Abstract
The brain is a lipid-rich organ and thus it is reasonable to question the role of fatty acids in normal brain function, including cognition. The purpose of this article is to examine our current knowledge on the relationship between omega-3 fatty acids (ω3FA) and cognitive function and explore the therapeutic implications of ω3FA in the prevention and treatment of cognitive impairment. Published cross-sectional and prospective observational research, though not fully consistent, predominantly support the role of ω3FA in decreasing the risk of cognitive decline. However, to date, the results from randomized controlled trials have been predominantly null, with the exception of supplementation in individuals with mild cognitive impairment. Whether lack of evidence is a result of insufficient study design or absence of actual benefit warrants further clinical research. Given the low side effect profile, high accessibility, and relatively low cost, it is reasonable to recommend, at minimum, the dietary intake of ω3FA or supplementation of fish oil in alignment with the 2010 Department of Health and Human Services Dietary Guidelines for Americans.
‘. . . ω3FA consumption, obtained mostly through fatty fish or fish oils, has decreased dramatically in the typical Western diet over the past few decades.’
The brain is a lipid-rich organ and thus it is reasonable to question the role of fatty acids in normal brain function, including cognition. Findings from animal studies strongly support a protective role of omega-3 fatty acids (ω3FA) in cognitive decline and dementia, including Alzheimer’s disease (AD). Though somewhat conflicting, human observational data also demonstrate beneficial effects of ω3FAs in proper brain development, cognitive function, and possibly even an attenuation of cognitive impairment in aging adults. Omega-3 fatty acids are dietary essential, that is, they cannot be synthesized by the body itself and thus must be consumed or supplemented through diet. At the same time, ω3FA consumption, obtained mostly through fatty fish or fish oils, has decreased dramatically in the typical Western diet over the past few decades. 1 The purpose of this article is to examine our current knowledge on the relationship between ω3FA and cognitive function and explore the therapeutic implications of ω3FA in the prevention and treatment of cognitive impairment.
Observational Studies
Published cross-sectional and prospective observational research, though not fully consistent, predominantly support the role of ω3FA in decreasing the risk of cognitive decline. 2 These studies assess ω3FA intake (either through the consumption of fish or fish oil supplements) and plasma ω3FA concentrations on the incidence of cognitive impairment.
Three large observational studies, the Rotterdam Study, the PAQUID study, and the CHAP study, each found an inverse relationship between fish intake and risk of cognitive decline.3-5 The Rotterdam study followed more than 5000 healthy (nondemented) individuals age 55 and older. The study found that increased fish intake was associated with a greater than 50% reduced risk of developing dementia over 2 years. 3 The PAQUID study followed 1600 adults aged 68 years and older for 7 years. Those who had at least one meal containing fish each week were found to have a 35% reduced risk of developing AD. 4 The CHAP study also assessed the effects of consuming at least one fish meal weekly, in 3700 individuals over the age of 65. The study found a reduced decline in global cognition over 6 years of follow-up. 5
The 3 aforementioned studies each used dietary recall to estimate the amount of fish consumed and, thus, ω3FA exposure in their study populations. A common limitation of these studies is the questionable reliability of self-reported ω3FA dietary intake. However, epidemiologic evidence supporting ω3FA for cognition also exists using fatty acid tissue profiles to approximate exposure. For example, the Framingham Study, which is generally known for its assessment of cardiovascular health risk factors, also examined the effects of ω3FA on cognition. 6 The prospective study, by Schaefer et al found that decreased ω3FA concentrations, specifically decreased plasma concentrations of docosahexaenoic acid (DHA), was related to subsequent cognitive decline in 899 participants, age 76 and greater, during the 9-year follow-up. These findings are supported by a second assessment of the Framingham cohort in the Offspring study, this time using ω3FA concentrations in red blood cells rather than the plasma. 7 This change in methods, albeit small, is significant. Fatty acid composition in red blood cells more reliably estimates the long-term dietary exposure of ω3FA and may be a more valuable marker of fatty acid intake than plasma concentrations. The study by Tan et al found that lower red blood cell concentrations of DHA and eicosapentaenoic acid (EPA) were associated with markers of accelerated cognitive decline in 1575 middle-aged adults free of clinical dementia. 7
Randomized Control Trial (RCT) Evidence
While observational study data seem to demonstrate promising effects of ω3FA on cognition, to date, the results from randomized controlled trials have been predominantly null. There are a few notable exceptions to this generalization, occurring in patients with mild cognitive impairment at baseline.
One such finding comes from a subgroup analysis of the Freund-Levi et al study. 8 The primary analysis followed 204 adults with mild to moderate AD, randomized to treatment with 1700 mg DHA + 600 mg EPA daily or placebo for 6 months. While no difference in cognitive decline was observed between groups for the 174 participants who completed the trial, a subgroup analysis of 32 participants with mild cognitive impairment demonstrated a statistically significant positive effect of ω3FA supplementation on Mini Mental State Examination results. 8 This finding suggests those with mild cognitive impairment may benefit most from ω3FA supplementation. This theory is further supported by Yurko-Mauro et al, who assessed the effects of daily DHA supplementation (900 mg/day) in 485 middle-aged adults with mild age-related cognitive decline. 9 The study observed a doubling of plasma DHA levels and an increase in performance of episodic memory to a level that correlated with a gain of 3.4 years of cognitive age over the 24-week follow-up period. 9
While small positive effects were observed in RCTs studying patients with mild cognitive impairment, no effects were observed in trials of healthy patients or those with moderate to severe AD. Common limitations of the RCTs include small sample size and short follow-up periods. Interestingly, treatment periods in human studies range from 6 months to 2 years, which is markedly shorter than the length of ω3FA supplementation in animal studies. In many animal studies, ω3FA supplementation takes place for >10% of the total lifespan. 10 In addition to short treatment periods, there is a lack of consistency in the treatment provided. Fish oil supplements are manufactured with varying proportions of EPA and DHA, and the most effective ratio has yet to be determined. Additionally, some studies did not treat with EPA at all, instead providing solely DHA for intervention. Another limitation is the lack of DHA assessment at baseline. It is questionable whether DHA supplementation in individuals who already have sufficient intake and tissue concentrations would result in beneficial cognitive changes.
A final limitation of many of the observational studies and several interventional trials is the lack of control for carriers of the ApoE4 allele. The possession of the ApoE4 allele is a known genetic predictor for AD and may confound the results of studies that did assess for carriage at baseline. A study by Dangour et al illustrates this concept. 11 The study enrolled 867 cognitively healthy adults and randomized them to treatment with 200 mg EPA + 500 mg DHA daily or placebo. While the findings from the primary analysis revealed no change over time from any of the cognitive testing, a subgroup analysis of ApoE4 allele carriers demonstrated a small benefit from ω3FA supplementation in the domain of attention. 11
Discussion and Conclusions
The majority of observational research supports a relationship between ω3FA intake/plasma levels and reduced risk of cognitive decline. Randomized controlled trials to date are predominantly null, with the exception of supplementation in individuals with mild cognitive impairment. Whether lack of evidence is a result of insufficient study design or absence of actual benefit warrants further clinical research. Given the low side effect profile, high accessibility, and relatively low cost, it is reasonable to recommend, at minimum, the dietary intake of ω3FA or supplementation of fish oil in alignment with the 2010 Department of Health and Human Services Dietary Guidelines for Americans. The guidelines recommend about 20% of total protein intake come from a variety of seafood, which translates to about 8 ounces, or 2 servings, of fish per week for most adults. 12 This recommendation provides approximately 250 mg of combined EPA and DHA daily.