[1] 9w Nutrition and the Brain -What Advice Should We Give?

[1] 151w The knowledge base of nutrition and the brain is steadily expanding. Much of the research is aimed at ways to protect the brain from damage. In adults, the major causes of brain damage are aging and dementia. The most prominent dementia, and the condition that grabs the most public attention, is Alzheimer's disease. The assumption in the field is that possibly some change in nutrition could protect the brain and prevent, delay, or minimize Alzheimer's damage. Presented here is a framework for understanding the implications of this research. There is a gap between publishing research results and change in public nutrition behavior. Several influencing elements intervene. These include regulatory agencies and all the organizations and people who advise the public, all with their own perspectives. In considering what advice to give, advisors may consider effectiveness, research model, persuasiveness, and risks, among other factors.Advice about nutrition and Alzheimer's today requires several caveats.

[1] 140w Many studies have shown an association of nutrition and the brain. (Bowman et al., 2012) A number of important studies are included in this issue. Unquestionably, the universe of new information is rapidly growing. What is the significance of all these new data? When contemplating new findings, it is useful to step back and look at the environment in which they will be used. The assumed model is that research results could lead to modification of nutritional intake which could protect the brain from damage, and therefore a change in public nutrition would be useful. One of the most prevalent conditions causing brain damage is dementia, and Alzheimer's disease is the most common dementia. That Alzheimer's disease could be reduced by nutritional modification is of great interest to the public and public health agencies, and has produced a large market.

[2] 134w While the end users of nutrition research would be the public, there are important modifiers before wide public impact might be achieved (Table 1). In a typical research project, a researcher designs a study, obtains support, performs the research, and publishes the findings, making them available to the public. There is a gap between the public's access to the research findings and any change in nutritional behavior. This gap sets the framework for understanding the implications of the research. Intermediaries in the gap include marketers of products, agencies that regulate health products, and those who directly advise individuals, such as clinicians and other health care providers, organizations, and media. This review discusses the perspectives of those in the gap between research results and change in public nutrition behavior, that is, marketers, agencies and advisers.

[3] 112w Nutrition is defined as "the science of food . . . in relation to health and disease." (National Agriculural Library, 1998). Food is not specifically defined by United States (US) agencies. In general, it is a substance that enters the stomach and provides energy and/or sustains normal metabolism. Minimum daily requirements of food categories (proteins, elements, and vitamins), now called Dietary Reference Intake amounts, have been established (Food and Nutrition Board, 2010). In the US, claims for health benefits from foods are regulated by the Food and Drug Administration (FDA) if the claim is for disease prevention or treatment, and otherwise by the Federal Trade Commission (FTC) (Food and Drug Administration, 2013).

[4] 122w Dietary supplements are considered to be food by the FDA (Government Printing Office, 2010). They contain "'dietary ingredients' like vitamins, minerals, herbs or other botanicals, amino acids, and enzymes." They are subject to food safety requirements, and cannot make claims to prevent or cure any disease. A product that is claimed to prevent or cure a disease is a "drug," and must show efficacy and be approved by the FDA in the US. Other claims that supplement marketers make, such as "May support brain health," might be allowed, but are subject to approval by the FDA, and must be based on acceptable scientific evidence. Further, advertising is subject to review by the FTC for misleading or exaggerated claims (Federal Trade Commission, 2013).

[5] 54w Medical foods are a relatively new category. Originally intended to refer to enteral (tube) feeding substances, medical foods must be administered under the direction of a licensed clinician, but do not need FDA approval. As with supplements, medical food vendors cannot claim disease prevention or treatment value, and the FTC can control advertising claims.

[6] 61w Dementia is a category of progressive degenerative brain disorders. The most commonly discussed dementia is Alzheimer's. The cause of Alzheimer's is unknown. Much is known about its changes in the brain, but there are competing hypotheses about the primary driving mechanism. At a recent international meeting to help formulate research, at least nine abnormalities were listed as possible primary etiologies (

[7] 128w Table 2) (National Institute of Neurological Disorders and Stroke, 2013). If any of these are primary (as opposed to being the result of another cause), then changes in nutrition would need to overcome the specific abnormality to be useful. To the public and most clinicians, Alzheimer's occurs when a set of clinical signs appear and other conditions are excluded, and this usually happens later in life. However, when a clinical diagnosis of Alzheimer's is made, it is now considered Stage 3 disease. Stage 2 disease is Mild Cognitive Impairment due to Alzheimer's. (Note that this is a special kind of Mild Cognitive Impairment, and can only be attributed to Alzheimer's by special tests not widely available. Definitions are not fully standardized.) Stage 1 Alzheimer's occurs years earlier, when

[8] 16w the disease process has started, but there are no or limited symptoms (Jack et al., 2011).

[9] 43w While the most prevalent dementia is commonly understood to be Alzheimer's, the role of vascular disease in Alzheimer's is so prominent that many consider the most prevalent dementia to be mixed dementia, with both amyloid plaques defining Alzheimer's and significant vascular disease injury.

[10] 34w No medication or medical intervention has been shown to prevent or modify the course of Alzheimer's. Some medications may improve symptoms. These are cholinesterase inhibitors (donepezil, galantamine, and rivastigmine), and an N-methyl-D-aspartate (NMDA) receptor

[11] 25w antagonist (memantine). Many specialists emphasize the value of behavioral therapy, in which caregivers are encouraged to modify their expectations as well as the patient's environment.

[12] 66w The public burden of Alzheimer's is immense. The cost of care now equals or is greater than the cost of care for heart disease or cancer (Hurd et al., 2013). A recent estimate of costs of care in the US for Alzheimer's patients was $159 billion to $215 billion a year (Assistant Secretary for Planning and Evaluation, 2013). The strongest risk factor for Alzheimer's is age.

[13] 47w One of three older people will die from or with dementia. Because deaths from other diseases such as certain cancers and heart disease have declined in the US, more people are surviving into the age range of higher Alzheimer's incidence, so the prevalence of Alzheimer's has increased.

[14] 24w As large population cohorts such as the "Baby Boomers" enter old age, the burden, both dollar cost and personal/family suffering, will continue to increase.

[15] 76w Good news is that the age specific incidence may be decreasing (Matthews et al., 2013;Rocca et al., 2011). This means that, while there may be more people in the high risk age pool and thus more cases overall, for any specific age, the rate of new cases may be lower. Since there is no known medical intervention to prevent Alzheimer's, the effect may be from improved environment or lifestyle. One speculated lifestyle improvement is better nutrition.

[16] 39w Over half of adult Americans take some sort of dietary supplement, spending over $20 billion annually, an amount increasing yearly (DaVanzo, 2009;Gahche, 2011). This market is understandable, as diseases like Alzheimer's are dreaded, and claims that certain foods and

[17] 46w The key concern of agencies and providers is whether or not a proposed change is effective. In this sense, effective has a special meaning. A change is effective only if the outcome is a meaningful benefit in a human population in "real life" circumstances (Gartlehner, 2006).

[18] 32w Benefit is net benefit, and must include consideration of costs. Costs include morbidity and mortality as well as economic cost. This is a simplified description of effectiveness. The subject can be complex.

[19] 60w For example, a controversial outcome is the surrogate benefit. If a nutritional intervention causes a surrogate benefit such as an improvement in a blood level or a positron emission tomography (PET) scan, is that a real benefit? Or must it also need to show a meaningful improvement in some function or symptom? As an illustration, a recent study examined the

[20] 116w A critical consideration in the path of a nutritional research finding to its implementation is, how persuasive is the argument for change? This is affected by societal value judgments and priorities, among other factors. An important part of persuasiveness is the concept of meaningful benefit. Even when an outcome is a beneficial functional benefit (shows effectiveness), it is not necessarily a clinically meaningful benefit. Small effect sizes may be statistically significant, but might not reflect a gain that is meaningful to the public. This determination is subjective, but can override statistically significant results, and represents an issue across healthcare research (Keefe et al., 2013). Another important factor in persuasiveness is the research model that was used.

[1] 98w If a modification in nutrition, either a specific diet or a supplement, can improve public health, and an agency is persuaded that the modification provides an overall public benefit, the agency could encourage the public to follow the modified diet, just as clinicians may encourage individuals. The Centers for Disease Control and Prevention (CDC), for instance, has found the Dietary Approaches to Stop Hypertension (DASH) diet effective to reduce cardiovascular risk, so the CDC recommends it to the public, stating, "To reduce your risk of heart disease and stroke-follow the DASH eating plan." (Centers for Disease Control, 2013).

[2] 122w However, in spite of the rapidly growing information flow about nutrition and the brain, so far no diet or dietary supplement has been proved to be effective to reduce the risk of Alzheimer's. The National Institutes of Health convened a group of experts in 2010. The panel reviewed available evidence and concluded, "Currently, no evidence of even moderate scientific quality exists to support the association of any modifiable factor (such as nutritional supplements, herbal preparations, dietary factors, prescription or nonprescription drugs, social or economic factors, medical conditions, toxins, or environmental exposures) with reduced risk for Alzheimer disease." (Daviglus et al., 2010). Consistent with this conclusion, no agency in the US recommends a diet or supplement to reduce the risk of Alzheimer's disease.

[3] 89w On the other hand, agencies do recommend a generally healthy diet. The National Institute on Aging (NIA) suggests that "a healthy eating pattern" could be either the DASH diet or the Dietary Guidelines for Americans from the Department of Agriculture (National Institute Yet the public sees research results that suggest dementia risk can be reduced, and with hopeful curiosity seeks advice from trusted sources. The rest of this discussion focuses on factors that may affect the perspective of those who must provide advice in the current environment of uncertainty.

[4] 28w The perspective of marketers is simple enough: is the product safe? And could it be profitable? The perspective of agencies is generally the same as health care providers.

[5] 164w 9 effects of antioxidant nutritional supplements on the brain (Galasko et al.,2012). Subjects received a combination of vitamin C, alpha-lipoic acid, and vitamin E as alpha-tocopherol. These antioxidants are often suggested as useful to prevent brain damage. Measures included cerebral spinal fluid analysis and brain function testing. The antioxidants did produce a reduction in oxidation products (a surrogate benefit). However, with respect to function, subjects receiving antioxidants had "accelerated decline in (brain function), a potential safety concern" (Galasko et al., 2012). While the surrogate benefit might have encouraged advice to take these antioxidants, the functional results suggested the supplements, instead of beneficial, might actually be harmful. Defining acceptable outcome measures vexes all aspects of Alzheimer's related research. One goal of the US National Alzheimer's Project is to "Develop standard outcome measures to enable data comparisons across studies. These include but are not limited to ecologically valid measures of real world function, quality of life, and physical and cognitive function." (National Institute of Aging, 2013b).

[6] 12w Many believe that reducing cardiovascular disease will reduce the risk of Alzheimer's.

[7] 87w Therefore it was of interest when in spring 2013, news sources announced that a new study showed high blood levels of plasma phospholipid omega-3 fatty acids seemed to protect against cardiovascular disease and death (Mozaffarian et al., 2013). The study was population-based in which subjects in the highest quintile of plasma phospholipid omega-3 fatty acid range were compared to those in the lowest quintile. The implication was that omega-3 fatty acids were protective, and the news encouraged advice to people to increase their omega-3 fatty acid intake.

[8] 13w Of course, the easiest way to do that is to take a supplement.

[9] 120w A few weeks later, a randomized controlled trial (RCT) showed that taking omega-3 fatty acid supplements did not protect against cardiovascular disease and death (Roncaglioni et al., 2013). As an RCT, the persuasive impact of this research is much stronger than a population study. Advice to take omega-3 fatty acid supplements to protect against cardiovascular disease now appears unwarranted. This is a recent example of the weakness of population observation studies, which cannot control for all variables. The lowest quintile subjects in the population study may have included more who were homeless or in grave poverty and not able to obtain balanced nutrition or health care. Observation studies are inherently less reliable than RCTs as a basis for making recommendations.

[10] 125w On the other hand, RCTs have issues of their own. External validity or generalization can be affected by subject inclusion/exclusion criteria, the outcome selected for study, and trial duration, for example. To achieve a representative sample, RCTs usually require cooperation of Good non-RCT research is valuable, then, even if it is not definitive in framing recommendations. Research can be seen as a spectrum. One can imagine a scale with case reports and convenience-sample observations on the left, and RCTs on the right. In between are animal studies, case control studies, and high grade population studies comparing high and low in the same population. The closer a study is to the right; the more persuasive the results are in making recommendations for changes in nutritional behavior.

[11] 24w Non-RCT studies can develop and test hypotheses, highlight opportunities, and provoke the need for RCTs. Additionally, observation studies can be useful for negative outcomes.

[12] 76w Failure to find benefit in a population observation study usually shuts off plans for a randomized study, saving time and effort. Observation studies sometimes are also the only way information can be found. A recent study showed that high levels of omega-3 fatty acids increased the risk of prostate cancer (Brasky et al., 2013). It would now be virtually impossible to initiate a randomized study of omega-3 fatty acid supplements in a general population of men.

[13] 93w It is often said about diet changes and nutritional supplements that even if they are not beneficial, at least they are not harmful. However, there can be a direct monetary cost to diet modification. Supplements can cost hundreds of dollars a month. Special diets and foods may be more expensive than routine foods; people adhering to the DASH diet may pay about 20% more for their food (Bertonie, 2013). Besides monetary loss, there may be lost opportunities. People following a special diet or taking supplements they believe will reduce their chance of dementia

[14] 18w 12 may be more complacent and not participate in exercise or other activity than could be more beneficial.

[15] 168w Also, there can be direct morbidity associated with a nutrition intervention. In one study, a group of men was divided into two groups and one group received a nutrition intervention, a low saturated fat diet; the other group was the control (Pearce and Dayton, 1971). Men in the low saturated fat group had fewer cardiovascular events, but more cancer. Looking at deaths, in the diet group, 31 of 174 deaths were due to cancer, while in the control group, only 17 of 178 deaths were from cancer (Pearce and Dayton, 1971). Hence, the diet intervention increased the risk of cancer. And as noted, recommendations to take omega-3 fatty acid supplements in the past increased the risk of prostate cancer in men who followed the recommendations. Another example: vitamin E had been recommended as a way to slow the progress of Alzheimer's disease (Sano et al., 1997). However, not only does vitamin E have no proven effectiveness, it increases the risk of cancer in men (Nicastro and Dunn, 2013).

[16] 105w A recent study of older Iowa women showed that taking any nutritional supplement was risky. This was especially true for iron: the overall increased mortality hazard ratio (HR) for iron takers was 10% higher than non-takers (HR 1.10 (1.03-1.17)). The longer the women took the supplement, the higher the HR, approaching 50% higher for some groups. The effect was doseresponsive-those taking more iron had higher risk. Lastly, even the popular and federallysupported advice to limit daily salt intake may be harmful, according to a review by the National Academies of Science (Institute of Medicine, 2013). and, the potential for harm, both economic and in morbidity.

[17] 176w So far, no nutritional intervention has been proved to be effective in reducing the risk or severity of Alzheimer's or any dementia. To be intellectually honest, recommendations to reduce the risk or severity of Alzheimer's by a specific diet or supplement must contain a disclaimer. It must be said that there is not sufficient evidence to claim effectiveness of the recommendation, and the recommendation may in fact lead to harm. On the other hand, it is warranted to recommend pursuing a generally healthy diet, and to provide direction to healthy diet options (Barnard, 2014). And encouragingly, a number of large RCT studies are underway to test the effectiveness of several nutrients, including coconut oil, blueberries, lipoic acid and omega-3 fatty acids (National Institute of Aging, 2013c). More findings will undoubtedly come as these RCTs are the natural follow-up of intermediate research on nutrition and the brain. For agencies, clinicians, and others who advise people, they may provide the confidence to make more firm recommendations, for or against, specific nutrition changes to reduce or control Alzheimer's disease.

[18] 76w M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D M A N U S C R I P T A C C E P T E D