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Fish Protects Against Dementia, Alzheimer Disease, EDITORIAL
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"Docosahexaenoic Acid and Alzheimer Disease"
EDITORIAL
Arch Neurol. Nov 11, 2006;63:1527-1528.
Martha Clare Morris, ScD
Rush University Medical Center, Chicago, IL
Dementia is a major cause of disability among the elderly, with Alzheimer disease being responsible for about 70% of cases. As well, HIV-infected individuals are at risk for dementia and cognitive impairment. Certain conditions associated with aging and cognitive impairment in the general population are more prevalent in HIV, including diabetes, impaired glucose tolerance, and elevated lipids. Age, family history, and the presence of the apolipoprotein E 4 allele have been found to be significant risk factors for the development of Alzheimer disease and all-cause dementia.1-3 More recently, a high plasma concentration of homocysteine has also been shown to be a risk factor for Alzheimer disease and dementia.4
Docosahexaenoic acid (DHA), an -3 polyunsaturated fatty acid found in some foods and many tissues in the body, also appears to be important in affecting the risk of dementia. Docosahexaenoic acid can be formed from -linolenic acid, an essential fatty acid that must be obtained from the diet or can be obtained directly by consuming foods rich in DHA such as fish or fish oil or supplements containing DHA. Docosahexaenoic acid appears to be important for central nervous system function.5-6 Cross-sectional studies have linked low DHA levels with dementia,7-10 while prospective studies have linked all-cause dementia and Alzheimer disease with decreased fish intake.11-14 Our hypotheses in this study were that plasma phosphatidylcholine (PC) DHA content is related to the risk of all-cause dementia and Alzheimer disease, as well as to dietary DHA and fish intake.
"....The study by Schaefer et al provides the first evidence that direct measure of DHA in human plasma is related to lower Alzheimer disease risk....Fish is the primary dietary source of the long-chain -3 polyunsaturated fatsDHA and EPA. Several prospective studies2, 7-8 found protective associations of fish and the risk of incident Alzheimer disease....To date, there are no published human studies on the brain effects of w-3 fatty acid supplementation, primarily because of very low use of these supplements in the general population.....Based on the available epidemiologic evidence, the amount of DHA required for protective benefit is likely small. For example, in previous epidemiologic studies, the protective effect was observed between persons who rarely or never consume fish to consumption of 1 fish meal per week.....
....There is increased concern over the harmful effects of mercury contaminated fish, and this has resulted in an apparent decrease in fish consumption in the United States. Unfortunately, there are few human studies that examined the direct health effects of mercury intake through eating fish. Most risk analyses are based on extrapolations from high-dose mercury toxicity levels and mercury content of selected fish samples. These hypothetical calculations of risk may not reflect the complexity of nutrient metabolism from fish consumption. In fact, harmful effects from fish consumption have not been borne out in epidemiologic studies, which consistently find positive health effects on mortality, cardiovascular risk factors, and now dementia. The only way to resolve the risk-benefit question is to examine, directly in humans, mercury intake from fish and its effect on various health outcomes relative to the beneficial effects of the w-3 fatty acids consumed."
The study by Schaefer et al in this issue of Archives of Neurology1 is an important contribution to a young field of study on diet and neurodegenerative diseases. The authors found lower 9-year risk of incident Alzheimer disease among persons with higher levels of plasma phosphatidylcholine docosahexaenoic acid (DHA). The association was specific to DHA as none of the other w-3 fatty acids was associated with Alzheimer disease risk. In a subset of their cohort, fish consumption was positively correlated with plasma DHA but was not statistically significantly associated with incident Alzheimer disease. However, it is possible that the analysis was underpowered to observe a protective association of fish consumption, as the inverse relative risk was based on a relatively small subsample of 488 subjects.
As one of the -3 fatty acids, an essential class of nutrients that cannot be synthesized endogenously by mammalians, DHA must be obtained through diet. The short-chain w-3 fatty acid, a-linolenic acid (18:3 w-3) can be obtained from terrestrial foods, including vegetable oils, soybeans, walnuts, wheat germ, and human milk. In mammalians, a-linolenic acid is elongated and desaturated to form the long-chain w-3 fatty acids, eicosapentaenoic acid (EPA) 20:5 -3) and DHA (22:6 -3). -Linolenic acid is readily converted to EPA in humans, but only a small percentage is converted to DHA. The conversion of these longer-chain w-3 polyunsaturated fatty acids can be attenuated by diets that are high in w-6 polyunsaturated fatty acids (eg, diets rich in corn, safflower, sunflower, and peanut oils) because the2 classes of fatty acids compete for the same enzyme for desaturation. Both DHA and EPA can be also directly consumed from marine sources. Although higher concentrations of EPA are found in cold-water fatty fish, the DHA content is fairly consistent across all types of fish.
An intensive body of research during the 1970s and 1980s revealed that the w-3 fatty acids have antiarrythmic, antithrombotic, and antiinflammatory properties. It is now fairly well established that EPA in particular prevents cardiac death, perhaps through its antiarrythmmic effects on ventricular tachycardia and fibrillation. It is interesting to note that the Schaefer et al study found an association of plasma DHA concentration with dementia risk, but no association with EPA. This finding is supported by that of the Chicago Health and Aging Project, in which dietary intake of DHA but not EPA was associated with lower risk of developing Alzheimer disease.2
There is a strong biological basis for the association of DHA and neuroprotection. Lipids are the primary structural component of the adult brain, making up 50% to 60% of the brain dry weight. The most abundant fatty acid in the phospholipids of the cerebral gray matter is DHA, which represents 45% to 65% percent of total phosphatidylserine in the mitochondria.3 The DHA is most concentrated in neurons of the cerebral cortex, synaptosomes, and the mitochondria-areas of the brain with the highest metabolic activity. In fact, DHA is found in significant concentrations only in the brain, the retina, and the testes. All of these areas are characterized by high metabolic activity. The chemical structure of the long-chain w-3 fatty acids make them particularly conducive to the fluidity required in this type of environment.
Intensive study during the 1980s and 1990s revealed that DHA is essential to neurocognitive development. These studies were driven by the fact that infant formulas did not contain w-3 fatty acids, yet there is selective uptake of DHA in utero, and human milk has a high DHA concentration. These studies found that DHA was important to the structural and functional maintenance of neuronal membranes, neuronal membrane fluidity and flexibility, neurotransmission, and modulation of ion channels, receptors, and ATPase. Indeed, the level of DHA in the brain has been shown to be very important for learning ability and memory in early life in studies of rodents, baboons, and humans. It is only recently that the w-3 fatty acids have been investigated for their importance to the aging brain. The DHA composition of the brain decreases with age as a result of increased oxidative damage to the lipid membranes. It has been shown through animal models that dietary intake of DHA in late life increases the DHA composition in the brain.3-4 Compared with aged rodents on DHA supplemented diets, those with DHA deficient diets had 90% more synaptic loss and inferior memory performance.5 In another aged rodent model, DHA-enriched diets reduced total amyloid production by 70% and the overall plaque burden by 40%.6
Fish is the primary dietary source of the long-chain w-3 polyunsaturated fatsDHA and EPA. Several prospective studies2, 7-8 found protective associations of fish and the risk of incident Alzheimer disease. One of these studies, the CHAP study,9 examined dietary intake of the different types of w-3 fatty acids in relation to 4-year risk of developing Alzheimer disease. Both DHA and total -3 fatty acid intake were associated with lower risk, and -linolenic acid had a strong inverse association only among persons with the APOE 4 allele. The Rotterdam study did not find a protective association of total w-3 fatty acid intake on Alzheimer disease risk, but did not examine the individual types of -3 fatty acids. This raised the question as to whether the observed association with fish consumption was due to dietary components in fish other than the w-3 fatty acids, or perhaps to some related food item or health behavior. Another explanation of the inconsistent findings is imprecise measure of w-3 fatty acid intake through dietary sources. The study by Schaefer et al provides the first evidence that direct measure of DHA in human plasma is related to lower Alzheimer disease risk. Studies that relate w-3 fatty acids to age-related cognitive decline are also informative because cognitive decline is the central characteristic of Alzheimer disease. In a large cohort study of older residents in Nantes, France, higher composition of w-3 fatty acids in erythrocyte membranes was associated with lower risk of cognitive decline as defined by a 2-point decrease or more in cognitive score over 4 years.10
To date, there are no published human studies on the brain effects of w-3 fatty acid supplementation, primarily because of very low use of these supplements in the general population. For example, less than 1% of CHAP study population reported consuming -3 fatty acids in supplement form. This question can be examined through clinical trials, although currently there are limited epidemiologic data to determine an effective dose level of DHA for clinical trial. Based on the available epidemiologic evidence, the amount of DHA required for protective benefit is likely small. For example, in previous epidemiologic studies, the protective effect was observed between persons who rarely or never consume fish to consumption of 1 fish meal per week.2, 8 This translates into 0.18 g/d of DHA (based on one 3-oz serving of cooked Atlantic salmon, for example). There is little evidence to suggest that there would be even greater benefit with higher intake. On the basis of these data, a trial that included participants who already consumed fish frequently may fail to observe a DHA effect on cognition because the placebo group would be already at the level of protective effect. To avoid this potential problem, future clinical trials should be designed to either eliminate current fish consumers, or be adequately powered to stratify by fish consumption.
There is increased concern over the harmful effects of mercury contaminated fish, and this has resulted in an apparent decrease in fish consumption in the United States. Unfortunately, there are few human studies that examined the direct health effects of mercury intake through eating fish. Most risk analyses are based on extrapolations from high-dose mercury toxicity levels and mercury content of selected fish samples. These hypothetical calculations of risk may not reflect the complexity of nutrient metabolism from fish consumption. In fact, harmful effects from fish consumption have not been borne out in epidemiologic studies, which consistently find positive health effects on mortality, cardiovascular risk factors, and now dementia. The only way to resolve the risk-benefit question is to examine, directly in humans, mercury intake from fish and its effect on various health outcomes relative to the beneficial effects of the w-3 fatty acids consumed.
REFERENCES
1. Schaefer EJ, Bongard V, Beiser AS, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: The Framingham Heart Study. Arch Neurol. 2006;63:1545-1550. FREE FULL TEXT
2. Morris MC, Evans DA, Bienias JL, et al. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003;60:940-946. FREE FULL TEXT
3. Gamoh S, Hashimoto M, Sugioka K, et al. Chronic administration of docosahexaenoic acid improves reference memory-related learning ability in young rats. Neuroscience. 1999;93:237-241. FULL TEXT | ISI | PUBMED
4. McGahon BM, Martin DS, Horrobin DF, Lynch MA. Age-related changes in synaptic function: analysis of the effect of dietary supplementation with omega-3 fatty acids. Neuroscience. 1999;94:305-314. FULL TEXT | ISI | PUBMED
5. Cole GM, Lim GP, Yang F, et al. Prevention of Alzheimer's disease: omega-3 fatty acid and phenolic anti-oxidant interventions. Neurobiol Aging. 2005;26:133-136. FULL TEXT | PUBMED
6. Lim GP, Calon F, Morihara T, et al. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci. 2005;25:3032-3040. FREE FULL TEXT
7. Barberger-Gateau P, Letenneur L, Deschamps V, Peres K, Dartigues JF, Renaud
S. Fish, meat, and risk of dementia: cohort study. BMJ. 2002;325:932-933. FREE FULL TEXT
8. Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A, Breteler MM. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol. 1997;42:776-782. FULL TEXT | ISI | PUBMED
9. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Diet and risk of dementia: does fat matter? Neurology. 2002;59:1915-1921. FREE FULL TEXT
10. Heude B, Ducimetiere P, Berr C. Cognitive decline and fatty acid composition of erythrocyte membranes: The EVA Study. Am J Clin Nutr. 2003;77:803-808. FREE FULL TEXT
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