A review of emerging science with regard to marine omega-3 fatty acids and cognitive health

Marine omega-3 fatty acids are important for the developing brain, adult brain health and protection against cognitive decline in the elderly. DHA is an important structural part of the nervous tissue whilst circulating EPA levels appear to be important in prevention of the onset of depression. This review will examine the current evidence with regard to efficacy.

Eicosapentaenoic Acid (EPA) and Docosahexaenoic acid (DHA) are the key omega-3 fatty acids found in marine oils. The health benefits of EPA and DHA are widely recognized by scientists and regulatory bodies around the world, with authorized health claims issued by the European Food Safety Authority (EFSA) for brain and visual health (1,2).

The adult brain comprises between 50% and 60% lipids on a dry weight basis (3). DHA is a major structural lipid in the brain, the central nervous system and the retina and accounts for around 8% of the dry weight of the human brain (4). In contrast, EPA and ALA account for less than 1% of the brain lipids (5). The turnover of DHA in the brain has been calculated using radioactive tracers as 3.8 mg/day, hence the half-life of the total content of DHA is around 2.5 years (6).

DHA is integrated into neuronal phospholipids and able to modulate the function of vital signal transduction molecules such as rhodopsin, a G protein coupled-receptor responsible for initiating the visual cascade biochemical pathway and enabling us to see (7).

DHA also has a number of functional roles in the nervous system. For example, it can be metabolized into Neuroprotectin D1 (a potent anti-inflammatory agent) and it facilitates myelination of nerve fibers (8) and synaptogenesis (the formation of synapses between neurons in the nervous system). DHA is thought to be neuro-protective by preventing plaque formation (atherosclerotic plaque in blood vessels and amyloid plaque in the brain), reducing inflammation and encouraging blood flow (9).

DHA is found in all human breast milk, though it varies widely (range: 0.06 to 1.4% of fatty acids) and its content responds to maternal diet (10). Supplementation of DHA, together with Arachidonic Acid (ARA), in infant formula is now widely practiced because of the proven effects of improving visual acuity. Indeed, according to the FAO/WHO, “DHA has convincing benefits for brain (and visual) development in infants” (11).

During gestation, DHA is preferentially transferred across the placenta to the developing fetus. The critical period of brain development in the infant is the rapid growth phase from the third trimester up to two years of age, which is accompanied by a large increase in the cerebral content of ARA and DHA (12). Consequently, the developing brain is particularly vulnerable to an inadequate supply of nutrients because of the rapid trajectory of several neurological processes, including synapse formation and myelination (13). The presence of DHA in breast milk is often cited as a possible reason why breastfed babies have superior cognitive function over infants fed with formula that is not supplemented with DHA (3).

There is also evidence that supplementation of infant formula with DHA and ARA provides cognitive benefits later in life. Colombo et al. (14) demonstrated that supplementation in the first 12 months of life provided significant improvements in standardized cognitive tests at 5 and 6 years, even though such benefits were not apparent at 18 months.

Blood concentrations of omega-3 fatty acids in British children have been shown to be low and associated with poor cognitive performance and behavior. In a randomized controlled trial, dietary supplementation of 600 mg per day of algal DHA for 16 weeks significantly improved reading performance and behavior in healthy but underperforming children aged 7 to 9 years (15).

In a placebo-controlled, multiple, functional MRI study, DHA supplementation has been shown to increase prefrontal cortex activation during sustained attention in healthy teenage boys (16). In another study, using university students, blood flow to the brain was shown to increase following supplementation with DHA-rich fish oil when the students were given cognitive tasks (17).

There are relatively little data on the effects of marine omega-3 in healthy adults. However, in a clinical trial involving 280 middle-aged adults aged 35 to 54, DHA supplementation yielded positive, linear associations with improved non-verbal reasoning, mental flexibility and working memory. No effects were observed for ALA or EPA (18).

As with heart health, whilst population studies show convincingly that higher levels of omega-3 fatty acids are beneficial for brain health, interventions with omega-3 fatty acids in clinical trials have not provided consistently positive results. While many of the reasons for this also apply to cardiovascular health, there are additional complications in brain health studies:

• As DHA accretion and turnover in the brain is slow (6), clinical trials need to be carried out over a long period of time, typically years.
• Direct measurement of DHA in brain tissue is usually only possible post-mortem.
• The minimum dose required to show a beneficial effect is relatively high (19).
• There is little global consistency with regard to biomarker measures of brain function, e.g. intelligence, memory, attention.
• Data from Magnetic Resonance Imaging (MRI) clinical trials showing changes of volume and blood flow in specific regions of the brain often do not correspond to changes in brain function.
• Older people have been shown to have higher blood plasma levels of DHA than younger people with the same intake levels of omega-3 fatty acids (20), but tissue levels remain the same. Hence, simple blood plasma measurements of DHA become decreasingly useful as an indicator of efficacy as older people age.
• Genetic variation in response to DHA intake.
• Interaction of omega-3 fatty acids with other nutrients or pharmacological treatments.

A Cochrane Review (21) carried out in 2006 stated: “There is a growing body of evidence from biological, observational and epidemiological studies that suggests a protective effect of omega-3 PUFA against dementia. However, until data from randomized trials become available for analysis, there is no good evidence to support the use of dietary or supplemental omega-3 PUFA for the prevention of cognitive impairment or dementia”. A meta-analysis of 5 studies incorporating 20,344 subjects calculated the attributable risk of developing Alzheimer’s disease (AD) in a population to be 22% (22). In an even larger meta-analysis of 21 studies and 181,850 participants (23), consumption of one portion of fish a week decreased the risk of onset of mild cognitive impairment (MCI) by 7%, while an intake of 100 mg/day of DHA decreased the risk by 37%. Many (though not all) patients with MCI go on to develop Alzheimer’s disease.

In the MIDAS (Memory Improvement after DHA Study) study, 485 men and women over 55 years of age who had a mild memory complaint were studied in a randomized, controlled, multi-center trial (24). An intervention of 900 mg algal DHA/day was given to the treatment arm for 6 months. The endpoint was a computer-administered test of episodic memory called the Paired Associate Learning test (PAL). The DHA-supplemented patients made far fewer errors in this test, the effect being equivalent to moving backwards on the age-performance curve by over 3 years.

In 2014, Witte et al. (25) conducted a double blinded clinical trial on a small cohort (n=65) of healthy older people aged between 50 and 75 years. The trial involved an intervention of 2.2g fish oil per day for 26 weeks to determine whether there was an improvement in cognition. They found significant beneficial effects on cognition and beneficial effects on brain structure, namely microstructural integrity of white matter and grey matter volume in the temporal, parietal and limbic areas. A recent meta-analysis (19) of 15 randomized, placebo-controlled studies showed that DHA alone, or DHA in combination with EPA, was associated with improved learning and memory recall in older adults with mild memory complaints. Specifically, episodic memory was significantly improved with a daily intervention of at least 1g of DHA and EPA per day.

The VITACOG study involved a two-year intervention of a B vitamin mix (folate, B6 and B12) in 266 participants who were aged 70 years or over with diagnosed mild cognitive impairment. This study showed that high omega-3 status was only protective against brain atrophy in participants with low homocysteine levels (26). The study also showed that the beneficial effects of B vitamins in reducing brain atrophy were strongly dependent on a patient's omega-3 status. The tertile with the highest marine omega-3 fatty acidplasma concentrations (˃590 µmol/L) showed a 40% reduction in atrophy rate in comparison with the placebo group. The subjects in the tertile with the lowest baseline marine omega-3 concentrations (˂390 µmol/L) did not achieve any reduction in the rate of brain shrinkage with B vitamin supplementation. In a further paper (27), it was found that 33% of the participants with a high marine omega-3 status had Clinical dementia Ratings (CDR) of more than zero, compared with 59% of participants who had low levels (at the end of the two-year Vitamin B intervention).

Verbal delayed recall and global cognition were also better in the high omega-3 status group. The paper also demonstrated that for the participants with low circulating marine omega-3 levels, the Vitamin B intervention had no effect in delaying the onset of mild cognitive impairment.

Many studies have used cross-sectional types of analysis or epidemiology to infer that eating fish or consuming EPA/DHA is associated with a lower incidence of dementia or Alzheimer’s disease (28). Many population studies have also shown that higher DHA levels in blood plasma and red blood cells are associated with reduced risk of cognitive decline in the elderly. Some but not all studies have shown reduced levels of DHA in the brain (20), particularly in the frontal cortex and hippocampus.

The hypothesis that DHA supplementation could benefit Alzheimer’s patients was tested in a large trial of over 400 patients by the Alzheimer’s Disease Study Group under the auspices of the US National Institute of Health (29). In this trial, 2g of DHA/d were given for 18 months alongside a series of cognitive tests. Overall, there was no beneficial effect on the cognitive test, the Alzheimer’s Disease Assessment Scale (ADAS-cog), which was the primary measure. However, in a pre-planned exploratory analysis, it was observed that there was a significant cognitive benefit of DHA supplementation in the ApoE4-negative patients. This is promising for the subgroup with this genotype, about half of all patients with Alzheimer’s.

Marine omega-3 fatty acid interventions also show promise as a therapeutic agent in other brain health conditions such as depression, very severe headaches and traumatic neurological injury.

A meta-analysis carried out in 2016 (30) of 13 studies comprising 1,233 participants has shown an overall benefit of marine omega-3 fatty acid interventions on depressive symptoms in major depressive disorder (MDD). A better response was found when patients were already being treated with conventional antidepressants and when the marine oil contained more EPA than DHA. This substantiates an earlier meta-analysis that demonstrated that the proportion of EPA needed to be at least 60% of the omega-3 fatty acid to provide a benefit (31).

Recent work by Ramsden et al. (32) at the NIH in Bethesda, MD, USA has demonstrated that a dietary intervention rich in marine omega-3 fatty acids but low in omega-6 fatty acids can provide an effective, complementary approach for managing chronic headaches. The beneficial effects were attributed to specific endocannabinoids derived from DHA.

There is also evidence that high intakes of DHA and EPA can be protective against the effects of neurological injury, and acute administration immediately after traumatic brain injury or spinal cord injury has been shown to assist in neuro-regeneration, though this research is at an early stage (33).

Brain Health Claims:
In the European Union (EU), two health claims related to brain health have been authorized for use.

• DHA contributes to the maintenance of normal brain function (European Commission, 2012 (1))
• Docosahexaenoic acid (DHA) maternal intake contributes to the normal brain development of the fetus and breastfed infants (European Commission, 2011 (2))

Unequivocal evidence of the benefits of EPA and DHA to the brain may never become available. However, the potential benefits of supplementation to both the developing, fully-formed and declining brain suggest that such interventions are, at the very least, a good insurance policy and could potentially offer a wide spectrum of benefits, particularly since omega-3 fatty acids have an excellent safety profile.

1. Commission Regulation (EU) 432/2012 of 16 May 2012. Official Journal of the European Union 25.2.12
   
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