The doctor of the future will . . . interest his patients in the care of the human frame, in diet and in the cause and prevention of disease.
Thomas Edison, “Edison Hails Era of Speed,” The Fort Wayne Sentinel, December 31, 1902
As we saw in chapters 5 and 6, nutrition plays a critical role in our physical health and can accelerate aging or slow it, depending on whether we eat inflammatory foods devoid of essential nutrients (fast foods, junk foods) or a well-balanced diet filled with anti-inflammatory nutrients. Because this is a proven fact, millions of people seek to improve their health by augmenting their diets with nutritional supplements, various herbs, oils, vitamins, and minerals. It is estimated that Americans spend between $14 billion and $20 billion annually on various nutritional supplements—the majority of which have no evidence of benefit and some of which are even harmful. In this chapter we will review the data on supplements with the best evidence for promoting brain health and reducing risk of dementia.
Omega-3 Fatty Acids
In chapter 6 we examined some evidence for omega-3 fatty acids, noting that there are three omega-3 forms: a short-chain form (alpha-linolenic acid [ALA]) found in plants such as flax and nuts and two long-chain forms (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) found primarily in oily fish. It is the long-chain forms (EPA/DHA) that the brain utilizes.
DHA is essential for healthy brain development, and deficiencies increase the risk of developmental delays.1 Studies have found that children with low levels of these essential fats perform worse in school and have more behavior problems as compared to children with normal amounts.2 This is one reason most obstetricians now include omega-3 supplements with prenatal vitamins. Because these fatty acids are essential to brain development, the mother’s body will give omega-3s to the developing fetus during pregnancy, thus reducing her stores of this essential fat. This reduction in omega-3 fatty acids is one factor that increases the risk of postpartum depression and another reason for prenatal supplementation.3
Once the brain is developed omega-3 fatty acids appear to play an ongoing role in reducing inflammation by scavenging oxidizing molecules and having an anti-amyloid effect on the brain. In one study it appears these benefits reduced the risk of developing AD.4 Another study that evaluated individuals without the ApoE4 gene found that those eating fish two to three times per week reduced their risk of AD by 50 percent over four years.5 In another study, which followed almost nine hundred people over nine years, researchers found that those with the highest DHA levels had a 47 percent reduction in developing AD.6
Interestingly, it appears that eating fish and taking fish oil supplements do not result in the exact same benefits. A meta-analysis of various studies showed that omega-3 supplements improved cognition and processing speed for those with mild cognitive impairment (symptoms before dementia occurs) but did not benefit those already demented and didn’t prevent the development of dementia.7 However, the ingestion of fish once per week was positively associated with larger brain volume, particularly in memory centers of the brain. In a study of 260 people who ate broiled or baked fish at least once per week researchers found that their brains had more gray matter than those who did not consume fish, and this benefit was independent of omega-3 fatty acid levels in their bodies.8 Battered and fried fish would not be expected to provide benefit, and are most likely harmful, due to the advanced glycation end-products and other oxidizing molecules.
The benefit of fish consumption was demonstrated in another very rigorous study published in the Journal of the American Medical Association in 2016. In this study the researchers did postmortem evaluations on participants in the Memory and Aging Project that followed individuals from 2004 to 2013. Of the 554 deceased participants, 286 brain autopsies were included in the study. The mean age at death for those in the study was 89.9 years. Seafood intake was measured by regular questionnaires during the years prior to death. Various dementia-related abnormalities were assessed, including those associated with AD, Lewy body dementia, large strokes, and small strokes. Tissue concentrations of mercury were also measured. After adjusting for age, gender, education, and total nutritional energy intake, those who ate one or more meals of fish per week had significantly less Alzheimer pathology in their brains. They had lower amounts of amyloid plaques and neurofibrillary tangles (conglomerations of tau proteins). And this benefit was specifically for those with the ApoE4 gene. Those with the highest genetic risk of developing AD had less AD pathology in their brain if they ate fish one or more times per week! Interestingly, fish oil supplements showed no statistical benefit with any pathological marker. Those with high ALA (plant omega-3) intake had lower risk of having large strokes.
There was a positive correlation between the amount of fish consumed and the concentration of mercury in the body, which means the more fish consumed the higher the mercury in the body. However, the mercury levels were not associated with any brain pathology. In other words, while the mercury levels were higher in those consuming fish, the higher levels were not sufficient to negatively impact brain health.9 This is good news for those who would like to consume fish but who are fearful to do so because of concerns about mercury.
Even though in the study above the higher mercury levels in those who consumed the most fish were not associated with brain pathology, many people have legitimate concerns about eating fish. For cultural or religious reasons some are vegetarians; others are concerned simply because mercury is a known toxin and there is no way to be certain any given piece of fish is not contaminated with high levels of mercury. Therefore, some choose vegetarian sources for omega-3 fatty acids. For those who prefer a vegetarian source of the long-chain (EPA/DHA) omega-3 fatty acids, there are marine algae sources. In fact, algae are the source from which the fish get their omega-3 fatty acids. The question that has not been studied is whether there is benefit from ingesting the omega-3s directly from the ocean plant sources (algae).10 My own hypothesis is that if this is ever studied it will show benefit.
The evidence is clear, long-chain omega-3 fatty acids (EPA/DHA) have multiple health-promoting effects that reduce inflammation, protect the brain, and lower the risk of dementia. Some of the mechanisms by which the omega-3s provide these healthy benefits are by scavenging oxidizing molecules, improving neural membrane fluidity, and altering gene expression.11 Omega-3 fatty acids lower the gene expression of multiple pro-inflammatory genes, significantly reducing inflammation in the body.12 This may be one reason those with the ApoE4 gene showed benefit from regular fish consumption.
Omega-3s are also blood thinners. So individuals on blood thinners should consult with their doctor before consuming large amounts of these oils.
Recommendations: Ensure long-chain omega-3 fatty acids (EPA/DHA) are part of your diet. The strongest beneficial evidence is for regular fish consumption; however, for vegetarians I would recommend supplements from algae high in EPA/DHA.
Ginkgo Biloba
Ginkgo biloba (GB) is a popular supplement touted for its memory and cognitive benefits. It comes from the leaf of the Maidenhair tree and is marketed over the counter in various formulations. GB has three identified active compounds: ginkgolides, bilobalides, and flavonoids. Ginkgolides are believed to have anti-inflammatory effects and to help reduce blood clotting and improve blood flow. Bilobalides are thought to also reduce blood clotting, but in addition they reduce the activity of a neurotransmitter called glutamate. Glutamate is the brain’s primary excitatory neurotransmitter. This means that glutamate is the most common agent in the brain to activate neurons and promote signaling. In proper amounts this is essential for thinking, learning, and memory. However, when glutamate levels are too high in the neural junctions (synapses) it creates noise that impairs clear signaling, thus reducing communication and impairing learning and memory. It would be similar to a radio station broadcasting on a specific frequency. When one station broadcasts, the signal is clear and communication is effective. But if multiple stations broadcast on the same frequency, there are too many signals coming in at once and communication is impaired.
As we discussed in chapter 14, the brain is capable of changing its structure based on use. It can grow new neurons and pathways and delete unused ones. This means that in a controlled fashion the brain has a mechanism to cause cell death. Glutamate is involved in this process. It triggers calcium channels to open and, by flooding the inside of the neurons with calcium, causes the cell to die. Thus, excessive glutamate not only impairs signaling and learning but also can cause neuronal death. One of the potential benefits of GB, therefore, is to reduce the activity of glutamate.
Finally, the flavonoids function as antioxidants, scavenging free radicals and thus reducing oxidative damage to the brain.13
Overall, most studies show that GB does provide memory and cognitive benefit in those who already have memory and cognitive disorders such as AD. There is little evidence that GB provides any improvements in memory and cognition in those who are cognitively unimpaired.14
Does GB have protective effects and reduce the risk of developing AD? The data is mixed. A study of three thousand people over seventy-five years of age failed to show any protective effects of GB in preventing dementia.15 Another study evaluating the preventative effects of GB in people ages seventy-two to ninety-six with either normal cognition or mild cognitive problems over a six-year time period also found no reduction in risk of developing dementia from using GB.16 In a large twenty-year study GB did show that it prevented dementia. However, the study was poorly documented with no GB dosage or duration of treatment recorded.17
It is difficult to compare findings from random-controlled trials and epidemiological studies (surveys of the population) because the epidemiological studies do not control for confounding variables. Overall, the evidence currently supports the use of GB for those who already have memory and cognitive impairments, but not for use as a preventative measure. Further, there appears to be no memory or cognitive benefit for individuals who are cognitively unimpaired. GB should be used with caution in those at risk for bleeding as it can act as a blood thinner, but studies have found it can be used safely alone or in patients on aspirin.18
Recommendations: Do not use ginkgo biloba as a preventative agent. It may be used if an individual is already experiencing memory and cognitive deficits; gauge continued use by response and any side effects.
Vitamin D
Over the last couple of decades research on the benefits of vitamin D has significantly increased, and the role of vitamin D in brain health has become clear. It appears vitamin D has a therapeutic window. This means that low levels of vitamin D contribute to a variety of health problems and early death,19 but levels too high also contribute to health problems (such as bone fractures)20 and early death.21 Studies differ on what levels of vitamin D are optimal, but all agree that blood levels below 25 nmol/L (this is the concentration measured in the blood and how the lab will report it to your doctor) are unhealthy and confer greater risk of mental health problems and early death, and blood levels above 140 nmol/L are associated with early death. In addition to mortality risks, low vitamin D levels increase the risk of mental decline and dementia. In fact, those with vitamin D levels below 25 nmol/L had 2.22 times the risk of developing dementia as compared to those in the normal range.22 A study of 1,927 older adults followed for 4.4 years found the highest risk for cognitive decline in individuals with vitamin D levels below 50 nmol/L and mild decline in those with levels between 50–75 nmol/L. This means that levels below 75 nmol/L are associated with increased risk of loss of cognitive abilities.23 Therefore, according to these studies, an optimal level would be between 75–100 nmol/L.
The proposed mechanism by which vitamin D reduces the risk of dementia is by activating the macrophages, the trash cleaners of the body, to ingest and remove b-amyloid protein deposits from the brain.24 If you remember from the chapter on pathological aging, b-amyloid is a protein that normally helps remove oxidizing trace chemicals such as copper and iron from the brain, but in AD it becomes fibrillated and builds up in the brain and can then begin damaging brain cells. Thus, clearing it from the brain has significant potential benefit.
Recommendations: Have your vitamin D level checked by your physician and take supplements as needed to achieve a level between 75–100 nmol/L.
Curcumin (Tumeric)
Curcumin is a yellow spice commonly used in Indian foods and has a long history of use in Eastern traditional medicine. It is known to have anti-inflammatory and antioxidant benefits, which is consistent with most edible plants that contain color. More recent lab studies noted that curcumin binds to amyloid protein and prevents its fibrillating,25 which kept the amyloid in a soluble form and suggests it would reduce deposits in the brain. Animal studies confirmed that curcumin did reduce amyloid and tau deposits in the brain. In human studies on individuals already diagnosed with AD curcumin showed no benefit in memory or cognitive function.26 This is likely due to the fact that by the time someone is diagnosed with AD the brain is already severely compromised with billions of cells lost. If curcumin has a benefit it would be in the preventative phases to help remove the buildup of amyloid from the brain and potentially reduce the cascade of events leading to accelerated neuronal death.
Evidence that curcumin might provide preventative benefits includes its known anti-inflammatory properties and its ability to help clear amyloid and tau proteins from the brain.27 Additionally, it has been reported that people ages seventy to seventy-nine living in India have a 4.4–fold lower rate of AD than people living in America—suggestive, but not proof, that a diet rich in curcumin might confer benefit.28 Lab studies have revealed that curcumin can bind copper and iron; if this occurs in the brain it would further reduce the oxidative damage from these trace chemicals.29 Curcumin is a very powerful free-radical scavenger, which can reduce damage to the neuronal membranes.30 And there are a host of other beneficial effects upon the brain that may reduce the risk of AD.31 Very few outcome studies examining the clinical impact of curcumin on human populations have been done. One trial did show curcumin reduced both triglycerides and plasma b-amyloid levels.32
Curcumin has been shown to be well tolerated with little or no adverse effects. One problem with dietary curcumin is that very little is absorbed into the body; thus, taking supplements of curcumin would seem to provide little benefit. However, studies have documented that black pepper, which contains piperine, increases the absorption of curcumin by 2,000 percent.33
Recommendations: Use curcumin in a variety of dishes and be sure to add black pepper in all preparations.
Walnuts
Adults who eat walnuts regularly have significantly better cognitive ability than those who do not. In a cross-sectional study published in the Journal of Nutrition, Health and Aging, researchers examined the link between walnut consumption and cognitive abilities in areas such as memory, concentration, and processing speed. They examined two age groups, twenty-nine to fifty-nine and sixty and older. Researchers reported, “Significantly better outcomes were noted in all cognitive test scores among those with higher walnut consumption.”34
This is certainly an interesting and encouraging finding, but why would researchers even think to look for a relationship between walnut consumption and cognitive performance? Because in 2004 other researchers discovered that walnut extract prevented b-amyloid from fibrillating—remember fibrillation is when this protein folds on itself, clumps together, and cannot be removed and therefore builds up in the brain. These clumps of b-amyloid, if bound with trace chemicals (iron and copper) in the presence of methionine, become little engines of destruction, contributing to increased oxidation and the phosphorylation of tau, which destabilizes microtubules and contributes to the death of neurons.
So it would be beneficial to prevent the clumping of b-amyloid. But researchers found that the walnut extract did even more—it dissolved the amyloid clumps that had already formed! In other words, in this study the walnut extract not only prevented the clumps from forming but also defribillized the fibrils of amyloid already formed.35 This research has led to the hypothesis that walnut consumption will decrease amyloid deposits in the brain and thereby reduce neuronal loss and provide cognitive benefit—something that seems to have been demonstrated to be true in the cross-sectional study cited above.
Recommendation: Eat a handful of raw walnuts daily.
Green Tea
Do you drink green tea? Perhaps you should consider it. Green tea is rich in antioxidants and flavonoids and studies demonstrate that those who drink it regularly have improved memory and cognition—even in those who have already demonstrated impairments.36 One beneficial effect of green tea is that it reduces b-amyloid buildup in the brain.37 Other research has demonstrated that higher green tea consumption results in decreased prevalence of cognitive problems in older adults.38 What is interesting about green tea is that it appears to not only prevent cognitive and memory decline but also improve performance in those with no deficits.39
These various studies demonstrate that green tea appears to have several benefits: slowing decline, improving performance in those with deficits, and improving performance in those without deficits. This suggests that green tea may have multiple mechanisms of action that contribute to its benefits. And research has documented this to be true.
One action of green tea is its antioxidant action, reducing oxidative damage. Another is its ability to clear amyloid. Both of these actions would explain some of its ability to prevent cognitive decline and how it possibly could contribute to cognitive improvement in those already showing some deficits. But these actions don’t explain why green tea enhances cognition in cognitively intact individuals. This led researchers to examine the effect of green tea on brain function, and they found very amazing results.
Functional brain-imaging studies reveal that the ingestion of green tea enhances neural activity and signaling in the part of the brain with which we reason, think, problem solve, and have working memory.40 What is happening is that green tea appears to improve the communication pathways between the various brain regions, allowing the thinking circuits of the brain to have quicker and easier access to the various brain regions in which memories and experiences are stored.41 All this research led brain scientists to examine whether green tea could actually cause neuronal connections to improve efficiency of signaling between frontal and other brain regions, allowing for better cognition and memory. And according to the researchers: “Our findings provide first evidence for the putative beneficial effect of green tea on cognitive functioning, in particular, on working memory processing at the neural system level by suggesting changes in short-term plasticity of parieto-frontal brain connections.”42
Recommendation: Consume green tea on a regular basis.
Pomegranate Juice
Pomegranate juice contains higher concentrations of antioxidant polyphenols than most other juices. This led researchers to wonder if this juice may provide antioxidant protection to the brain and perhaps even prevent b-amyloid buildup in the brain. In order to investigate this hypothesis researchers used genetically modified mice. These mice were genetically engineered to have higher than normal amounts of b-amyloid deposits in their brains. The mice were randomized into two groups and both fed the same diet, except the experimental group received the human equivalent of eight ounces of pomegranate juice per day. Results showed that the mice who received the pomegranate juice not only learned faster and performed better on various tests but also had significantly less buildup of b-amyloid in the memory circuits of their brains.43
While this study was done on mice and has not been replicated in humans, it is consistent with epidemiological research in human populations done by researchers at Vanderbilt University. In a study examining the relationship between the consumption of fruit and vegetable juices and the development of AD, researchers found that those who consume three or more servings of juice per week were 76 percent less likely to develop AD as compared to those who ingested fewer than one serving per week. This protective benefit of drinking juice was even more pronounced in those who had the at-risk ApoE4 gene. Researchers believed these benefits were due to the polyphenol content in the juices and not the vitamins, such as vitamins C and E, contained in the juices, as no benefit was demonstrated from supplements of vitamins alone.44
The Vanderbilt researchers’ conclusion that the antioxidant benefit from the juices was due to polyphenols and not the vitamins was supported by later research that examined the antioxidant benefit of pomegranate juice versus apple juice in older adults. In this study twenty-six older adults were randomized into two groups and assigned to drink eight ounces of either apple juice (low antioxidant) or pomegranate juice (high antioxidant) for four weeks. The researchers measured blood antioxidant capacity and levels of antioxidant enzymes as well as levels of vitamins C and E and other molecules. Additionally, researchers examined DNA damage in white blood cells. Researchers found that the group drinking daily pomegranate juice demonstrated significantly improved antioxidant activity while those drinking apple juice did not. Plasma levels of vitamins C and E did not differ between the two groups, supporting the likelihood that the benefit from pomegranate juice was due to its high polyphenol levels.45
A more recent animal study examined the potential mechanism by which pomegranate juice may be neuroprotective. In this study researchers used mice genetically modified to deposit amyloid into their brains, which mirrors AD pathology. The mice were randomized into two groups with both having access to the same diet, but the experimental group had their water augmented with pomegranate juice. Both groups of mice were given standardized maze tests, which tested learning and memory. After three months of receiving pomegranate juice the experimental mice demonstrated significant improvements in navigating the maze as compared to their initial scores and their control-fed counterparts. Their brains had lower levels of inflammatory factors (tumor necrosis factor alpha [TNF]) and lower nuclear factor of activated T-cell (NFAT) transcriptional activity. This means their brains had fewer molecules that cause oxidative damage in the brain. Additionally, upon microscopic examination of the brains of the mice receiving pomegranate juice it was found that their brains had fewer clumps of white brain cells and b-amyloid. The researchers identified two polyphenol components of pomegranate juice, punicalagin and ellagic acid, that reduced the activity of NFAT and decreased the b-amyloid secretion of TNF. Researchers concluded: “These data indicate that dietary pomegranate produces brain anti-inflammatory effects that may attenuate AD progression.”46
Recommendation: Drink one eight-ounce glass of 100 percent pomegranate juice per day.
When I began this book I had certain biases—expectations that I assumed to be true due to my upbringing and previously held beliefs. I was raised not to drink coffee or other caffeinated drinks and taught that these drinks were unhealthy and should be avoided. Therefore, I was surprised to discover that caffeine functions much more like a medicine than the other substances discussed in this chapter, meaning that while it does have risks and side effects, it also has some significant benefits. We will discover that in certain individuals with known health problems caffeinated coffee intake can contribute to worsening health. In others, however, evidence demonstrates marked health advantages, including a significantly reduced risk of developing AD!
A large study published in the New England Journal of Medicine, which followed more than fifty thousand men and women for thirteen years, found that, after adjusting for other risk factors such as smoking, regular coffee consumption reduced all-cause mortality (risk of death). Specifically, those who regularly consumed coffee had reduced risk of dying from heart disease, respiratory disease, stroke, injuries and accidents, diabetes, and infections, but not cancer.47 In a different study researchers reviewed articles published between 1990 and 2012 that examined coffee consumption and health impact and found that regular coffee consumption is also associated with reduced risks of a variety of diseases, including diabetes, liver disease, and Parkinson’s disease.48
Some might wonder how a substance that can transiently increase blood pressure, as caffeine does, can reduce risk of death from cardiovascular disease (CVD) when high blood pressure is a known risk factor for CVD. The reason is likely because the increases in blood pressure from coffee are small and transient and therefore clinically insignificant, while at the same time coffee contains antioxidants that reduce low-density lipoprotein (LDL) cholesterol and prevent it from oxidizing and building up in arterial walls, as well as reducing other markers of inflammation.49 In fact, in one ten-year study moderate coffee consumption (one to four cups per day) showed reduced heart disease risk during the entire study period;50 other research revealed that coffee consumption reduces the risk of heart failure.51
The benefits of coffee consumption are not restricted to the heart. Stroke risk is also reduced by regular coffee consumption. A 2011 meta-analysis found that regular, moderate coffee consumption (one to six cups per day) reduced the risk of stroke by 17 percent.52 And a study of Swedish women who were followed for ten years found that regular coffee consumption reduced strokes by 22 to 25 percent.53
Regular coffee consumption also appears to reduce the risks of type 2 diabetes (T2DM), obesity, high cholesterol, and high blood pressure—what are commonly called metabolic syndrome. Numerous studies have demonstrated that regular coffee consumption improves glucose metabolism and insulin secretion and reduces T2DM.54 One reason for this may be coffee’s effect on b-amyloid.
It is known that in T2DM, b-amyloid (the same protein that builds up in the brain in AD) is known to misfold (fibrillate) and build up in the cell clusters (islet cells) in the pancreas that secrete insulin. This buildup is believed to be one factor that impairs glucose metabolism and contributes to T2DM. Coffee extracts have three identified active components: caffeine, caffeic acid (CA), and cholorogenic acid (CGA). CA and CGA have an active metabolite (a new molecule that is produced when they are metabolized) called dihydrocaffeic acid (DHCA). All these components have been shown to inhibit the misfolding of amyloid and thereby reduce its toxic buildup in the pancreas. CA showed the greatest potency and caffeine the least potency in preventing amyloid misfolding.55
While the New England Journal of Medicine study mentioned above did not find reduced mortality from cancers associated with coffee consumption, other studies have found reduced risk of developing multiple cancers in moderate coffee drinkers. Studies reveal reduced cancer risk for endometrial cancer for those who drank four cups per day,56 for prostate for those who drank six cups per day,57 for head and neck (four cups per day),58 for basal cell carcinoma (three cups per day),59 and for estrogen receptor-negative breast cancer (five cups per day).60 These benefits are thought to be at least partially due to the anti-inflammatory and antioxidant effects of coffee.61
As amazing as all these potential benefits of coffee are, the most important findings for this book are the effects upon the brain and the evidence that coffee not only enhances cognition and memory but also actually reduces the risk for AD. In a study published in the Journal of Alzheimer’s Disease researchers found that those who consumed moderate daily coffee (three to five cups per day) at midlife decreased their risk of dementia by 65 percent later in life.62 Additional research found that individuals who are already experiencing mild cognitive impairment but had high-plasma caffeine levels due to drinking three to five cups of coffee per day avoided progressing to dementia over the next two to four years.63
These benefits are likely due to the same anti-amyloid and anti-inflammatory benefits from coffee that provided benefit in reducing metabolic syndrome. In studies of mice genetically altered to mimic AD, the animals that received caffeine in their drinking water from young adulthood through older age showed protection from memory loss and had lower levels of b-amyloid in their brains than the mice without the caffeine. Not only that, but mice that were allowed to develop memory problems and amyloid deposits in their brains exhibited memory restoration and reduction of amyloid in their brains after one to two months of caffeine treatment. The researchers concluded the benefits were due to the caffeine itself, as animals that received caffeinated coffee demonstrated the benefit while the animals that received decaffeinated coffee did not. The benefits were achieved with the human equivalent of moderate coffee consumption (five cups per day).64
But it appears that it is not caffeine alone that provides the benefit. Other research suggests that the benefits to the brain result from a combination of the caffeine and other active compounds found in coffee. In this study of AD mice, researchers examined the effects of caffeinated versus noncaffeinated coffee on plasma cytokines (granulocyte-colony stimulating factor [GCSF], IL-10, IL-6), comparing the results to that of caffeine alone. In both the AD mice and the non-AD comparison mice researchers found treatment with caffeinated coffee greatly increased anti-inflammatory cytokines, whereas neither caffeine alone nor decaffeinated coffee demonstrated this positive effect. The increase in GCSF was thought to be particularly important because this compound among all those measured was most specifically associated with improved cognitive performance. The researchers concluded that “coffee may be the best source of caffeine to protect against AD because of a component in coffee that synergizes with caffeine to enhance plasma GCSF levels, resulting in multiple therapeutic actions against AD.”65
The idea that coffee may be the best source of caffeine to provide neuroprotective benefits is supported by other research that examined various caffeinated drinks and their impact on mental health. The National Institutes of Health–AARP Diet and Health study, which was a prospective study of over five hundred thousand people ages fifty to seventy-one followed over ten years, found differences between soft drinks, fruit drinks, and coffee and the rates of depression. Those who drank soft drinks and fruit drinks had increased risk of developing depression, while those who drank coffee had slightly lower risk. Additionally, when they evaluated sweeteners they found that artificial sweeteners increased the risk of depression whereas sugar and honey did not. As little as one soft drink per day increased the risk for depression, regardless of whether the soft drink was caffeinated or decaffeinated. Decaffeinated teas were associated with slight increased risk of depression; however, caffeinated teas were not. Hot caffeinated tea had no relationship with depression and caffeinated iced tea had a weak decreased association with depression.66
This association with depression is an important finding because one of the primary factors contributing to depression is inflammation, which is the same underlying problem driving AD.67 And research shows that a history of depression increases the risk for AD later in life.68
In addition, the neuroprotective benefits of coffee found to reduce risk of AD have also been associated with reducing the risk of Parkinson’s disease (PD). But in the case of PD, researchers have identified specific gene variants in people who are at risk for PD that coffee specifically interacts with to reduce the risk of PD. A gene that regulates brain signaling that controls movement (GRIN2A) has been found to have more than one form in humans. Researchers found that heavy coffee drinkers with one gene variant had an 18 percent lower risk for PD compared to light coffee drinkers, whereas heavy coffee drinkers with another variant of the same gene had a 59 percent lower risk for PD compared to light coffee drinkers. The researchers emphasized that drinking coffee reduced risk of PD only in those with the specific gene variants.69
So what does all this mean? Caffeinated coffee appears to have an overall health-promoting benefit due to a combination of caffeine and antioxidant compounds working together. These benefits include reducing oxidizing chemicals and preventing amyloid from misfolding and building up in both the brain and pancreas, thereby reducing risk of T2DM, CVD, obesity, and AD. Other caffeinated beverages, with the exception of tea, most likely increase risk of health-related problems, while tea is either neutral or has a very slight positive effect. Natural sweeteners such as sugar and honey in beverages were not associated with increased mental health risks, whereas artificial sweeteners did increase risks for mental health problems.
There are several cautions when it comes to caffeine consumption that must be taken into consideration. Caffeine decreases seizure threshold, which means it increases the likelihood of having a seizure; for those with known seizure disorder, drinking beverages with caffeine may undermine seizure control.70 In fact, caffeine is so good at increasing seizures that when doctors desire to lengthen seizures in patients receiving electroconvulsive therapy (ECT) for depression, they will give IV caffeine.71 Individuals with seizure disorders should be very cautious about consuming beverages with caffeine.
Additionally, for some individuals caffeine can delay sleep onset and reduce total hours of sleep. There is wide variation to the sleep response of caffeine from person to person. Some individuals may have marked sleep impairment from mild to moderate caffeine consumption. If so, those individuals should limit caffeine because, as we discussed in chapter 9, sleep is a physical requirement to life and health, and chronic sleep disturbance increases risk of dementia.
Finally, caffeine is also a vasoconstrictor and has been demonstrated to reduce blood flow to the brain, the retinas, and throughout the body.72 Therefore, health conditions with known circulatory compromise (CAD, macular degeneration, Raynaud’s, etc.) may be worsened by caffeine use.
Recommendations: Drink one to six cups of caffeinated coffee per day (as long as sleep remains at 7–8 hours per night, no known circulatory or seizure risk factors exist, and no other intolerable side effects manifest). If desired, use sugar or honey to sweeten and avoid artificial sweeteners and all soft drinks. I personally use maple syrup as a coffee sweetener as recent research has documented that maple syrup not only has anti-inflammatory benefits but also reduces the aggregation of both b-amyloid and tau proteins.73
Vitamins E and C
Vitamin E supplementation as a medical strategy has had a rocky history. Early studies demonstrated vitamin E had antioxidant properties and could inhibit the oxidation of bad cholesterol and its buildup in arteries (atherosclerosis).74 Some studies even showed that the higher the plasma vitamin E level, the lower the risk of dying of heart disease.75 Other studies also noted an association with higher vitamin E and reduced cardiovascular disease risk.76 Additionally, observational data also seemed to indicate that vitamin E supplementation reduced cancer risk.77 Because of these observations, randomized clinical trials were undertaken to specifically examine and measure the effect of vitamin E supplementation. However, these various studies demonstrated no reduction in cardiovascular disease, cancer, or mortality from vitamin E supplementation.78 Further, a meta-analysis of high-dose vitamin E supplementation found an increased risk of dying in those taking the supplemental vitamin E.79 So what is going on with vitamin E?
Vitamin E occurs in nature in eight different forms divided into two classes, tocopherols and tocotrienols. When one ingests vitamin E from food one receives all eight forms. However, many over-the-counter vitamin E supplements have not provided the same natural balance. This difference may account for the variation in benefit noted in the various studies. For instance, in studies examining those with high vitamin E from dietary sources investigators found reduced risk of vascular disease and risk of death.80 But in studies where supplements were used no health benefit was found.81
Animal studies support the benefit of dietary vitamin E on reducing the risk of AD. Vitamin E is a fatty vitamin, which means it will concentrate in the fatty tissues of the body. Within the brain this would be the lipid membranes of the neurons. Neuronal membrane health is critical to overall cellular health, as the membranes separate the internal machinery of the cells from outside forces. The membranes also act as gatekeepers regulating the flow of various molecules and compounds in and out of the cell and as filters keeping out potentially harmful substances. Vitamin E serves a critical role in this protective function. Vitamin E concentrating in the lipid membrane serves as a free-radical scavenger preventing these damaging molecules from entering the neurons and causing injury. Additionally, vitamin E in younger animals prevented the buildup of b-amyloid protein in the brain.82 Two prospective studies in human populations have shown that dietary vitamin E lowers AD risk.83 However, vitamin E supplements showed no benefit in reducing AD in human studies.84
Another factor in vitamin E’s effectiveness may be the relationship between vitamins E and C. While E is fatty and concentrates in the lipid membrane, vitamin C is water-soluble and concentrates in fluid inside the cells. Vitamin C is a powerful antioxidant and plays a direct role in scavenging free radicals and reducing oxidative stress, and vitamin C has a number of other functions acting as a coenzyme in many critical pathways.85 Additionally, vitamins E and C work together to protect the brain from oxidative damage. As free radicals try to enter the neuron, vitamin E in the lipid membrane works to scavenge and remove them; if free radicals make it past the lipid membrane, then vitamin C acts to inactivate it. But vitamin C also works to reactivate the antioxidant properties of vitamin E.86 Studies demonstrate that vitamin C provides health benefits from both dietary and supplemental sources.
Recommendations: Get vitamin E from food sources, not supplements (recommended foods with the highest-to-lowest concentration of vitamin E include sunflower seeds, almonds, spinach, safflower oil, pumpkin, red pepper, asparagus, collard greens, and peanut butter).
Vitamin C from food or supplements should be 500–1,000 mg per day.
N-Acetyl Cysteine
N-acetyl cysteine (NAC) is an antioxidant that has been used to treat acetaminophen overdose for over thirty years. Recently, NAC has been shown to play a significant role in promoting and maintaining the brain’s antioxidant defenses. One of the brain’s primary antioxidant agents is glutathione, which directly and indirectly neutralizes both reactive oxygen and nitrogen molecules. In this role glutathione maintains the oxidative balance within cells and is highly concentrated in the white cells of the brain, which provide protection and support to the neurons. NAC is a direct precursor to glutathione and thus supplemental NAC increases glutathione production. Further, NAC is a direct free-radical scavenger and adds its protective effects to glutathione, further reducing oxidative damage in the brain.87
In a study comparing connective tissue (fibroblasts) of AD patients to controls, researchers found that NAC and lipoic acid supplements exerted an antioxidant protective effect, reducing oxidative damage and markers of cell death. NAC not only increased glutathione but also stabilized mitochondria. Mitochondria are the organelles inside cells that produce energy. Under inflammatory conditions they can become unstable and release damaging free radicals. NAC stabilizes the mitochondria and thereby reduces the oxidative damage in patients with AD.88 Other research confirms the mitochondrial-stabilizing properties of NAC that reduce the production of oxidizing molecules and subsequently decrease programmed cell death.89 Finally, in animal models of AD, NAC has been shown to delay age-associated memory impairments.90
Recommendations: First check with your doctor, then take a daily supplement of NAC, 500–1,500 mg per day.
Vitamin B12, Folic Acid, and Homocysteine
It has been known for decades that vitamin B12 and folic acid (vitamin B9) are essential nutrients required for brain and body health. Deficiencies in these nutrients contribute to anemia91 and psychiatric and neurological disorders,92 including neural tube defects (spina bifida) in newborns.93 More recent research has demonstrated that these two vitamins also play a key role in cardiovascular health; deficiencies increase the risk of atherosclerosis, heart attacks, and strokes.94 It has been well documented that chronic, high alcohol consumption depletes these vitamins as well as thiamine (vitamin B1) and contributes to memory and language problems.95 Other research has implicated deficiencies in these two vitamins with increased risk of AD.96
Deficiencies in vitamin B12 and folic acid contribute to a wide range of health problems because they are utilized in numerous physiological activities and metabolic processes in our bodies. These vitamins are required as cofactors for the production of the building blocks of our DNA (purine and thymidine),97 production of neurotransmitters,98 maintenance of brain cell health, production of blood by the bone marrow, and cell reproduction. One additional role both B12 and folic acid play in our bodies is to neutralize, recycle, and/or remove an inflammatory by-product of metabolism—homocysteine.
One pathway by which vitamin B12 and folic acid deficiencies contribute to increased risk for atherosclerosis, cognitive decline, and increased risk of AD is by the subsequent high levels of homocysteine.99 Additionally, studies indicate that low levels of these essential B vitamins can accelerate brain volume loss. In a five-year study of 107 older adults (ages sixty-one to eighty-seven) living in the community (not in nursing homes), brain volume loss was greatest among those with the lowest B12 levels.100 This is particularly concerning because studies have found that vitamin B12 deficiency occurs in more than one in five older adults but is often unrecognized because the symptoms are so subtle. Causes for this include impaired absorption (>60 percent of all cases), pernicious anemia (15–20 percent of all cases), and diets deficient in B12.101 Recently, studies have found that older adults with anemia are at higher risk of developing dementia than older adults without anemia.102 The researchers could not determine the exact reason for this association between anemia and dementia, but possible factors include reduced oxygenation of the brain and overall increased oxidative stress, which affect both bone marrow and the brain, among other factors. Perhaps one other common link could be vitamin B deficiencies.
It is known that the low pH acidic environment of the stomach is necessary to activate the enzyme pepsinogen to become pepsin to release vitamin B12 from B12-containing foods so that it can be absorbed. This has led some to hypothesize that recent medicines to treat heartburn (proton pump inhibitors [PPIs], Nexium [esomeprazole], Protonix [pantoprazole], Prilosec [omeprazole], Prevacid [lanzoprazole], etc.) have become so effective in raising stomach pH that they might be contributing to B12 deficiencies. In fact, some short-term studies found that use of these acid-reducing medicines did reduce B12 absorption.103 However, multiple long-term studies have demonstrated that use of PPIs does not cause B12 deficiencies,104 with the possible exception of two special situations. These are, first, in persons with a specific disorder in which tumors grow in the gastrointestinal system (Zollinger-Ellison syndrome)105 and, second, in older adults who have reflux due to a stomach infection (H. Pylori) and develop chronic inflammation of the lining of the stomach (atrophic gastritis).106 In these two circumstances, PPI use has been shown to reduce B12 absorption.
An additional problem for our health is that multiple gene mutations exist within the genes that metabolize and utilize folic acid and B12. One of the most publicized is the MTHFR gene, which is involved in folic acid metabolism. It is well documented that persons with this gene defect cannot utilize folic acid properly and therefore have higher levels of the inflammatory by-product homocysteine.107 Various studies have found this gene defect in 50–60 percent of individuals suffering with either coronary artery disease or depression.108
The good news is that as complex as all this seems, the solution is very simple: regular supplements of vitamin B12 and folic acid. If there is a history of depression or heart disease in either yourself or your family, I would recommend talking with your physician about getting genetic testing to determine if you have the MTHFR gene defect. If you do, simply taking the methylated form of folic acid, which is available in various strengths either over the counter or as a prescription, resolves the risk caused by the gene defect. And studies show that supplemental B vitamins do reduce the risk of AD.109
Recommendation: Talk with your doctor to determine your risk of deficiency and which supplemental form would be best for you.
Rhodiola Rosea
Rhodiola rosea, commonly known as golden root or rose root, is a perennial flowering plant in the Crassulaceae family that grows naturally in the arctic regions of Europe, Asia, and North America. It has been used in folk medicine for centuries to promote physical endurance and long life. The roots have a high concentration of phytochemicals such as flavonoids, monoterpenes, triterpenes, and phenols, which are pharmacologically active antioxidants, anti-inflammatories, anticancer, cardioprotective, and beneficial in the treatment of depression,110 fatigue, and cognitive dysfunction.111 Its strong neuroprotective effects have been documented in multiple studies.112
Because of the plethora of health-promoting benefits believed to be associated with this herb, a double-blind, placebo-controlled study evaluating the impact of Rhodiola rosea in treating individuals suffering from stress-related fatigue was conducted. Males and females between twenty and fifty-five years of age with diagnosis of chronic fatigue syndrome were selected. They were randomized into two groups, and for twenty-eight days one received 576 mg per day of Rhodiola rosea extract and the other received a placebo. The participants were evaluated on multiple scales: quality of life (SF-36 questionnaire), symptoms of fatigue Pines’ burnout scale), depression (Montgomery-Asberg depression rating scale [MADRS]), attention (Conners’ computerized continuous performance test II [CPT II]), and saliva cortisol response to awakening.
While both groups showed improvement in quality of life, depression, and burnout, significant positive effects were noted in the active-treatment group in the burnout and attention measures. The researchers concluded that “repeated administration of R. rosea extract SHR-5 exerts an anti-fatigue effect that increases mental performance, particularly the ability to concentrate, and decreases cortisol response to awakening stress in burnout patients with fatigue syndrome.”113
More importantly for our study, Rhodiola rosea has demonstrated antiaging,114 neuroprotective, and cognitive-enhancing properties. The cognitive-enhancing properties, such as improved attention, speed in task completion, and reduction in error rate, were seen within two hours of ingestion.115 While the neuroprotective effects are likely related to the actions of the numerous phytochemicals, the cognitive improvement is most likely due to enhancement of neural-signaling chemicals such as dopamine and acetylcholine.116
Recommendation: Talk with your doctor about adding a daily morning dose of 150–600 mg of Rhodiola rosea.
Hormone Replacement Therapy
Over the last several decades there has been conflicting information regarding the potential benefit of hormone replacement therapy (HRT) for women. Initially, reports came out that HRT reduced heart disease risk in postmenopausal women. Later reports seemed to question the overall health benefits. One possible reason for this conflicting data may be the timing of when HRT is initiated. A recent report in the journal Neurology examining the results of a twenty-year follow-up study of over eight thousand Finnish women found that any estrogen replacement reduced the risk of AD; however, it did not reach statistical significance unless taken for ten years or more. For those who did take estrogen replacement for ten years or more, their risk of developing AD was significantly reduced by 40–50 percent.117 This outcome was consistent with another study conducted in one county in Utah. In the Cache County, Utah, study investigators found that if estrogen was started within five years of menopause and continued for ten years or more, HRT was associated with reduction in developing AD.118
The timing or “critical window” theory may be one reason for conflicting data in studies that found no improved outcomes with HRT when the initiation of HRT happened after the first five years after menopause. This idea of a critical window is supported by other research that has demonstrated cardiovascular benefits to HRT if started within the first five years after menopause.119
Recommendation: Take this research to your doctor and discuss the risk versus benefits to you of starting HRT.
LEARNING POINTS