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Neurobiology of Aging 35 (2014) S79eS83 Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging Review Nutrition and the brain: what advice should we give? James K. Cooper* Department of Medicine/Geriatrics and Palliative Care, George Washington University Medical Center, Washington, DC, USA a r t i c l e i n f o a b s t r a c t Article history: Received 4 November 2013 Accepted 27 February 2014 Available online 15 May 2014 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 disease 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 disease today requires several caveats. Ó 2014 Elsevier Inc. Open access under CC BY-NC-ND license. Keywords: Brain Dementia Alzheimer’s disease Nutrition Regulatory agencies 1. Introduction 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 that could protect the brain from damage; 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. Although 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 * Corresponding author at: Department of Medicine/Geriatrics and Palliative Care, George Washington University Medical Center, 2150 Pennsylvania Ave. NW, Washington, DC 20037, USA. Tel.: þ1 202 741 2191; fax: þ1 202 741 2791. E-mail address: [email protected]. 0197-4580 Ó 2014 Elsevier Inc. Open access under CC BY-NC-ND license. http://dx.doi.org/10.1016/j.neurobiolaging.2014.02.029 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. 2. Definitions and background “Nutrition” is defined as “the science of food ... in relation to health and disease” (National Agricultural Library, 1998). “Food” is not specifically defined by US agencies. In general, it is a substance that enters the stomach, 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 United States, 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) (FDA, 2013). “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 United States. 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. S80 J.K. Cooper / Neurobiology of Aging 35 (2014) S79eS83 Table 1 Typical trail from researcher to change in public nutrition behavior Researcher Sponsor Researcher Public platform Vendor (sometimes) FDA FTC Advisory groups Personal advisors Insurers Public Initiates and develops project Fund researcher Performs research, preliminary, intermediary, or randomized trial Displays results in journal, Web site, and conference Markets product Monitors if claims are made for disease prevention or treatment Monitors claims if they are not under jurisdiction of FDA and have interstate commerce implications Some independent, some commercially funded, they make and state positions. They include the Centers for Disease Control and the US Department of Agriculture Clinicians, journalists, other media, either push recommendations or are pulled to do so. Recommendations can be negative Decide if the change is covered Accepts or ignores recommendations and changes behavior or not Key: FDA, Food and Drug Administration; FTC, Federal Trade Commission. Furthermore, advertising is subject to review by the FTC for misleading or exaggerated claims (FTC, 2013). “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. “Dementia” is a category of progressive degenerative brain disorders. The most commonly discussed dementia is Alzheimer’s disease. The cause of Alzheimer’s disease 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 9 abnormalities were listed as possible primary etiologies (Table 2) (National Institute of Neurological Disorders and Stroke, 2013). If any of these is 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 disease 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 disease is made, it is now considered Stage 3 disease. Stage 2 disease is mild cognitive impairment because of Alzheimer’s disease. (Note that this is a special kind of mild cognitive impairment and can only be attributed to Alzheimer’s disease by special tests not widely available. Definitions are not fully standardized.) Stage 1 Alzheimer’s disease occurs years earlier, when the disease process has started, but there are no or limited symptoms (Jack et al., 2011). Although the most prevalent dementia is commonly understood to be Alzheimer’s disease, the role of vascular disease in Alzheimer’s disease is so prominent that many consider the most prevalent dementia to be “mixed dementia,” with both amyloid plaques defining Alzheimer’s disease and significant vascular disease injury. No medication or medical intervention has been shown to prevent or modify the course of Alzheimer’s disease. Some medications may improve symptoms. These are cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) and an N-methyl-Daspartate receptor antagonist (memantine). Many specialists emphasize the value of behavioral therapy, in which caregivers are encouraged to modify their expectations and the patient’s environment. 3. Public impact The public burden of Alzheimer’s disease 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 cost of care in the US for Alzheimer’s patients was $159e$215 billion a year (Assistant Secretary for Planning and Evaluation, 2013). The strongest risk factor for Alzheimer’s disease is age. One of 3 older people will die from or with dementia. Because deaths from other diseases such as certain cancers and heart disease have declined in the United States, more people are surviving into the age range of higher Alzheimer’s disease incidence; so, the prevalence of Alzheimer’s disease has increased. 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. Good news is that the age-specific incidence may be decreasing (Matthews et al., 2013; Rocca et al., 2011). This means that, although 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. Because there is no known medical intervention to prevent Alzheimer’s disease, the effect may be from improved environment or lifestyle. One speculated lifestyle improvement is better nutrition. 4. Public demand Over half of adult Americans take some sort of dietary supplement, spending more than $20 billion annually, an amount increasing yearly (DaVanzo et al., 2009; Gahche et al., 2011). This market is understandable, as diseases like Alzheimer’s are dreaded, and claims that certain foods and supplements may reduce the risk are strongly appealing. A challenge for providers and other advisors is deciding what to tell individuals about their nutrition and the brain. 5. Advice from national agencies 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 strokedfollow the DASH eating plan” (CDC, 2013). Table 2 Possible primary etiologic mechanisms for Alzheimer’s diseasea Imbalance in brain beta-amyloid production vs. destruction (Wildsmith et al., 2013) Toxic fragments of beta-amyloid precursor protein (Hartmann, 1999) Abnormal phosphorylation of tau (Dugger et al., 2013) Inflammation/oxidation (Griffin, 2013) Insulin resistance (Craft et al., 2013) Infection (herpes, cytomegalovirus, others) (Carbone et al., 2013) Vascular disease: poor blood perfusion (Zlokovic, 2011) Vascular disease: strokes, silent strokes, and accumulation of ischemic damage (Lo and Jagust, 2012) Vascular disease: endovascular malfunction in blood brain barrier (Zlokovic, 2011) a Nine possible primary etiologies for Alzheimer’s disease as discussed at a national meeting to focus research funding (National Institute of Neurological Disorders and Stroke, 2013). Deficiency of acetylcholine, a brain neurochemical, is often cited as etiologic for Alzheimer’s disease but must be secondary to some underlying causation. J.K. Cooper / Neurobiology of Aging 35 (2014) S79eS83 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 disease. The National Institutes of Health convened a group of experts in 2010. The panel reviewed available evidence and concluded that “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 United States recommends a diet or supplement to reduce the risk of Alzheimer’s disease. On the other hand, agencies do recommend generally a healthy diet. The National Institute on Aging 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 on Aging, 2013a). Whereas agencies and organizations such as the Alzheimer’s Association often recommend a healthy diet, none recommend a specific diet or specific food or supplement to prevent Alzheimer’s disease. 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. 6. Perspectives of groups in the gap The perspective of marketers is simple enough: is the product safe? Could it be profitable? The perspective of agencies is generally the same as health-care providers. 6.1. Effectiveness The key concern of agencies and providers is whether 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 et al., 2006). “Benefit” is net benefit and must include consideration of costs. “Costs” include morbidity, mortality, and economic cost. This is a simplified description of effectiveness. The subject can be complex. 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 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 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 alphatocopherol. 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). Although the surrogate benefit might have encouraged advice to take these antioxidants, the functional results suggested that the supplements, instead of beneficial, might actually be harmful. Defining acceptable outcome measures vexes all aspects of Alzheimer-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 S81 of life, and physical and cognitive function” (National Institute on Aging, 2013b). 6.2. Persuasiveness 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 health-care research (Keefe et al., 2013). Another important factor in persuasiveness is the research model that was used. 7. Nutrition research models: strengths and weaknesses Many believe that reducing cardiovascular disease will reduce the risk of Alzheimer’s disease. Therefore, it was of interest when in spring 2013, news sources announced that a new study that 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 with 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. Of course, the easiest way to do that is to take a supplement. 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. 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 multiple sites and can be very expensive. The logistics for an RCT to intervene in Stage 1 Alzheimer’s disease, years before clinical signs appear, could be overwhelming. 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, case-control, 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. 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. 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 S82 J.K. Cooper / Neurobiology of Aging 35 (2014) S79eS83 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. 8. At least it is not harmful 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 e 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 may be more complacent and not participate in exercise or other activity than could be more beneficial. Also, there can be direct morbidity associated with a nutrition intervention. In one study, a group of men were divided into 2 groups: one group received a nutrition intervention, a low saturated fat diet, and 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 because of cancer, whereas 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. 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 is that vitamin E had been recommended as a way to slow the progress of Alzheimer’s disease (Sano et al., 1997). However, vitamin E not only has no proven effectiveness but also increases the risk of cancer in men (Nicastro and Dunn, 2013). 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 [1.03e1.17]). The longer the women took the supplement, the higher the HR, approaching 50% higher for some groups. The effect was dose responsivedthose taking more iron had higher risk. Last, even the popular and federally supported advice to limit daily salt intake may be harmful, according to a review by the National Academies of Science (Institute of Medicine, 2013). 9. Advice to give today In summary, the products of nutrition research often lead to suggestions to change diets or consume supplements to achieve preventive or disease mitigating benefits for the public. No national agency in the United States recommends a specific change to prevent or modify Alzheimer’s disease. Before recommending such a change, agencies and clinicians consider the following critical aspects of the research: the effectiveness of the change, with the special meaning of effectiveness; the research model used; the outcome that would be modified and the degree of relevance if it is a surrogate outcome; if the estimated outcome effect is clinically meaningful; and the potential for harm, both economic and in morbidity. So far, no nutritional intervention has been proved to be effective in reducing the risk or severity of Alzheimer’s disease or any dementia. To be intellectually honest, recommendations to reduce the risk or severity of Alzheimer’s disease by a specific diet or supplement must contain a disclaimer. It must be said that there is no 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 on Aging, 2013c). More findings will undoubtedly come as these RCTs are the natural follow-up of intermediate research on nutrition and the brain. 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