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MacLean CH, Issa AM, Newberry SJ, et al. Effects of Omega-3 Fatty Acids on Cognitive Function with Aging, Dementia, and Neurological Diseases. Rockville (MD): Agency for Healthcare Research and Quality (US); 2005 Feb. (Evidence Reports/Technology Assessments, No. 114.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Effects of Omega-3 Fatty Acids on Cognitive Function with Aging, Dementia, and Neurological Diseases.

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1Introduction

This report is one of a group of evidence reports prepared by three Agency for Healthcare Research and Quality (AHRQ)-funded Evidence-Based Practice Centers (EPCs) on the role of omega-3 fatty acids (both from food sources and from dietary supplements) in the prevention or treatment of a variety of diseases. These reports were requested by the National Institutes of Health Office of Dietary Supplements and several institutes at the National Institutes of Health (NIH). The three EPCs - the Southern California EPC (SCEPC, based at RAND), the Tufts-New England Medical Center (NEMC) EPC, and the University of Ottawa EPC - have each produced evidence reports. To ensure consistency of approach, the three EPCs collaborated on selected methodological elements, including literature search strategies, rating of evidence, and data table design.

The aim of these reports is to summarize the current evidence on the effects of omega-3 fatty acids on prevention and treatment of cardiovascular diseases, cancer, child and maternal health, eye health, gastrointestinal/renal diseases, asthma, immune-mediated diseases, tissue/organ transplantation, mental health, and neurological diseases and conditions. In addition to informing the research community and the public on the effects of omega-3 fatty acids on various health conditions, it is anticipated that the findings of the reports will also be used to help define the agenda for future research.

This report focuses on the effects of omega-3 fatty acids on cognitive function with aging, dementia, and neurological diseases. Other reports from the SCEPC focus on cancer and immune-mediated diseases, bone metabolism, and gastrointestinal/renal diseases.

This chapter provides a brief review of the current state of knowledge about the metabolism, physiological functions, and sources of omega-3 fatty acids.

The Recognition of Essential Fatty Acids

Dietary fat has long been recognized as an important source of energy for mammals, but in the late 1920s, researchers demonstrated the dietary requirement for particular fatty acids, which came to be called essential fatty acids. It was not until the advent of intravenous feeding, however, that the importance of essential fatty acids was widely accepted: Clinical signs of essential fatty acid deficiency are generally observed only in patients on total parenteral nutrition who received mixtures devoid of essential fatty acids or in those with malabsorption syndromes. These signs include dermatitis and changes in visual and neural function. Over the past 40 years, an increasing number of physiological functions, such as immunomodulation, have been attributed to the essential fatty acids and their metabolites, and this area of research remains quite active.1, 2

Fatty Acid Nomenclature

The fat found in foods consists largely of a heterogeneous mixture of triacylglycerols (triglycerides)--glycerol molecules that are each combined with three fatty acids. The fatty acids can be divided into two categories, based on chemical properties: saturated fatty acids, which are usually solid at room temperature, and unsaturated fatty acids, which are liquid at room temperature. The term “saturation” refers to a chemical structure in which each carbon atom in the fatty acyl chain is bound to (saturated with) four other atoms, these carbons are linked by single bonds, and no other atoms or molecules can attach; unsaturated fatty acids contain at least one pair of carbon atoms linked by a double bond, which allows the attachment of additional atoms to those carbons (resulting in saturation). Despite their differences in structure, all fats contain approximately the same amount of energy (37 kilojoules/gram, or 9 kilocalories/gram).

The class of unsaturated fatty acids can be further divided into monounsaturated and polyunsaturated fatty acids. Monounsaturated fatty acids (the primary constituents of olive and canola oils) contain only one double bond. Polyunsaturated fatty acids (PUFAs) (the primary constituents of corn, sunflower, flax seed, and many other vegetable oils) contain more than one double bond. Fatty acids are often referred to using the number of carbon atoms in the acyl chain, followed by a colon, followed by the number of double bonds in the chain (e.g., 18:1 refers to the 18-carbon monounsaturated fatty acid, oleic acid; 18:3 refers to any 18-carbon PUFA with three double bonds).

PUFAs are further categorized on the basis of the location of their double bonds. An omega or n notation indicates the number of carbon atoms from the methyl end of the acyl chain to the first double bond. Thus, for example, in the omega-3 (n-3) family of PUFAs, the first double bond is 3 carbons from the methyl end of the molecule. The trivial names, chemical names and abbreviations for the omega-3 fatty acids are detailed in Table 1.1.

Table 1.1 Nomenclature of omega-3 fatty acids.

Table

Table 1.1 Nomenclature of omega-3 fatty acids.

Finally, PUFAs can be categorized according to their chain length. The 18-carbon n-3 and n-6 shorter-chain PUFAs are precursors to the longer 20- and 22-carbon PUFAs, called very-long-chain PUFAs (VLCPUFAs).

Fatty Acid Metabolism

Mammalian cells can introduce double bonds into all positions on the fatty acid chain except the n-3 and n-6 position. Thus, the shorter-chain alpha-linolenic acid (ALA, chemical abbreviation: 18:3n-3) and linoleic acid (LA, chemical abbreviation: 18:2n-6) are essential fatty acids. No other fatty acids found in food are considered ‘essential’ for humans, because they can all be synthesized from the shorter chain fatty acids.

Following ingestion, ALA and LA can be converted in the liver to the long chain, more-unsaturated n-3 and n-6 VLCPUFAs by a complex set of synthetic pathways that share several enzymes (Figure 1.1). VLC PUFAs retain the original sites of desaturation (including n-3 or n-6).

Figure 1. Classical Omega-3 and Omega-6 Fatty acid synthesis pathways and the role of omega-3 fatty acid in regulating health/disease markers.

Figure

Figure 1. Classical Omega-3 and Omega-6 Fatty acid synthesis pathways and the role of omega-3 fatty acid in regulating health/disease markers.

The omega-6 fatty acid LA is converted to gamma-linolenic acid (GLA, 18:3n-6), an omega-6 fatty acid that is a positional isomer of ALA. GLA, in turn, can be converted to the longer-chain omega-6 fatty acid, arachidonic acid (AA, 20:4n-6). AA is the precursor for certain classes of an important family of hormone-like substances called the eicosanoids (see below).

The omega-3 fatty acid ALA (18:3n-3) can be converted to the long-chain omega-3 fatty acid, eicosapentaenoic acid (EPA; 20:5n-3). EPA can be elongated to docosapentaenoic acid (DPA 22:5n-3), which is further elongated, desaturated, and beta-oxidized to produce docosahexaenoic acid (DHA; 22:6n-3). EPA and DHA are also precursors of several classes of eicosanoids and docosanoids, respectively, are known to play several other critical roles, some of which are discussed further below.

The conversion from parent fatty acids into the VLC PUFAs - EPA, DHA, and AA - appears to occur slowly in humans. In addition, the regulation of conversion is not well understood, although it is known that ALA and LA compete for entry into the metabolic pathways.

Physiological Functions of EPA and AA

As stated earlier, fatty acids play a variety of physiological roles. The specific biological functions of a fatty acid are determined by the number and position of double bonds and the length of the acyl chain.

Both EPA (20:5n-3) and AA (20:4n-6) are precursors for the formation of a family of hormone-like agents called eicosanoids. Eicosanoids are rudimentary hormones or regulatory molecules that appear to occur in most forms of life. However, unlike endocrine hormones, which travel in the blood stream to exert their effects at distant sites, the eicosanoids are autocrine or paracrine factors, which exert their effects locally - in the cells that synthesize them or adjacent cells. Processes affected include the movement of calcium and other substances into and out of cells, relaxation and contraction of muscles, inhibition and promotion of clotting, regulation of secretions including digestive juices and hormones, and control of fertility, cell division, and growth.3

The eicosanoid family includes subgroups of substances known as prostaglandins, leukotrienes, and thromboxanes, among others. As shown in Figure 1.1, the long-chain omega-6 fatty acid, AA (20:4n-6), is the precursor of a group of eicosanoids that include series-2 prostaglandins and series-4 leukotrienes. The omega-3 fatty acid, EPA (20:5n-3), is the precursor to a group of eicosanoids that includes series-3 prostaglandins and series-5 leukotrienes. The AA-derived series-2 prostaglandins and series-4 leukotrienes are often synthesized in response to some emergency such as injury or stress, whereas the EPA-derived series-3 prostaglandins and series-5 leukotrienes appear to modulate the effects of the series-2 prostaglandins and series-4 leukotrienes (usually on the same target cells). More specifically, the series-3 prostaglandins are formed at a slower rate and work to attenuate the effects of excessive levels of series-2 prostaglandins. Thus, adequate production of the series-3 prostaglandins seems to protect against heart attack and stroke as well as certain inflammatory diseases like arthritis, lupus, and asthma.3

EPA (0522:6 n-3) also affects lipoprotein metabolism and decreases the production of substances - including cytokines, interleukin 1β (IL-1β), and tumor necrosis factor α (TNF-α) - that have pro-inflammatory effects (such as stimulation of collagenase synthesis and the expression of adhesion molecules necessary for leukocyte extravasation [movement from the circulatory system into tissues]).2 DPA (22:5n-3), the elongation product of EPA, is metabolized to DHA (22:6n-3). DHA (22:6n-3) is the precursor to a newly-described metabolite called 10,17S-docosatriene,4 which is part of a family of compounds called ‘resolvins.’5 They are in the brain in response to an ischemic insult and counteract the pro-inflammatory actions of infiltrating leukocytes by blocking interleukin 1-beta-induced NF-kappaB activation and cyclooxygenase-2 expression.6 DHA also plays a role in retinal rod outer segments by influencing membrane fluidity so as to optimize G protein coupled signaling.7 The mechanism responsible for the suppression of cytokine production by omega-3 LC PUFAs and VLCPUFAs remains unknown, although suppression of omega-6-derived eicosanoid production by omega-3 fatty acids may be involved, because the omega-3 and omega-6 fatty acids compete for common enzymes in the fatty acid metabolic pathway, including delta-6 desaturase, as well as the rate-limiting enzymes in the eicosanoid pathway - phospholipases A2, cyclooxygenase, and lipoxygenase.

DPA (22:5n-3) (the elongation product of EPA) and its metabolite DHA (22:6n-3) are frequently referred to as very long chain n-3 fatty acids (VLCFA). Along with AA, DHA is the major PUFA found in the brain and is thought to be important for brain development and function. Recent research has focused on this role and the effect of supplementing infant formula with DHA (since DHA is naturally present in human breast milk but not in formula).

Dietary Sources and Requirements

Both ALA and LA are present in a variety of foods. LA is present in high concentrations in many commonly used oils, including safflower, sunflower, soy, and corn oil. ALA is present in some commonly used oils, including canola and soybean oil, and in some leafy green vegetables. Thus, the major dietary sources of ALA and LA are PUFA-rich vegetable oils. The proportion of LA to ALA as well as the proportion of those PUFAs to others varies considerably by the type of oil. With the exception of flaxseed, canola, and soybean oil, the ratio of LA to ALA in vegetable oils is at least 10 to 1. The ratios of LA to ALA for flaxseed, canola, and soy are approximately 1: 3.5, 2:1, and 8:1, respectively; however, flaxseed oil is not typically consumed in the North American diet. It is estimated that on average in the U.S., LA accounts for 89 percent of the total PUFAs consumed, and ALA accounts for 9 percent. Another estimate suggests that Americans consume 10 times more omega-6 than omega-3 fatty acids.8 Table 1.2 shows the proportion of omega-3 fatty acids for a number of foods.

Table 1.2 Sources and proportions of omega-3 fatty acids in common foods and supplements.

Table

Table 1.2 Sources and proportions of omega-3 fatty acids in common foods and supplements.

Several lines of research have suggested that the high ratio of omega 6s to low levels of omega-3 fatty acids currently consumed in the U.S. promotes a number of chronic diseases. Whether or not the relatively high intake of omega-6 fatty acids independently contributes to this problem8 is currently uncertain. Because of the slow rate of elongation and further desaturation of the essential FA, the importance of VLC PUFAs to many physiological processes, and the overwhelming ratio of LA (omega 6s) to ALA (omega 3s) in the average U.S. diet, nutrition experts are increasingly recognizing the need for humans to augment the body's synthesis of omega-3 VLC PUFAs by consuming foods that are rich in these compounds. According to data from two population-based surveys, the major dietary sources of LC omega-3 fatty acids in the U.S. population are fish, fish oil, vegetable oils (principally canola and soybean), walnuts, wheat germ, and some dietary supplements, and the primary dietary sources of omega-6 VLC PUFAs are meats and dairy products. These surveys, the Continuing Food Survey of Intakes by Individuals 1994-98 (CSFII) and the third National Health and Nutrition Examination (NHANES III) 1988-94 surveys, are the main sources of dietary intake data for the U.S. population. The CSFII has the advantage of collecting dietary recall data over a period of several days, which may permit estimates of omega-3 intake that more accurately reflect individual intakes than do those of NHANES, which represent 24-hour dietary recalls. However, NHANES intake data have the advantage of being able to be linked to health outcomes. Table 1.3 provides a list of food sources of omega-3 fatty acids.

Table 1.3 Good food sources* of omega-3 fatty acids.

Table

Table 1.3 Good food sources* of omega-3 fatty acids.

Table 1.4 shows the mean and median intakes of omega-3 and omega-6 fatty acids reported by NHANES III.i Table 1.5 shows the mean and median intakes of omega-3 and omega-6 fatty acids reported by CSFII.

Table 1.4 Estimates of the mean intake of LA, ALA, EPA, and DHA in the U.S. Population from analysis of NHANES III data.*.

Table

Table 1.4 Estimates of the mean intake of LA, ALA, EPA, and DHA in the U.S. Population from analysis of NHANES III data.*.

Table 1.5 Mean, range, and median usual daily Intakes (ranges) of n-6 and n-3 PUFAs, in the U.S. population, from analysis of CSFII data (1994 to 1998).*.

Table

Table 1.5 Mean, range, and median usual daily Intakes (ranges) of n-6 and n-3 PUFAs, in the U.S. population, from analysis of CSFII data (1994 to 1998).*.

Lacking sufficient evidence from research on the effects or correction of dietary deficiencies to establish Recommended Dietary Allowances (RDAs) for the essential fatty acids, the Food and Nutrition Board (FNB) of the Institute of Medicine9 has set adequate intakesii (AI) for the essential fatty acids, based on the average intakes of healthy CSFII participants. The AIs for the essential fatty acids vary by age group and sex, as well as for particular conditions such as pregnancy and breastfeeding. For ALA, the AI for men 19 and older, is 1.6 grams/day and the AI for (non-pregnant, non-breastfeeding) women is 1.1 grams/day. The AI for LA is 17 grams/day for men and 11 grams/day for women.

Based on evidence suggesting a role in prevention or treatment of some chronic diseases, the FNB has also established Acceptable Macronutrient Distribution Ranges (AMDR) for the essential fatty acids. An AMDR is defined as “a range of intakes for a particular energy source that is associated with reduced risk of chronic disease while providing adequate intake of essential nutrients.”9 The AMDR is expressed as a percentage of total energy intake: The AMDR for LA is set at five to 10 percent of usual energy intake, and the AMDR for ALA is 0.6 to 1.2 percent of energy intake. Of this amount, up to 10 percent can be consumed as EPA and/or DHA, the omega-3 VLC PUFAs. For a person who consumes 2000 kcal/day, ALA intake should range from 1.3 to 2.6 grams/day, and EPA/DHA intake can substitute for 0.13 to 0.26 of that quantity. Table 1.3 lists foods that provide 10 percent or more of these recommended intakes per serving, which may be referred to as “good sources.”iii Table 1.6 provides the actual omega-3 content per 100 gm for a variety of foods.

Table 1.6 The omega-3 fatty acid content, in grams per 100 g food serving, of a representative sample of commonly consumed fish, shellfish, fish oils, nuts and seeds, and plant oils.*.

Table

Table 1.6 The omega-3 fatty acid content, in grams per 100 g food serving, of a representative sample of commonly consumed fish, shellfish, fish oils, nuts and seeds, and plant oils.*.

Physiological Role of Omega-3 Fatty Acids in the Brain

About 50 to 60 percent of the dry weight portion of the human brain consists of lipids. PUFAs constitute approximately 35 percent of that lipid content.10 Omega-3 fatty acids, particularly EPA and DHA, play important roles in the development and maintenance of normal central nervous system (CNS) structure and function. Along with the omega-6 fatty acid, AA, DHA is a major constituent of neuronal membranes, making up about 20 percent of the brain's dry weight.11 Synapses contain a high concentration of DHA, which appears to play a role in synaptic signal transduction.12 The metabolic pathways of the essential fatty acids that play an important role in neuronal signal transduction are schematically illustrated in Figure 1.2. Release of these fatty acids is involved in the phospholipase A2 cycle following activation of various neurotransmitter receptors. DHA is also important for normal cognitive development.13 In addition, the anti-inflammatory compounds for which DHA is a precursor may function in the brain to protect against ischemic damage. PUFAs in general play important roles in structural and functional maintenance of neuronal membranes, neurotransmission, and eicosanoid biosynthesis,10, 14 as well as in the maintenance of membrane fluidity and flexibility and in the modulation of ion channels, receptors, and ATPases. The importance of PUFAs in maintenance of adequate membrane rigidity is evidenced by the loss of fluidity that follows decreased in PUFAs,15, 16 leading to changes in the orientation and function of receptors and ion channels, such as calcium and sodium channels.16

Figure 1.2 Schematic diagram illustrating the role of the metabolism of the essential fatty acids in neuronal signal transduction.

Figure

Figure 1.2 Schematic diagram illustrating the role of the metabolism of the essential fatty acids in neuronal signal transduction.

Work in animal models has reported superior learning and memory in animals fed omega-3 fatty acids compared with control animals.17, 18 In transgenic mouse models, dietary DHA improved memory, increased synapse density and decreased amyloid beta toxicity, thus providing evidence of protection against AD and cognitive decline.19, 20

Omega-3 Fatty Acids in Neurologic Disorders

Deficiencies in omega-3 FA and/or an imbalance in the ratio of omega-6 FA to omega-3 FA have been implicated in a variety of disorders affecting the CNS, including Alzheimer's disease (AD),21–26 the peroxisomal biogenesis disorders (a collection of relatively rare neurological conditions, of which Zellweger's syndrome is one of the most common),27–32 several psychiatric disorders,9, 11, 13, 33 Parkinson's disease,34, 35 amyotrophic lateral sclerosis (ALS),36 Huntington's disease,37–39 ischemic brain injury,36 and multiple sclerosis (MS).40–49 Indeed, dietary intake of omega-3 FA has been associated with a reduced incidence of MS since the early studies of Swank in the 1950s.50

Various animal and human studies have suggested several possible biological mechanisms for the role of FA in disease processes. Evidence for a positive association between intake of omega-3 FA and reduction of cardiovascular risk and adverse outcomes,51 along with the finding that certain forms of dementia have been related to cardiovascular risk factors, suggest that one mechanism linking FA and cognitive function or dementia may be atherosclerosis and thrombotic events.52 Inflammation is another mechanism that may explain the role that omega-3 fatty acids play in dementia.53

Several intervention trials in human infants have investigated the effects of omega-3 FA on cognitive development.50, 54 Research has also shown these FA to be important in human infant visual development. A meta-analysis of several intervention trials showed that healthy pre-term infants who were administered DHA-supplemented formula had significantly higher visual resolution acuity at two and four months of age compared with infants fed DHA-free formula.55

However, few clinical intervention trials have examined the role of omega-3 FA in changes in cognitive function with aging and adult neurological conditions. The studies that have investigated the relationship between omega-3 FA intake and cognitive function, dementia, or other neurological diseases are mainly observational.

Rationale for and Organization of this Report

Epidemiological studies have suggested that groups of people who consume diets high in omega-3 FAs may experience a lower prevalence of certain neurological conditions, particularly cognitive impairment and dementia disorders. In addition, several studies have attempted to assess the effects of adding omega-3 FA to the diet, either as omega-3 FA-rich foods or as dietary supplements (primarily fish oils) in the treatment of certain neurological diseases, notably MS.

In response to this evidence, a number of omega-3 FA-containing dietary supplements that claim to protect against a variety of conditions have appeared on the market. Thus, AHRQ and the National Institutes of Health (NIH) Office of Dietary Supplements (ODS) have requested a synthesis of the research to date on the health effects of diets rich in omega-3 FA.

The remainder of this report is organized into four chapters. Chapter Two describes the methods we used to identify and review studies related to the role of omega-3 FA in cognitive function with aging, dementia, and other neurological diseases/conditions. We did not analyze any studies on the role of omega-3 fatty acids in stroke because this topic has been addressed by the New England EPC in their report on Effects of Omega-3 Fatty Acids on Cardiovascular Disease. Chapter Three presents our findings related to the effects of omega-3 FA on those diseases/conditions. Chapter Four presents our conclusions and recommendations for future research in this area.

Footnotes

i

The population represented by NHANES III includes individuals ages 2 months and older. Mexican Americans and non-Hispanic African-Americans, children 5 years old and younger, and adults 60 years of age and over were over-sampled to produce more precise estimates for these population groups. There were no imputations for missing 24-hour dietary recall data. A total of 29,105 participants had complete and reliable dietary recall data. The NHANES III also included a physical examination and health survey of each participant.

ii

An Adequate Intake (AI) is defined as “the recommended average daily intake level based on observed or experimentally determined approximations or estimates of nutrient intake, by a group (or groups) of apparently healthy people, that are assumed to be adequate - used when a recommended dietary allowance cannot be determined.”9 An AI is set when data are insufficient or inadequate to establish an Estimated Average Requirement, on which the RDA is based, and indicate the need for more and better research. The EAR is “the average daily nutrient intake level estimated to meet the requirement of half the healthy individuals in a particular life stage and gender group,” based on a specific indicator or criterion of adequacy.

iii

Identifying a food as a “good source” of a nutrient strictly means that one standard serving of the food supplies 10 to 19 percent of the Daily Value for that nutrient. The Daily Values are based on the FDA's Daily Reference Values, standards for the macronutrients (fats, protein, carbohydrates, and dietary fiber), which are similar, although not identical to the DRIs (RDAs) and are based on the amount of energy consumed per day (2000 kcal/d is the reference for calculating DVs). In the case of the PUFAs, no DVs have been established: For this report, the FNB's AIs and AMDRs, have been used instead.

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