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Caffeine for Cognition

Image of Coffee for the article Caffeine for Cognition | MCI 911

by Ari Magill, MD

For many, a morning cup of joe or two is part of their daily routine. The positive effects of coffee are quick and often clearly felt, increasing alertness, drive, and energy. Negative effects such as anxiety and jitteriness can be seen when too much coffee is consumed. What is less clear is the long-term cognitive effects of coffee or more generally caffeine and other stimulants, such as those prescribed for attention deficit disorder (ADD). Do the short-term cognitive benefits of these compounds translate into protection against development of Alzheimer’s disease (AD) and its immediate precursor, mild cognitive impairment (MCI)?

The Takeaway:

Caffeine can be beneficial for brain health as long as you drink it in moderation.

Studies in Lab Animals

Glossary:

Beta Amyloid—a sticky compound that accumulates in the brain, disrupting communication between brain cells and eventually killing them

Granulocyte colony-stimulating factor (GCSF)—a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream

Transgenic Mouse Model—a genetically modified mouse commonly used in research

Using a transgenic mouse model of Alzheimer’s disease, Arendash et al showed that caffeine placed in drinking water had a positive impact on working memory in older mice.1 The dosage used was the human equivalent of five cups of coffee (around 500 mg). Earlier, Arendash et al had shown a positive effect from caffeine on working memory as well as recognition skills and spatial learning in younger transgenic mice.2 Corresponding to the functional improvement in memory, the researchers found that caffeine reduced production of beta amyloid in areas of the brain that play a central role in memory consolidation, which are first affected by Alzheimer’s disease.1,2 Buildup of beta amyloid protein is one of the key pathological features of Alzheimer’s.

Another way that caffeine might lower beta amyloid buildup in the brain was demonstrated in rats from a study by Wostyn et al.3 Caffeine appears to increase production of cerebrospinal fluid, which decreases with age and improves blood flow in the brain. Cerebrospinal fluid is thought to help clear out buildup of the beta amyloid protein that is associated with Alzheimer’s disease pathology. Plasma levels of caffeine are also correlated with decreased levels of inflammation in the hippocampus, the brain’s primary memory center.4

Coffee is a complex compound, with many different components. In addition to caffeine, it contains powerful antioxidants, including polyphenols and chlorogenic acids, and small quantities of vitamins and minerals, which have a beneficial impact on health.5 Caffeinated coffee appears to have additional benefits over caffeine alone. A study by Cao et al, which used a transgenic Alzheimer’s disease mouse model, showed that caffeinated coffee raises levels of granulocyte colony-stimulating factor (GCSF), which stimulates the bone marrow to produce more immune cells and stem cells.6 Levels of GCSF were not raised by the administration of decaffeinated coffee or by caffeine alone.

Epidemiologic Studies of Humans

Many epidemiological studies on humans suggest that caffeine and coffee protect against development of cognitive impairment and Alzheimer’s disease. Driscoll et al conducted a study using a pool of postmenopausal women aged 65 years and older from the Women’s Health Initiative Memory Study who were followed more than 10 years to see if caffeine intake related to the incidence of dementia or any cognitive impairment.7 They found that higher daily intake of caffeine (an average of 261 mg) decreased the likelihood of developing dementia or any cognitive impairment compared to lower intake of caffeine (an average of 64 mg).
A review article by Eskelinen and Kivipelto looked at multiple studies that evaluated intake of caffeinated products, including coffee and tea, with a special emphasis on the authors’ Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study.8 Although somewhat inconsistent, a majority of the studies showed a protective effect of coffee against cognitive decline, dementia, or Alzheimer’s disease, with effects from tea being less clear. The CAIDE study showed a reduced likelihood of developing dementia or Alzheimer’s disease by around 65% in late life as a consequence of drinking three to five cups of coffee daily in midlife. Correlating with the epidemiological data, a study by Kim et al on human subjects showed that having two or more cups of coffee daily protects against abnormal levels of beta amyloid protein deposition.5 PET scan imaging was used to visualize beta amyloid deposition in the brain.
A case-control study by Cao et al evaluated 124 people aged 65 to 88.9 Participants were assessed cognitively and had blood samples taken to assess plasma caffeine levels and other biomarkers. The researchers found that participants with MCI who went on to develop dementia had significantly lower plasma caffeine levels than those participants with MCI whose cognition did not worsen. Furthermore, there was a key level of plasma caffeine (1200 ng/mL) above which no MCI participant developed dementia during the two to four years of follow-up, while half of the MCI cohort who did not develop dementia during this period had caffeine levels above this level. MCI study participants whose cognition did not worsen derived most or all of their caffeine from coffee.

In conclusion, there is good evidence that caffeine, especially in the form of moderate coffee intake as a part of an overall healthy lifestyle, can be beneficial for the brain as long as you are maintaining a level to avoid negative side effects such as increased anxiety and cardiovascular stress.

References

1. Arendash GW, et al. Caffeine reverses cognitive impairment and decreases brain amyloid-β levels in aged Alzheimer’s disease mice. J Alz Dis. 2009;17(3):661-680. DOI: 10.3233/JAD-2009-1087.

2. Arendash GW, et al. Caffeine protects Alzheimer’s mice against cognitive impairment and reduces brain β-amyloid production. Neuroscience. 2006;142(4):941-952. DOI: 10.1016/j.neuroscience.2006.07.021.

3. Wostyn P, et al. Increased cerebrospinal fluid production as a possible mechanism underlying caffeine’s protective effect against Alzheimer’s disease. Int J Alz Dis. 2011;2011:617420. DOI: 10.4061/2011/617420.

4. Cao C, et al. Caffeine suppresses amyloid-β levels in plasma and brain of Alzheimer’s disease transgenic mice. J Alz Dis. 2009;17(3):681-697. DOI: 10.3233/JAD-2009-1071.

5. Kim JW, et al. Coffee intake and decreased amyloid pathology in human brain. Trans Psychiatr. 2019;9(1):1-10. DOI: 10.1038/s41398-019-0604-5.

6. Cao C, et al. Caffeine synergizes with another coffee component to increase plasma GCSF: linkage to cognitive benefits in Alzheimer’s mice. J Alz Dis. 2011;25(2):323-335. DOI: 10.3233/JAD-2011-110110.

7. Driscoll I, et al. Relationships between caffeine intake and risk for probable dementia or global cognitive impairment: the Women’s Health Initiative Memory Study. J Gerontol A Biol Sci Med Sci. 2016;71(12):1596-1602. DOI: 10.1093/gerona/glw078.

8. Eskelinen MH, Miia K. Caffeine as a protective factor in dementia and Alzheimer’s disease. J Alz Dis. 2010;20(suppl 1):S167-S174. DOI: 10.3233/JAD-2010-1404.

9. Cao C, et al. High blood caffeine levels in MCI linked to lack of progression to dementia. J Alz Dis. 2012;30(3):559-572. DOI: 10.3233/JAD-2012-111781.

About the Author

Dr. Ari Magill is a holistic neurologist and medical consultant based in Scottsdale, AZ. He received medical school training at University of Texas Southwestern in Dallas and residency training at the University of Arizona in Tucson. He is passionate about finding innovative treatments for cognitive impairment, emphasizing lifestyle change and natural supplements.