Download Nutrition and the brain: what advice should we give?

Neurobiology of Aging 35 (2014) S79eS83
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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.
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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
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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
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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. 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.
Disclosure statement
The author declares no conflicts of interest or other disclosures.
References
Assistant Secretary for Planning and Evaluation, U.S. Department of Health and
Human Services. 2013. National Plan to Address Alzheimer’s Disease: 2013
Update. Available at: http://www.aspe.hhs.gov/daltcp/napa/NatlPlan2013.pdf.
Accessed June 1, 2014.
Barnard, N.D., 2014. Guidelines for the Prevention of Alzheimer’s Disease. Neurobiol.
Aging (this issue).
Bertonie, A.G., Whitt-Glover, M.C., 2013. DASH for cash? JAMA Intern. Med. 173,
1924e1925.
Bowman, G.L., Silbert, L.C., Howieson, D., Dodge, H.H., Traber, M.G., Frei, B.,
Quinn, J.F., 2012. Nutrient biomarker patterns, cognitive function, and MRI
measures of brain aging. Neurology 78, 241e249.
Brasky, T.M., Darke, A.K., Song, X., Tangen, C.M., Goodman, P.J., Thompson, I.M.,
Kristal, A.R., 2013. Plasma phospholipid fatty acids and prostate cancer risk in
the SELECT trial. J. Natl. Cancer Inst. 105, 1132e1141.
Carbone, I., Lazzarotto, T., Ianni, M., Porcellini, E., Forti, P., Masliah, E., Licastro, F.,
2013. Herpes virus in Alzheimer’s disease: relation to progression of the disease.
Neurobiol. Aging 35, 122e129.
Centers for Disease Control and Prevention (CDC). 2013. Most Americans Consume
Too Much Sodium. Available at: http://www.cdc.gov/bloodpressure/sodium.
htm. Accessed June 1, 2014.
Craft, S., Cholerton, B., Baker, L.D., 2013. Insulin and Alzheimer’s disease: untangling
the web. J. Alzheimers Dis. 33, S263eS275.
DaVanzo J.E., Heath S., El-Gamil, A., Dobson, A., 2009. The Economic Contribution
of the Dietary Supplement IndustrydAnalyses of the Economic Benefits to
the U.S. Economy. Available at: http://www.naturalproductsfoundation.org/
clientuploads/NPF%20-%20Economic%20Impact%20Study.pdf.
Daviglus, M.L., Bell, C.C., Berrettini, W., Bowen, P.E., Connolly Jr., E.S., Cox, N.J.,
Trevisan, M., 2010. National Institutes of Health State-of-the-Science Conference
statement: preventing Alzheimer’s disease and cognitive decline. Ann. Intern.
Med. 153, 176e181.
Dugger, B.N., Hidalgo, J.A., Chiarolanza, G., Mariner, M., Henry-Watson, J., Sue, L.I.,
Beach, T.G., 2013. The distribution of phosphorylated tau in spinal cords of
Alzheimer’s disease and non-demented individuals. J. Alzheimers Dis. 34,
529e536.
Federal Trade Commission (FTC), 2013. Dietary Supplements. Available at: http://
www.consumer.ftc.gov/articles/0261-dietary-supplements. Accessed August
16, 2013.
Food and Drug Administration (FDA). 2013. Claims That Can Be Made for Conventional Foods and Dietary Supplements. Available at: http://www.fda.gov/Food/
IngredientsPackagingLabeling/LabelingNutrition/ucm111447.htm.
Accessed
September 20, 2013.
Food and Nutrition Board, Institute of Medicine, National Academies, 2010.
Dietary Reference Intakes (DRIs). Estimated Average Requirements. Available at:
http://www.iom.edu/Activities/Nutrition/SummaryDRIs/w/media/Files/Activity
%20Files/Nutrition/DRIs/5_Summary%20Table%20Tables%201-4.pdf.
Accessed
16 August 2013.
Gahche J., Bailey R., Burt, V., Hughes, J., Yetley, E., Dwyer, J., Picciano, M.F., McDowell,
M., Sempos, C., 2011. Dietary supplement use among U.S. adults has increased
since NHANES III (1988e1994). NCHS Data Brief No. 61. Available at: http://
www.cdc.gov/nchs/data/databriefs/db61.htm. Accessed August 16, 2013.
Galasko, D.R., Peskind, E., Clark, C.M., Quinn, J.F., Ringman, J.M., Jicha, G.A., Aisen, P.,
2012. Antioxidants for Alzheimer disease: a randomized clinical trial with
cerebrospinal fluid biomarker measures. Arch. Neurol. 69, 836e841.
Gartlehner G., Hansen R.A., Nissman D, Lohr, K.N., Carey, T.S., 2006. Criteria for
distinguishing effectiveness from efficacy trials in systematic reviews. Technical
Review, No. 12. Available at: http://www.ncbi.nlm.nih.gov/books/NBK44024/.
Accessed August 16, 2013.
Government Printing Office, 2010. Food and Drugs. Chapter 9: Federal Food, Drug,
and Cosmetic Act. Subchapter II: Definitions (21 U.S.C. (ff)). United States Code.
J.K. Cooper / Neurobiology of Aging 35 (2014) S79eS83
Available at: http://www.gpo.gov/fdsys/pkg/USCODE-2010-title21/html/USCODE2010-title21-chap9-subchapII.htm. Accessed August 16, 2013.
Griffin, W.S., 2013. Neuroinflammatory cytokine signaling and Alzheimer’s disease.
N. Engl. J. Med. 368, 770e771.
Hartmann, T., 1999. Intracellular biology of Alzheimer’s disease amyloid beta
peptide. Eur. Arch. Psychiatry Clin. Neurosci. 249, 291e298.
Hurd, M.D., Martorell, P., Langa, K.M., 2013. Monetary costs of dementia in the
United States. N. Engl. J. Med. 369, 489e490.
Institute of Medicine, 2013. National Academy of Sciences. Sodium Intake in
Populations: Assessment of Evidence. Available at: http://www.nap.edu/
openbook.php?record_id¼18311.
Jack Jr., C.R., Albert, M.S., Knopman, D.S., McKhann, G.M., Sperling, R.A.,
Carrillo, M.C., Phelps, C.H., 2011. Introduction to the recommendations from the
National Institute on Aging-Alzheimer’s Association workgroups on diagnostic
guidelines for Alzheimer’s disease. Alzheimers Dement. 7, 257e262.
Keefe, R.S., Kraemer, H.C., Epstein, R.S., Frank, E., Haynes, G., Laughren, T.P.,
Leon, A.C., 2013. Defining a clinically meaningful effect for the design and
interpretation of randomized controlled trials. Innov. Clin. Neurosci. 10, 4Se19S.
Lo, R.Y., Jagust, W.J., 2012. Vascular burden and Alzheimer disease pathologic
progression. Neurology 79, 1349e1355.
Matthews, F.E., Arthur, A., Barnes, L.E., Bond, J., Jagger, C., Robinson, L., Brayne, C.,
2013. A two-decade comparison of prevalence of dementia in individuals aged
65 years and older from three geographical areas of England: results of the
Cognitive Function and Ageing Study I and II. Lancet.
Mozaffarian, D., Lemaitre, R.N., King, I.B., Song, X., Huang, H., Sacks, F.M.,
Siscovick, D.S., 2013. Plasma phospholipid long-chain omega-3 fatty acids and
total and cause-specific mortality in older adults: a cohort study. Ann. Intern.
Med. 158, 515e525.
National Agricultural Library, 1998. Joint Collection Development Policy: Human
Nutrition and Food. Available at: http://www.nlm.nih.gov/pubs/cd_hum.nut.
html. Accessed August 16, 2013.
S83
National Institute of Neurological Disorders and Stroke, 2013. Alzheimer’s DiseaseRelated Dementias: Research Challenges and Opportunities. Available at: http://
videocast.nih.gov/summary.asp?live¼12655. Accessed August 16, 2013.
National Institute on Aging, 2013a. Search for Clinical Trials. Available at: http://
http://www.nia.nih.gov/alzheimers/clinical-trials/results.
National Institute on Aging, 2013b. Alzheimer’s Disease Research Summit Offers
Research Recommendations May 15, 2013. Available at: http://www.nia.nih.
gov/newsroom/announcements/2012/05/alzheimers-disease-research-summitoffers-research-recommendations. Accessed August 16, 2013.
National Institute on Aging, 2013c. Plans for Healthy Eating. Available at: http://
www.nia.nih.gov/health/publication/whats-your-plate/plans-healthy-eating.
Nicastro, H.L., Dunn, B.K., 2013. Selenium and prostate cancer prevention: insights
from the selenium and vitamin E cancer prevention trial (SELECT). Nutrients 5,
1122e1148.
Pearce, M.L., Dayton, S., 1971. Incidence of cancer in men on a diet high in polyunsaturated fat. Lancet 1, 464e467.
Rocca, W.A., Petersen, R.C., Knopman, D.S., Hebert, L.E., Evans, D.A., Hall, K.S., White, L.R.,
2011. Trends in the incidence and prevalence of Alzheimer’s disease, dementia,
and cognitive impairment in the United States. Alzheimer’s Dement. 7, 80e93.
Roncaglioni, M.C., Tombesi, M., Avanzini, F., Barlera, S., Caimi, V., Longoni, P.,
Marchioli, R., 2013. n-3 fatty acids in patients with multiple cardiovascular risk
factors. N. Engl. J. Med. 368, 1800e1808.
Sano, M., Ernesto, C., Thomas, R.G., Klauber, M.R., Schafer, K., Grundman, M.,
Thal, L.J., 1997. A controlled trial of selegiline, alpha-tocopherol, or both as
treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study.
N. Engl. J. Med. 336, 1216e1222.
Wildsmith, K.R., Holley, M., Savage, J.C., Skerrett, R., Landreth, G.E., 2013. Evidence
for impaired amyloid beta clearance in Alzheimer’s disease. Alzheimers Res.
Ther. 5, 33.
Zlokovic, B.V., 2011. Neurovascular pathways to neurodegeneration in Alzheimer’s
disease and other disorders. Nat. Rev. Neurosci. 12, 723e738.