly. The Alzheimer's mice received the equivalent of five 8-oz. cups of regular coffee a day (or two cups of Starbucks coffee, or 14 cups of tea). Moreover, the brains of the caffeinated mice showed nearly a 50% reduction in levels of beta amyloid. The effect appears to be through suppression of both β-secretase and presenilin 1 /g-secretase expression. Caffeine had this effect only on those with Alzheimer’s; normal mice given caffeine through adulthood showed no cognitive benefit.
Arendash, G.W. et al. 2009. Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-β Levels in Aged Alzheimer's Disease Mice. Journal of Alzheimer's Disease, 17 (3), 661-680.
Cao, C. et al. 2009. Caffeine Suppresses Amyloid-β Levels in Plasma and Brain of Alzheimer's Disease Transgenic Mice. Journal of Alzheimer's Disease, 17 (3), 681-697.
High doses of nicotinamide, a form of vitamin B3, has been found to dramatically lower levels of tau protein in mice with Alzheimer's disease. The vitamin also increased proteins that strengthen microtubules, the scaffolding within brain cells along which information travels. Not only did the vitamin prevent memory loss in Alzheimer’s mice, it also slightly improved cognitive performance in normal mice. Nicotinamide is a water-soluble vitamin sold in health food stores. It generally is safe but can be toxic in very high doses. Clinical trials have shown it benefits people with diabetes complications and has anti-inflammatory properties that may help people with skin conditions. Clinical trials with Alzheimer’s patients are now underway.
Green, K.N. et al. 2008. Nicotinamide Restores Cognition in Alzheimer's Disease Transgenic Mice via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-Phosphotau. Journal of Neuroscience, 28, 11500-11510.
A study of 847 Alzheimer's patients has found that those who took 1,000 international units of vitamin E twice a day, were 26% less likely to die over a five-year period than people who didn't take vitamin E. It also appears that taking vitamin E plus a cholinesterase inhibitor may be more beneficial than taking either agent alone.
The research was presented at the American Academy of Neurology Annual Meeting in Chicago, April 12 – April 19.
Several studies have shown that eating fish, which is high in omega-3 fatty acids, may protect against Alzheimer's disease. A Swedish study has now tested whether supplements could have similar effects. Patients with mild-to-moderate Alzheimer’s who took 1.7 grams of DHA and .6g of EPA showed the same rate of cognitive decline as those taking a placebo, however, among a subgroup of 32 patients with very mild cognitive impairment, those who took the fatty acids experienced less decline in six months compared with those who took placebo. It may be that anti-inflammatory effects are an important reason for the benefit, potentially explaining why effects were seen only in those with very early-stage disease, when levels of inflammation seem to be higher.
Freund-Levi;, Y. et al. 2006. w-3 Fatty Acid Treatment in 174 Patients With Mild to Moderate Alzheimer Disease: OmegAD Study: A Randomized Double-blind Trial. Archives of Neurology, 63, 1402-1408.
A "cocktail" of dietary supplements (omega-3 fatty acids, uridine and choline) has been found to dramatically increase the amount of membranes that form brain cell synapses in gerbils. The treatment is now in human clinical trials. It is hoped that such treatment may significantly delay Alzheimer's disease. The treatment offers a different approach from the traditional tactic of targeting amyloid plaques and tangles. Choline can be found in meats, nuts and eggs, and omega-3 fatty acids are found in a variety of sources, including fish, eggs, flaxseed and meat from grass-fed animals. Uridine, which is found in RNA and produced by the liver and kidney, is not obtained from the diet, although it is found in human breast milk.
Wurtman, R.J., Ulus, I.H., Cansev, M., Watkins, C.J., Wang L. & Marzloff, G. 2006. Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Research, Available online ahead of print 21 April 2006.
In cell studies, resveratrol has been found to lower levels of amyloid-beta peptides. Resveratrol is a natural compound occurring in abundance in grapes, berries and peanuts. The highest concentration has been reported in wines prepared from Pinot Noir grapes. The anti-amyloidogenic effect of resveratrol observed in cell cultures does not however necessarily mean that the beneficial effect can result simply from eating grapes or drinking wine. Further research aims to develop more active and more stable compounds.
Marambaud, P., Zhao, H. & Davies, P. 2005. Resveratrol Promotes Clearance of Alzheimer's Disease Amyloid- Peptides. Journal of Biological Chemistry, 280, 37377-37382.
In a study of people with mild cognitive impairment, those who took the drug donepezil were at reduced risk of progressing to a diagnosis of Alzheimer's during the first years of the trial, but by the end of the 3-year study there was no benefit from the drug. Of the 769 participants, 212 developed possible or probable Alzheimer’s within the 3-year study period; the donepezil group's risk of progression to a diagnosis of Alzheimer’s was reduced by 58% one year into the study, and 36% at 2 years, but no risk reduction at the end of three years. Vitamin E was also tested in the study and was found to have no effect at any point in the study.
Petersen, R.C. et al. 2005. Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment. New England Journal of Medicine, 352 (23), 2379-2388.
A study using genetically engineered mice has found that those mice on a diet rich in curcumin (the yellow pigment in the curry spice turmeric) developed 85% few Alzheimer’s plaques then the control group. Curcumin has antioxidant, anti-inflammatory, and cholesterol lowering properties, and has long been used in India as treatment for a variety of ailments. A human trial involving 33 Alzheimer's patients will soon commence.
Yang, F., Lim, G.P., Begum, A.N., Ubeda, O.J., Simmons, M.R., Ambegaokar, S.S., Chen, P.P., Kayed, R., Glabe, C.G., Frautschy, S.A. & Cole, G.M. 2004. Curcumin inhibits formation of Abeta oligomers and fibrils and binds plaques and reduces amyloid in vivo. Journal of Biological Chemistry, published online ahead of print December 7, 2004A copy of the full paper can be found on the Journal of Biological Chemistry Web site athttp://tinyurl.com/5bzbs
A three-month study of 55 elderly patients with mild or moderate Alzheimer’s found that those given EV-1, a dietary supplement containing, among other things, the putative antioxidant ingredient of red wine, showed no deterioration during the trial. The supplement is designed to interfere with a defective mitochondrial cycle thought to contribute to the metabolic disturbances associated with late onset Alzheimer’s. The Krebs tricarboxylic acid cycle is fuelled by glucose and regulates levels of reactive oxygen species in the body. EV-1 contains glucose, a compound called malate that primes or maintains the Krebs cycle, and resveratrol - the antioxidant component of red wine that is thought to soak up reactive oxygen species. More studies are needed to confirm this result.
The findings were presented in November at the annual meeting of the Society for Neuroscience (SFN) in New Orleans.
A study involving 44 middle-aged overweight men who consumed 70 grams of dark chocolate per day over two periods of four weeks, has found that dark chocolate helps restore flexibility to arteries while also preventing white blood cells from sticking to the walls of blood vessels. Both arterial stiffness and white blood cell adhesion are known factors that play a significant role in atherosclerosis.
Mice given decaffeinated green tea and regular exercise lost weight and improved their health after 16 weeks. Specifically, they reduced body mass by 27% (on average), reduced abdominal fat by 37%; reduced blood glucose level by 17%, plasma insulin level by 65%, and insulin resistance by 65%..
Neither green tea alone, nor exercise alone, produced such significant changes. The amount of green tea was a lot: the equivalent of 8-10 cups a day. Decaffeination may not be important; it was done to keep the effects of caffeine out of the study.
Caffeine occurs naturally in the nectar of coffee and citrus flowers. A study of honeybees has revealed that those fed on caffeinated nectar were three times more likely to remember a flower's scent than bees fed sugar alone, after 24 hours. After three days, they were still twice as likely to remember the flower than those fed sugar alone.
A mouse study indicates that caffeine can help prevent inflammation occurring in the brain, by blocking an early response to cell damage.
Caffeine has been associated with a lower of developing Alzheimer's disease in some recent studies. A recent human study suggested that the reason lies in its effect on proteins involved in inflammation. A new mouse study provides more support for this idea.
In the study, two groups of mice, one of which had been given caffeine, were exposed to hypoxia, simulating what happens in the brain during an interruption of breathing or blood flow. When re-oxygenated, caffeine-treated mice recovered their ability to form a new memory 33% faster than the other mice, and the caffeine was observed to have the same anti-inflammatory effect as blocking interleukin-1 (IL-1) signaling.
Inflammation is a key player in cognitive impairment, and IL-1 has been shown to play a critical role in the inflammation associated with many neurodegenerative diseases.
It was found that the hypoxic episode triggered the release of adenosine, the main component of ATP (your neurons’ fuel). Adenosine is released when a cell is damaged, and this leakage into the environment outside the cell begins a cascade that leads to inflammation (the adenosine activates an enzyme, caspase-1, which triggers production of the cytokine IL-1β).
But caffeine blocks adenosine receptors, stopping the cascade before it starts.
The finding gives support to the idea that caffeine may help prevent cognitive decline and impairment.
A mouse study adds to evidence that green tea may help protect against age-related cognitive impairment, by showing how one of its components improves neurogenesis.
Green tea is thought to have wide-ranging health benefits, especially in the prevention of cardiovascular disease, inflammatory diseases, and diabetes. These are all implicated in the development of age-related cognitive impairment, so it’s no surprise that regular drinking of green tea has been suggested as one way to help protect against age-related cognitive decline and dementia. A new mouse study adds to that evidence by showing how a particular compound in green tea promotes neurogenesis.
The chemical EGCG, (epigallocatechin-3 gallate) is a known anti-oxidant, but this study shows that it also has a specific benefit in increasing the production of neural progenitor cells. Like stem cells, these progenitor cells can become different types of cell.
Mice treated with EGCG displayed better object recognition and spatial memory than control mice, and this improved performance was associated with the number of progenitor cells in the dentate gyrus and increased activity in the sonic hedgehog signaling pathway (confirming the importance of this pathway in adult neurogenesis in the hippocampus).
The findings add to evidence that green tea may help protect against cognitive impairment and dementia.
Full text available at http://onlinelibrary.wiley.com/doi/10.1002/mnfr.201200035/abstract
A 4-year study of older adults has found that low levels of caffeine were linked to MCI progressing to dementia, apparently by mediating lower levels of anti-inflammatory proteins.
Following on from mouse studies, a human study has investigated whether caffeine can help prevent older adults with mild cognitive impairment from progressing to dementia.
The study involved 124 older adults (65-88) who were thoroughly cognitively assessed, given brain scans, and had a fasting blood sample taken. They were then followed for 2 to 4 years, during which their cognitive status was re-assessed annually. Of the 124 participants, 69 (56%) were initially assessed as cognitively normal (average age 73), 32 (26%) with MCI (average age 76.5), and 23 (19%) with dementia (average age 77). The age differences were significant.
Those with MCI on initial assessment showed significantly lower levels of caffeine in their blood than those cognitively healthy; levels in those with dementia were also lower but not significantly. Those initially healthy who developed MCI over the study period similarly showed lower caffeine levels than those who didn’t develop MCI, but again, due to the wide individual variability (and the relatively small sample size), this wasn’t significant. However, among those with MCI who progressed to dementia (11, i.e. a third of those with MCI), caffeine levels were so much lower that the results were significant.
This finding revealed an apparently critical level of caffeine dividing those who progressed to dementia and those who did not — more specifically, all of those who progressed to dementia were below this level, while around half of those who remained stable were at the level or above. In other words, low caffeine would seem to be necessary but not sufficient.
On the other hand (just to show that this association is not as simple as it appears), those already with dementia had higher caffeine levels than those with MCI who progressed to dementia.
The critical factor may have to do with three specific cytokines — GCSF, IL-10, and IL-6 — which all showed markedly lower levels in those converting from MCI to dementia. Comparison of the three stable-MCI individuals with the highest caffeine levels and the three with the lowest levels, and the three from the MCI-to-dementia group with comparable low levels, revealed that high levels of those cytokines were matched with high caffeine levels, while, in both groups, low caffeine levels were matched to low levels of those cytokines.
These cytokines are associated with inflammation — an established factor in cognitive decline and dementia.
The level of coffee needed to achieve the ‘magic’ caffeine level is estimated at around 3 cups a day. While caffeine can be found in other sources, it is thought that in this study, as in the mouse studies, coffee is the main source. Moreover, mouse research suggests that caffeine is interacting with an as yet unidentified component of coffee to boost levels of these cytokines.
This research has indicated that caffeine has several beneficial effects on the brain, including suppressing levels of enzymes that produce amyloid-beta, as well as these anti-inflammatory effects.
It’s suggested that the reason high levels of caffeine don’t appear to benefit those with dementia is because higher levels of these cytokines have become re-established, but this immune response would appear to come too late to protect the brain. This is consistent with other evidence of the importance of timing.
Do note that in mouse studies, the same benefits were not associated with decaffeinated coffee.
While this study has some limitations, the findings are consistent with previous epidemiologic studies indicating coffee/caffeine helps protect against cognitive impairment and dementia. Additionally, in keeping with the apparent anti-inflammatory action, a long-term study tracking the health and coffee consumption of more than 400,000 older adults recently found that coffee drinkers had reduced risk of dying from heart disease, lung disease, pneumonia, stroke, diabetes, infections, injuries and accidents.
Cao, C., Loewenstein, D. a, Lin, X., Zhang, C., Wang, L., Duara, R., Wu, Y., et al. (2012). High Blood Caffeine Levels in MCI Linked to Lack of Progression to Dementia. Journal of Alzheimer’s disease : JAD, 30(3), 559–72. doi:10.3233/JAD-2012-111781
Freedman, N.D. et al. 2012. Association of Coffee Drinking with Total and Cause-Specific Mortality. N Engl J Med, 366, 1891-1904.
Rosemary is a herb long associated with memory. A small study now provides some support for the association, and for the possible benefits of aromatherapy. And a rat study indicates that your attitude to work might change how stimulants affect you.
A small study involving 20 people has found that those who were exposed to 1,8-cineole, one of the main chemical components of rosemary essential oil, performed better on mental arithmetic tasks. Moreover, there was a dose-dependent relationship — higher blood concentrations of the chemical were associated with greater speed and accuracy.
Participants were given two types of test: serial subtraction and rapid visual information processing. These tests took place in a cubicle smelling of rosemary. Participants sat in the cubicle for either 4, 6, 8, or 10 minutes before taking the tests (this was in order to get a range of blood concentrations). Mood was assessed both before and after, and blood was tested at the end of the session.
While blood levels of the chemical correlated with accuracy and speed on both tasks, the effects were significant only for the mental arithmetic task.
Participants didn’t know that the scent was part of the study, and those who asked about it were told it was left over from a previous study.
There was no clear evidence that the chemical improved attention, but there was a significant association with one aspect of mood, with higher levels of the scent correlating with greater contentment. Contentment was the only aspect of mood that showed such a link.
It’s suggested that this chemical compound may affect learning through its inhibiting effect on acetylcholinesterase (an important enzyme in the development of Alzheimer's disease). Most Alzheimer’s drugs are cholinesterase inhibitors.
While this is very interesting (although obviously a larger study needs to confirm the findings), what I would like to see is the effects on more prolonged mental efforts. It’s also a little baffling to find the effect being limited to only one of these tasks, given that both involve attention and working memory. I would also like to see the rosemary-infused cubicle compared to some other pleasant smell.
Interestingly, a very recent study also suggests the importance of individual differences. A rat study compared the effects of amphetamines and caffeine on cognitive effort. First of all, giving the rats the choice of easy or hard visuospatial discriminations revealed that, as with humans, individuals could be divided into those who tended to choose difficult trials (“workers”) and those who preferred easy ones (“slackers”). (Easy trials took less effort, but earned commensurately smaller reward.)
Amphetamine, it was found, made the slackers worked harder, but made the workers take it easier. Caffeine, too, made the workers slack off, but had no effect on slackers.
The extent to which this applies to humans is of course unknown, but the idea that your attitude to cognitive effort might change how stimulants affect you is an intriguing one. And of course this is a more general reminder that factors, whatever they are, have varying effects on individuals. This is why it’s so important to have a large sample size, and why, as an individual, you can’t automatically assume that something will benefit you, whatever the research says.
But in the case of rosemary oil, I can’t see any downside! Try it out; maybe it will help.
First study: http://www.medscape.com/viewarticle/759506 (free reg reqd)
Second study: http://the-scientist.com/2012/03/28/stimulants-fail-to-stimulate/
Recent studies show why a low-fat, low-carb diet, and caffeinated coffee, help protect against developing Alzheimer’s disease.
In a study involving 20 healthy older adults (mean age 69.3) and 29 older adults who had amnestic mild cognitive impairment (mean age 67.6), half the participants were randomly assigned to a high–saturated fat/high–simple carbohydrate diet (HIGH) and half to a low–saturated fat/low–simple carbohydrate diet (LOW) for four weeks, in order to investigate the effects on biomarkers associated with Alzheimer’s.
For the healthy participants, the LOW diet decreased the level of amyloid-beta 42 in the cerebrospinal fluid, while the HIGH diet increased its level. The HIGH diet also lowered the CSF insulin concentration. For those with aMCI, the LOW diet increased the levels of amyloid-beta 42 and increased the CSF insulin concentration. For both groups, the level of apolipoprotein E in the CSF increased in the LOW diet and decreased in the HIGH diet.
For both groups, the LOW diet improved performance on delayed visual recall tests, but didn’t affect scores on other cognitive measures (bear in mind that the diet was only followed for a month).
The researchers suggest that the different results of the unhealthy diet in participants with aMCI may be due to the diet’s short duration. The fact that diet was bringing about measurable changes in CSF biomarkers so quickly, and that the HIGH diet moved healthy brains in the direction of Alzheimer’s, speaks to the potential of dietary intervention.
Support for the value of coffee in decreasing the risk of Alzheimer’s comes from a mouse study, which found that an as yet unidentified ingredient in coffee interacts with caffeine in such a way that blood levels of a growth factor called GCSF (granulocyte colony stimulating factor) increases. GCSF is a substance greatly decreased in patients with Alzheimer's disease and demonstrated to improve memory in Alzheimer's mice.
The finding points to the value of caffeinated coffee, as opposed to decaffeinated coffee or to other sources of caffeine. Moreover, only "drip" coffee was used; the researchers caution that they don’t know whether instant caffeinated coffee would provide the same GCSF response.
There are three ways that GCSF seems to improve memory performance in the Alzheimer's mice: by recruiting stem cells from bone marrow to enter the brain and remove beta-amyloid protein; by increasing the growth of new synapses; by increasing neurogenesis.
The amount of coffee needed to provide this protection, however, is estimated to be about 4 to 5 cups a day. The researchers also believe that this daily coffee intake is best begun at least by middle age (30s – 50s), although starting even in older age does seem to have some protective effect.
Weirdly (I thought), the researchers remarked that "The average American gets most of their daily antioxidants intake through coffee". Perhaps this points more to the defects in their diet than to the wonders of coffee! But the finding is consistent with other research showing an association between moderate consumption of coffee and decreased risk of Parkinson's disease, Type II diabetes and stroke.
A just-completed clinical trial has investigated GCSF treatment to prevent Alzheimer's in patients with mild cognitive impairment, and the results should be known soon.
Cao, C., Wang, L., Lin, X., Mamcarz, M., Zhang, C., Bai, G., Nong, J., Sussman, S. & Arendash, G. 2011.Caffeine Synergizes with Another Coffee Component to Increase Plasma GCSF: Linkage to Cognitive Benefits in Alzheimer's Mice. Journal of Alzheimer's Disease, 25(2), 323-335.
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