Friday, December 5, 2014

Coffee Consumption: Cognitive Decline/Dementia Benefits

Caffeine against Alzheimer's disease

As part of a German-French research project, a team led by Dr. Christa E. Müller from the University of Bonn and Dr. David Blum from the University of Lille was able to demonstrate for the first time that caffeine has a positive effect on tau deposits in Alzheimer's disease. The two-years project was supported with 30,000 Euro from the non-profit Alzheimer Forschung Initiative e.V. (AFI) and with 50,000 Euro from the French Partner organization LECMA. The initial results were published in the online edition of the journal "Neurobiology of Aging."
Tau deposits, along with beta-amyloid plaques, are among the characteristic features of Alzheimer's disease. These protein deposits disrupt the communication of the nerve cells in the brain and contribute to their degeneration. Despite intensive research there is no drug available to date which can prevent this detrimental process. Based on the results of Prof. Dr. Christa Müller from the University of Bonn, Dr. David Blum and their team, a new class of drugs may now be developed for the treatment of Alzheimer's disease.
Caffeine, an adenosine receptor antagonist, blocks various receptors in the brain which are activated by adenosine. Initial results of the team of researchers had already indicated that the blockade of the adenosine receptor subtype A2A in particular could play an important role. Initially, Prof. Müller and her colleagues developed an A2A antagonist in ultrapure and water-soluble form (designated MSX-3). This compound had fewer adverse effects than caffeine since it only blocks only the A2A adenosine receptor subtype, and at the same time it is significantly more effective. Over several weeks, the researchers then treated genetically altered mice with the A2A antagonist. The mice had an altered tau protein which, without therapy, leads to the early development of Alzheimer's symptoms.
In comparison to a control group which only received a placebo, the treated animals achieved significantly better results on memory tests. The A2A antagonist displayed positive effects in particular on spatial memory. Also, an amelioration of the pathogenic processes was demonstrated in the hippocampus, which is the site of memory in rodents.
"We have taken a good step forward," says Prof. Müller. "The results of the study are truly promising, since we were able to show for the first time that A2A adenosine receptor antagonists actually have very positive effects in an animal model simulating hallmark characteristics and progression of the disease. And the adverse effects are minor."
The researchers now want to test the A2A antagonist in additional animal models. If the results are positive, a clinical study may follow. "Patience is required until A2A adenosine receptor antagonists are approved as new therapeutic agents for Alzheimer's disease. But I am optimistic that clinical studies will be performed," says Prof. Müller.

Caffeine Enhances Memory

The consumption of caffeine is the energy boost of choice for millions to wake up or stay up. Now, however, researchers at the Johns Hopkins University have found another use for the stimulant: memory enhancer.

Michael Yassa, assistant professor of psychological and brain sciences in the Krieger School of Arts and Sciences at Johns Hopkins, and his team of scientists found that caffeine has a positive effect on long-term memory in humans. Their research, published by the journal Nature Neuroscience, shows that caffeine enhances certain memories at least up to 24 hours after it is consumed.

"We've always known that caffeine has cognitive-enhancing effects, but its particular effects on strengthening memories and making them resistant to forgetting has never been examined in detail in humans," said Yassa, senior author of the paper. "We report for the first time a specific effect of caffeine on reducing forgetting over 24 hours."

The Johns Hopkins researchers conducted a double-blind trial; which participants who did not regularly eat or drink caffeinated products received either a placebo or a 200-milligram caffeine tablet five minutes after studying a series of images. Salivary samples were taken from the participants before they took the tablets to measure their caffeine levels. Samples were taken again one, three and 24 hours afterwards.

The next day, both groups were tested on their ability to recognize images from the previous day's study session. On the test, some of the visuals were the same as from the day before, some were new additions and some were similar but not the same as the items previously viewed. More members of the caffeine group were able to correctly identify the new images as "similar" to previously viewed images versus erroneously citing them as the same.

The brain's ability to recognize the difference between two similar but not identical items, called pattern separation, reflects a deeper level of memory retention, the researchers said.

"If we used a standard recognition memory task without these tricky similar items, we would have found no effect of caffeine," Yassa said. "However, using these items requires the brain to make a more difficult discrimination -- what we call pattern separation, which seems to be the process that is enhanced by caffeine in our case."

The memory center in the human brain is the hippocampus, a seahorse-shaped area in the medial temporal lobe of the brain. The hippocampus is the switchbox for all short-term and long-term memories. Most research done on memory -- the effects of concussions in athletics to war-related head injuries to dementia in the aging population -- are focused on this area of the brain.

Until now, caffeine's effects on long-term memory had not been examined in detail. Of the few studies done, the general consensus was that caffeine has little or no effect on long-term memory retention.

The research is different from prior experiments because the subjects took the caffeine tablets only after they had viewed and attempted to memorize the images.

"Almost all prior studies administered caffeine before the study session, so if there is an enhancement, it's not clear if it's due to caffeine's effects on attention, vigilance, focus or other factors. By administering caffeine after the experiment, we rule out all of these effects and make sure that if there is an enhancement, it's due to memory and nothing else," said Yassa.

According to the U.S. Food and Drug Administration, 90 percent of people worldwide consume caffeine in one form or another. In the United States, 80 percent of adults consume caffeine every day. The average adult has an intake of about 200 milligrams -- the same amount used in the Yassa study -- or roughly one strong cup of coffee or two small cups of coffee per day.

Yassa's team completed the research at Johns Hopkins before his lab moved to the University of California-Irvine at the start of this year.

"The next step for us is to figure out the brain mechanisms underlying this enhancement," he said. "We can use brain-imaging techniques to address these questions. We also know that caffeine is associated with healthy longevity and may have some protective effects from cognitive decline like Alzheimer's disease. These are certainly important questions for the future."

High blood caffeine levels linked to avoidance of Alzheimer's disease 

Those cups of coffee that you drink every day to keep alert appear to have an extra perk – especially if you're an older adult. A recent study monitoring the memory and thinking processes of people older than 65 found that all those with higher blood caffeine levels avoided the onset of Alzheimer's disease in the two-to-four years of study follow-up. Moreover, coffee appeared to be the major or only source of caffeine for these individuals.

Researchers from the University of South Florida ( and the University of Miami ( the case control study provides the first direct evidence that caffeine/coffee intake is associated with a reduced risk of dementia or delayed onset. Their findings appeared in the Journal of Alzheimer's Disease, published by IOS Press. The collaborative study involved 124 people, ages 65 to 88, in Tampa and Miami.

"These intriguing results suggest that older adults with mild memory impairment who drink moderate levels of coffee -- about 3 cups a day -- will not convert to Alzheimer's disease -- or at least will experience a substantial delay before converting to Alzheimer's," said study lead author Dr. Chuanhai Cao, a neuroscientist at the USF College of Pharmacy and the USF Health Byrd Alzheimer's Institute "The results from this study, along with our earlier studies in Alzheimer's mice, are very consistent in indicating that moderate daily caffeine/coffee intake throughout adulthood should appreciably protect against Alzheimer's disease later in life."

The study shows this protection probably occurs even in older people with early signs of the disease, called mild cognitive impairment, or MCI. Patients with MCI already experience some short-term memory loss and initial Alzheimer's pathology in their brains. Each year, about 15 percent of MCI patients progress to full-blown Alzheimer's disease. The researchers focused on study participants with MCI, because many were destined to develop Alzheimer's within a few years.

Blood caffeine levels at the study's onset were substantially lower (51 percent less) in participants diagnosed with MCI who progressed to dementia during the two-to-four year follow-up than in those whose mild cognitive impairment remained stable over the same period.

No one with MCI who later developed Alzheimer's had initial blood caffeine levels above a critical level of 1200 ng/ml – equivalent to drinking several cups of coffee a few hours before the blood sample was drawn. In contrast, many with stable MCI had blood caffeine levels higher than this critical level.

"We found that 100 percent of the MCI patients with plasma caffeine levels above the critical level experienced no conversion to Alzheimer's disease during the two-to-four year follow-up period," said study co-author Dr. Gary Arendash.

The researchers believe higher blood caffeine levels indicate habitually higher caffeine intake, most probably through coffee. Caffeinated coffee appeared to be the main, if not exclusive, source of caffeine in the memory-protected MCI patients, because they had the same profile of blood immune markers as Alzheimer's mice given caffeinated coffee. Alzheimer's mice given caffeine alone or decaffeinated coffee had a very different immune marker profile.

Since 2006, USF's Dr. Cao and Dr. Arendash have published several studies investigating the effects of caffeine/coffee administered to Alzheimer's mice. Most recently, they reported that caffeine interacts with a yet unidentified component of coffee to boost blood levels of a critical growth factor that seems to fight off the Alzheimer's disease process.

"We are not saying that moderate coffee consumption will completely protect people from Alzheimer's disease," Dr. Cao cautioned. "However, we firmly believe that moderate coffee consumption can appreciably reduce your risk of Alzheimer's or delay its onset."

Alzheimer's pathology is a process in which plaques and tangles accumulate in the brain, killing nerve cells, destroying neural connections, and ultimately leading to progressive and irreversible memory loss. Since the neurodegenerative disease starts one or two decades before cognitive decline becomes apparent, the study authors point out, any intervention to cut the risk of Alzheimer's should ideally begin that far in advance of symptoms.

"Moderate daily consumption of caffeinated coffee appears to be the best dietary option for long-term protection against Alzheimer's memory loss," Dr. Arendash said. "Coffee is inexpensive, readily available, easily gets into the brain, and has few side-effects for most of us. Moreover, our studies show that caffeine and coffee appear to directly attack the Alzheimer's disease process."

In addition to Alzheimer's disease, moderate caffeine/coffee intake appears to reduce the risk of several other diseases of aging, including Parkinson's disease, stroke, Type II diabetes, and breast cancer. However, supporting studies for these benefits have all been observational (uncontrolled), and controlled clinical trials are needed to definitively demonstrate therapeutic value.

A study tracking the health and coffee consumption of more than 400,000 older adults for 13 years, and published earlier this year in the New England Journal of Medicine, found that coffee drinkers reduced their risk of dying from heart disease, lung disease, pneumonia, stroke, diabetes, infections, and even injuries and accidents.

With new Alzheimer's diagnostic guidelines encompassing the full continuum of the disease, approximately 10 million Americans now fall within one of three developmental stages of Alzheimer's disease -- Alzheimer's disease brain pathology only, MCI, or diagnosed Alzheimer's disease. That number is expected to climb even higher as the baby-boomer generation continues to enter older age, unless an effective and proven preventive measure is identified.

"If we could conduct a large cohort study to look into the mechanisms of how and why coffee and caffeine can delay or prevent Alzheimer's disease, it might result in billions of dollars in savings each year in addition to improved quality of life," Dr. Cao said.

Coffee could protect against Alzheimer's disease

A daily dose of caffeine blocks the disruptive effects of high cholesterol that scientists have linked to Alzheimer's disease. A study in the open access publication, Journal of Neuroinflammation revealed that caffeine equivalent to just one cup of coffee a day could protect the blood-brain barrier (BBB) from damage that occurred with a high-fat diet.

The BBB protects the central nervous system from the rest of the body's circulation, providing the brain with its own regulated microenvironment. Previous studies have shown that high levels of cholesterol break down the BBB which can then no longer protect the central nervous system from the damage caused by blood borne contamination. BBB leakage occurs in a variety of neurological disorders such as Alzheimer's disease.

In this study, researchers from the University of North Dakota School of Medicine and Health Sciences gave rabbits 3 mg caffeine each day – the equivalent of a daily cup of coffee for an average-sized person. The rabbits were fed a cholesterol-enriched diet during this time.

After 12 weeks a number of laboratory tests showed that the BBB was significantly more intact in rabbits receiving a daily dose of caffeine.

“Caffeine appears to block several of the disruptive effects of cholesterol that make the blood-brain barrier leaky,” says Jonathan Geiger, University of North Dakota School of Medicine and Health Sciences. “High levels of cholesterol are a risk factor for Alzheimer's disease, perhaps by compromising the protective nature of the blood-brain barrier. For the first time we have shown that chronic ingestion of caffeine protects the BBB from cholesterol-induced leakage.”

Caffeine appears to protect BBB breakdown by maintaining the expression levels of tight junction proteins. These proteins bind the cells of the BBB tightly to each other to stop unwanted molecules crossing into the central nervous system.

The findings confirm and extend results from other studies showing that caffeine intake protects against memory loss in aging and in Alzheimer’s disease.

“Caffeine is a safe and readily available drug and its ability to stabilise the blood-brain barrier means it could have an important part to play in therapies against neurological disorders,” says Geiger.

 Caffeine may block inflammation linked to mild cognitive impairment

Recent studies have linked caffeine consumption to a reduced risk of Alzheimer's disease, and a new University of Illinois study may be able to explain how this happens.

"We have discovered a novel signal that activates the brain-based inflammation associated with neurodegenerative diseases, and caffeine appears to block its activity. This discovery may eventually lead to drugs that could reverse or inhibit mild cognitive impairment," said Gregory Freund, a professor in the U of I's College of Medicine and a member of the U of I's Division of Nutritional Sciences.

Freund's team examined the effects of caffeine on memory formation in two groups of mice—one group given caffeine, the other receiving none. The two groups were then exposed to hypoxia, simulating what happens in the brain during an interruption of breathing or blood flow, and then allowed to recover.

The caffeine-treated mice recovered their ability to form a new memory 33 percent faster than the non-caffeine-treated mice. In fact, caffeine had the same anti-inflammatory effect as blocking IL-1 signaling. IL-1 is a critical player in the inflammation associated with many neurodegenerative diseases, he said.

"It's not surprising that the insult to the brain that the mice experienced would cause learning memory to be impaired. But how does that occur?" he wondered.

The scientists noted that the hypoxic episode triggered the release of adenosine by brain cells.

"Your cells are little powerhouses, and they run on a fuel called ATP that's made up of molecules of adenosine. When there's damage to a cell, adenosine is released," he said.

Just as gasoline leaking out of a tank poses a danger to everything around it, adenosine leaking out of a cell poses a danger to its environment, he noted.

The extracellular adenosine activates the enzyme caspase-1, which triggers production of the cytokine IL-1β, a critical player in inflammation, he said.

"But caffeine blocks all the activity of adenosine and inhibits caspase-1 and the inflammation that comes with it, limiting damage to the brain and protecting it from further injury," he added.

Caffeine's ability to block adenosine receptors has been linked to cognitive improvement in certain neurodegenerative diseases and as a protectant against Alzheimer's disease, he said.

"We feel that our foot is in the door now, and this research may lead to a way to reverse early cognitive impairment in the brain. We already have drugs that target certain adenosine receptors. Our work now is to determine which receptor is the most important and use a specific antagonist to that receptor," he said.

In women, caffeine may protect memory

Caffeine may help older women protect their thinking skills, according to a study published in the August 7, 2007, issue of Neurology, the medical journal of the American Academy of Neurology.

The study found that women age 65 and older who drank more than three cups of coffee (or the equivalent in tea) per day had less decline over time on tests of memory than women who drank one cup or less of coffee or tea per day. The results held up even after researchers adjusted for other factors that could affect memory abilities, such as age, education, disability, depression, high blood pressure, medications, cardiovascular disease, and other chronic illnesses.

“Caffeine is a psychostimulant which appears to reduce cognitive decline in women,” said study author Karen Ritchie,. “While we have some ideas as to how this works biologically, we need to have a better understanding of how caffeine affects the brain before we can start promoting caffeine intake as a way to reduce cognitive decline. But the results are interesting – caffeine use is already widespread and it has fewer side effects than other treatments for cognitive decline, and it requires a relatively small amount for a beneficial effect.”

The study involved 7,000 people whose cognitive abilities and caffeine consumption were evaluated over four years. Compared to women who drank one cup or less of coffee per day, those who drank over three cups were less likely to show as much decline in memory. Moreover, the benefits increased with age – coffee drinkers being 30 percent less likely to have memory decline at age 65 and rising to 70 percent less likely over age 80.
Caffeine consumers did not seem to have lower rates of dementia. “We really need a longer study to look at whether caffeine prevents dementia; it might be that caffeine could slow the dementia process rather than preventing it,” said Ritchie.

Ritchie said researchers aren’t sure why caffeine didn’t show the same result in men. “Women may be more sensitive to the effects of caffeine,” she said. “Their bodies may react differently to the stimulant, or they may metabolize caffeine differently.”

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