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American Journal of Clinical Nutrition, Vol. 83, No. 6, S1494-1498S, June 2006
© 2006 American Society for Nutrition

Supplement: n–3 Fatty Acids: Recommendations for Therapeutics and Prevention

Potential role of dietary n–3 fatty acids in the prevention of dementia and macular degeneration1,2,3,4

Elizabeth J Johnson and Ernst J Schaefer

1 From the Carotenoid & Health and Lipid Metabolism Laboratories, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA

2 Presented at the symposium "n–3 Fatty Acids: Recommendations for Therapeutics and Prevention," held at the Institute of Human Nutrition, Columbia University, New York, NY, 21 May 2005

3 Supported by USDA 581950-9-001 and 53-3K06-5-10 and contract HV-83-03 from the National Institutes of Health,

4 Reprints not available. Address correspondence to Elizabeth J Johnson, Carotenoid & Health Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111. E-mail: elizabeth.johnson{at}tufts.edu.

ABSTRACT

Dementia and age-related macular degeneration (AMD) are major causes of disability in the elderly. n–3 Fatty acids, particularly docosahexaenoic acid (DHA), are highly concentrated in brain and retinal tissue and may prevent or delay the progression of dementia and AMD. Low dietary intakes and plasma concentrations have been reported to be associated with dementia, cognitive decline, and AMD risk. The major dietary sources of DHA are fish and fish oils, although dietary supplements are available. At this point, it is not possible to make firm recommendations regarding n–3 fatty acids and the prevention of dementia and AMD. Our own unpublished observations from the Framingham Heart Study suggest that ≥180 mg/d of dietary DHA ({approx}2.7 fish servings/wk) is associated with an {approx}50% reduction in dementia risk. At least this amount of DHA is generally found in one commercially available 1-g fish oil capsule given daily.

Key Words: n–3 Fatty acids • docosahexaenoic acid • dementia • age-related macular degeneration

INTRODUCTION

Fatty acids are chains of carbon with hydrogens attached and an alpha or carboxylic acid end (COOH) and an omega or methyl end (CH3). Fatty acids are critical for energy storage as triacylglycerol (3 fatty acids attached to a glycerol backbone), for cell membrane formation with a phospholipids bilayer (2 fatty acids attached to a phospholipid polar head group), and for the formation of cholesteryl esters (one fatty acid attached to free cholesterol). The most abundant fatty acids in human plasma are the saturated fatty acids palmitic acid (16:0) and stearic acid (18:0), the monounsaturated fatty acid oleic acid (18:1n–9), and the polyunsaturated fatty acid linoleic acid (18:2n–6). The body cannot place a double bond at the third carbon position or the sixth carbon position from the methyl or omega end of the fatty acid chain. For this reason, the only 2 dietary fatty acids that are essential in the diet are linoleic acid and {alpha}-linolenic acid (18:3n–3) (1).

There are 3 major n–3 fatty acids in the diet and also in human plasma and tissues. These are {alpha}-linolenic acid, eicosapentaenoic acid (EPA, 20:5n–3), and docosahexaenoic acid (DHA, 22:6n–3). Of these, DHA is the most abundant fatty acid in plasma, as well as in brain and retinal cell membranes (2-4). Moreover, DHA content in brain and retina is {approx}10-fold that in plasma ({approx}40% compared with 4% of fatty acid content), which indicates that this fatty acid is markedly enriched in brain and retinal tissue.

DHA can be made from {alpha}-linolenic acid by desaturation and elongation in human liver or can be obtained directly in the diet from fish, fish oil, meat, or supplements that are rich in DHA. Fish oil contains both EPA and DHA, whereas sources of DHA without EPA from algae are also available. The efficiency of the conversion of {alpha}-linolenic acid to DHA is decreased in premature infants and may also decline with aging (1). In addition, the phylum Carnivora (cat family) lacks the enzymes necessary for this conversion and therefore are obligate fish and meat eaters.

DIETARY INTAKES OF n–3 FATTY ACIDS

In the United States, intake of n–3 fatty acids is {approx}1.6 g/d, or {approx}0.7% of total energy intake (5), of which 1.4 g is {alpha}-linolenic acid, and 0.1–0.2 g is EPA and DHA. The primary sources of {alpha}-linolenic acid are vegetable oils, primarily soybean and canola. The major sources of EPA and DHA are fish and fish oils (Table 1Go; 6, 7). A variety of n–3 fatty acid supplements are also available to consumers. Many of these supplements are derived from marine oils and contain 180 mg EPA and 120 mg DHA per capsule (5). A vegetarian source of DHA derived from algae is also available (5). To date, no official dietary recommendations have been made for n–3 fatty acids in the United States.


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  		TABLE 1. n–3 Fatty acid content of selected seafood1

 
n–3 FATTY ACIDS AND DEMENTIA

Dementia is a major cause of disability among the elderly, and Alzheimer disease is responsible for {approx}70% of the cases. Age, family history, and the presence of the apolipoprotein {varepsilon}4 allele have been found to be significant risk factors for the development of Alzheimer disease and all-cause dementia (8-13). More recently, high plasma concentrations of homocysteine were also shown to be a risk factor for Alzheimer disease and dementia (14). DHA, a fatty acid found in the diet as well as in many tissues in the body, also appears to be important in affecting the risk of dementia. Fatty acids with multiple double bonds confer increased fluidity to membranes. Each double bond causes a 37° angle in the carbon chain, thus resulting in a fatty acid that is not easily compressible (15). The phospholipids in the brain membranes are enriched in DHA. DHA appears to be important for central nervous system function (2, 16, 17). Two inherited disorders, Zellweger syndrome and neonatal adrenal leukodystrophy, which present early in life with severe neurologic symptoms, are associated with markedly lower amounts of DHA in plasma and brain than in healthy controls (18). It is known that the final step in DHA formation occurs in the peroxisome in the liver via beta oxidation, and patients with Zellweger syndrome lack peroxisomes and do not adequately convert {alpha}-linolenic acid to DHA.

Several investigators have analyzed the links between plasma DHA status and dementia. Patients with dementia due to Alzheimer disease have been reported to have 30% less DHA in brain tissue than do age-matched controls (18). Conquer et al (19) studied differences in the plasma fatty acid composition of various phospholipid fractions in 65 patients with dementia or impaired cognitive function and 19 healthy elderly subjects. This cross-sectional analysis showed significantly lower content of plasma phosphatidylethanolamine and phosphatidylcholine (PC) DHA in the groups with Alzheimer disease, other types of dementia, or with cognitive impairment than in the cognitively normal group. Tully et al (20) reported significantly lower content of serum cholesteryl-ester DHA in 148 patients with dementia than in 45 control subjects. Heude et al (21) reported an inverse association between cognitive decline and the ratio of n–3 to n–6 fatty acids in erythrocytes in a prospective cohort study of 246 men and women. Kalmijn et al (22) reported that increased fish and DHA intake were protective of cognitive decline. In a cohort of 815 elderly subjects, Morris et al (23) reported a 60% reduction in the risk of developing Alzheimer disease in subjects consuming fish at least once per week compared with those who rarely or never ate fish. In addition, recent studies in a mouse model of Alzheimer disease suggest that the disease can be markedly delayed in terms of onset or prevented by dietary DHA supplementation (24).

In our own recent data from the Framingham Heart Study, plasma PC DHA content predicted the occurrence of new dementia, independently of age, sex, apolipoprotein E4 genotype, plasma homocysteine, and education level (25). Subjects with baseline plasma PC DHA concentrations in the upper quartile experienced a significant 47% lower risk of dementia than did participants in the lower 3 quartiles. No other plasma PC fatty acid was independently linked to the risk of dementia. Top-quartile plasma PC was associated with a mean intake of dietary fish of {approx}3 servings of fish per week or {approx}180 mg DHA/d, less than that found in one fish oil capsule.

Plasma PC DHA content is determined both by the degree of conversion of {alpha}-linolenic acid (found in plant oils) to DHA within the liver and by the consumption of foods rich in DHA. In our study, the correlation between plasma PC DHA content and fish intake was high, and subjects with plasma PC DHA in the highest quartile were those with the greatest fish consumption, which indicates that fish intake is a major source of DHA. The major fatty acids in fish are DHA and EPA. We found no relation of dementia with plasma PC EPA, whereas the association with plasma PC DHA was significant. These results suggest that, among all fatty acids, DHA may play a specific role in brain function and in the development of dementia. This is consistent with earlier data showing high concentrations of DHA in brain tissue, and the report of low DHA content in the brain of persons with Alzheimer disease (18).

Further suggestion of a relation between DHA status and cognitive function comes from intervention studies. Suzuki et al (26) recently reported that feeding 30 subjects 640–800 mg DHA (oil containing 15% DHA and 3% EPA) for 6 mo improved performance on a dementia scale in 18 of 30 subjects (in 12 of 22 subjects with dementia and in 6 of 8 subjects without dementia). Hamasaki et al (27) reported that 1.5 g DHA/d decreased aggressive behavior significantly over 6 mo versus placebo in a total of 40 subjects.

n–3 FATTY ACIDS AND AGE-RELATED MACULAR DEGENERATION

Although the evidence for a role of DHA in the prevention of AMD is not as strong as that for dementia, a review of this topic is warranted in light of the upcoming Age-Related Eye Disease Study II (AREDS II), which will begin in early 2006 (Internet: http://www.nei.nih.gov/neitrials/viewStudyWeb.aspx?id=120). This study aims to refine the findings of AREDS, which showed that oral supplementation with high-dose antioxidant vitamin and minerals (vitamins C and E, ß-carotene, zinc, and copper) reduced the risk of advanced AMD by 25% (28). AREDS II aims to improve on this by evaluating the role of n–3 fatty acids as well as of the carotenoids lutein and zeaxanthin.

Age-related losses in visual function are major health concerns in many industrialized countries, where AMD is a leading cause of blindness (29). The macula is located in the center of the retina and is responsible for detailed, fine central vision. AMD is a disease that affects the central vision. Nearly 30% of Americans over the age of 75 y have early signs of AMD, and 7% have late-stage disease; the respective prevalences among Americans aged 43–54 y are 8% and 0.1% (30, 31). This number is expected to triple with the increase in the aging population in the next 30 to 40 y. Because there are currently no effective treatment strategies for most patients with AMD, attention has focused on efforts to stop the progression of the disease or to prevent the damage leading to AMD.

It has been suggested that atherosclerosis of the blood vessels that supply the retina contributes to the risk of AMD, analogous to the mechanism underlying coronary heart disease (32). Therefore, dietary fat components related to coronary heart disease may also be related to AMD (33, 34). Long-chain n–3 fatty acids may have a special role in the function of the retina in addition to their antithrombotic and hypolipidemic effects on the cardiovascular system. DHA is a key fatty acid found in the retina (3) and is usually present in large amounts in this tissue. Although the role of DHA in visual development is well documented (15, 35, 36), its role in retinal function is unclear. Rod outer segments of vertebrate retina have a high DHA content (3, 4). Because photoreceptor outer segments are constantly being renewed, a constant supply of DHA may be required for proper retinal function, and a marginal depletion may impair retinal function and influence the development of AMD. Biophysical and biochemical properties of DHA may affect photoreceptor membrane function by altering permeability, fluidity, thickness, lipid phase properties, and the activation of membrane-bound proteins (37, 38). DHA-rich membranes influence the dynamics of the inter- and intracellular communication in the retinal membrane outer segment discs (39-44). The tissue status of DHA affects retinal cell signaling mechanisms involved in phototransduction (39, 40), which suggests an essential role for DHA in vision. EPA, the substrate for DHA, is the parent fatty acid for a family of eicosanoids that affect arachidonic acid–derived eicosanoids implicated in abnormal retinal neovascularization, vascular permeability, and inflammation (45).

Epidemiologic studies examining the relation of DHA or fish intake with AMD suggest a trend toward a protective relation. In a prospective follow-up study of participants in the Nurse's Health Study and the Health Professionals Follow-up Study, 72 489 men and women with no diagnosis of AMD were followed for 10–12 y. Five hundred sixty-seven patients with AMD were accrued. Odds of AMD (with visual loss of 20/30 or worse in a least one eye) decreased with increased DHA intake (top versus bottom quintile of relative risk: 0.70; 95% CI: 0.52, 0.93; P for trend = 0.05). However, the relation of DHA did not persist [odds ratio (OR) for highest versus lowest DHA intake = 0.8; 95% CI: 0.5, 1.1] when modeled simultaneously with intake of other dietary lipids, although the OR favored protection. Because fish is a major source of DHA, these investigators also examined the association of fish intake with AMD risk. Fish intake contributed 77% of DHA intake in women and 80% in men. Consumption of >4 servings of fish/wk was associated with a 35% lower risk of AMD compared with ≤3 servings/mo (relative risk: 0.65; 95% CI: 0.46, 0.91; P for trend = 0.0009) in pooled multivariate analysis (46). Of the individual fish types examined, a significant inverse association was found only with tuna intake. The pooled risk ratio of participants who ate canned tuna more than once per week compared with those who consumed it less than once per month was 0.61 (95% CI: 0.45, 0.83). These authors concluded that a high intake of fish may reduce the risk of AMD.

The Dietary Ancillary Study of the Eye Disease Case-Control Study (47) reported results for 349 participants with neovascular AMD and 504 control subjects without AMD (48). In demographically adjusted analyses, increasing intake of linoleic acid was significantly associated with a higher prevalence of AMD (P for trend: 0.004). This association persisted in multivariate analyses, with an OR for the fifth versus first quintile of 2.00 (95% CI: 1.19, 3.37; P for trend: 0.02). Conversely, intake of n–3 fatty acids showed an inverse relation with AMD in demographically adjusted analyses (P for trend: 0.01). This association became nonsignificant after control for confounding variables, most notably, cigarette smoking. When the study population was stratified by linoleic acid intake (≤5.5 or ≥5.6 g/d), the risk of AMD was significantly reduced with high intake of n–3 fatty acids among those with low linoleic acid intake (P for trend: 0.05; P for continuous variable: 0.03). In contrast, among individuals with high linoleic acid intake, no significant association was seen for n–3 fatty acid intake after control for other confounding variables. The authors commented that these findings suggest a competition between n–3 and n–6 fatty acids and that both the concentrations of n–3 fatty acids and their ratio to the n–6 acids are important. These results are similar to a more recent report involving a prospective cohort study of 261 persons aged ≥60 y at baseline with an average follow-up of 4.6 y. In this study, 101 patients with AMD progressed to advanced AMD. It was reported that higher fish intake (>2 servings/wk versus <1 serving/wk) was associated with a lower risk of progression to advanced AMD among subjects with lower linoleic acid intake (OR: 0.36; 95% CI: 0.14, 0.95) (49).

A relation between fish intake and late age-related maculopathy (ARM or neovascular AMD) or geographic atrophy was not measured in the Beaver Dam Eye Study, a retrospective population-based study. However, fish intakes were less than in subsequent reports (50). These investigators suggested that the intake of n–3 fatty acids in this population was not varied enough to detect a difference in risk of AMD.

Heuberger et al (51) evaluated the associations between fish intake and ARM in the third National Health and Nutrition Examination Survey. Persons aged 40 to 79 y (n = 7405) were included in analyses for early ARM (n = 644); those aged ≥60 y (n = 4294) were included in analyses for late ARM (n = 53). Consuming fish more than once per week compared with once per month or less was associated with ORs of 1.0 for early ARM (95% CI: 0.7, 1.4) and of 0.4 for late ARM (95% CI: 0.2, 1.2) after adjustment for age and race. Adjustment for other possible risk factors did not significantly influence these relations. These investigators concluded that no associations were observed between fish intake and ARM in this population. However, associations with late ARM, although not statistically significant, were consistent with observations of an inverse association reported by others (46, 52).

The Blue Mountains Eye Study was a population-based survey of vision, common eye diseases, and diet in an urban population of 3654 persons aged ≥49 y (52). In the 2915 subjects evaluated for fish intake, 240 cases of early ARM and 72 cases of late ARM were identified. In this study, more frequent consumption of fish appeared to protect against late ARM after adjustment for age, sex, and smoking. The protective effect of fish intake commenced at a relatively low frequency of consumption (1–3 times/mo compared with intake <1 time per month; OR: 0.23; 95% CI: 0.08, 0.63). The ratio of cases to controls in these intake groups was 6/777 and 17/380, respectively. The OR for intake >5 times/wk compared with <1 time/mo was 0.46 (95% CI: 0.12, 1.68). The authors suggested that there may be a threshold protective effect at low fish intakes, with no increased protection from ARM at increased fish intake. In this study, there was little evidence of protection against early ARM.

CONCLUSIONS

At this point in time, it is not possible to make firm recommendations regarding n–3 fatty acids and the prevention of dementia and macular degeneration. Randomized, placebo-controlled intervention trials are needed in this regard, and some are beginning to be carried out. For example, the National Eye Institute Division of the National Institutes of Health will begin a randomized double-masked study of DHA that will evaluate the rate of disease progression in {approx}4000 patients with AMD. Such data may prove useful because DHA tissue status is modifiable by dietary intake. Furthermore, n–3 fatty acids are not widely distributed in the food supply and the efficiency of tissue uptake is highest when they are ingested in the preformed state. Our own observations from the Framingham Heart Study suggest that ≥180 mg dietary DHA/d, or {approx}2.7 fish servings per week, is associated with an {approx}50% reduction in dementia risk (25). This amount of DHA is generally found in one commercially available fish oil capsule. From the available data, the World Health Organization recommendation that 1–2% of calories come from n–3 fatty acids is certainly not unreasonable (53).

ACKNOWLEDGMENTS

EJS was responsible for the review of n–3 fatty acids and dementia. EJJ was responsible for the review of n–3 fatty acids and macular degeneration. None of the authors had any advisory board affiliations of financial interest in any organization sponsoring the review.

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