Brain health – does omega-3 fatty acid help?

A/Prof Chee L Khoo, 23rd January 2025

Omega-3 fatty acids?

We explored the benefits (or lack of) of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) back in early December 2024 when we look at the indications and criteria to initiate icosapent ethyl in patients with residual hypertriglyceridaemia for cardiovascular benefit. Now, omega-3 fatty acid (O3FA) supplements often contain a combination of EPA and DHA. If you recall, we highlighted the importance of EPA in reducing cardiovascular (CV) events. Sadly, all the CV benefits from EPA, are potentially negated by the less favourable DHA. But that is all about cardiovascular risk reduction. What about the benefits of O3FA in improving brain function including cognition improvement and dementia prevention?

O3FA structure and sources

The 3 O3FAs involved in human physiology are α-linoleic acid (ALA), EPA and DHA. Humans are unable to synthesize ALA and thus, we need to obtain it from the diet. We can convert ALA to EPA and from there to DHA but the efficiency is less than 5% and varies with individuals (1). Thus, most of the EPA and DHA we need comes from our diet.

When we think of dietary O3FA sources, we think about the oily fishes including salmon. Like humans, salmon are also inefficient at converting ALA into EPA and from EPA to DHA. They too, have to obtain O3FAs through their diet which is (micro)algae and plankton. The only problem is that at least 50% of the world’s fish and seafood for human consumption comes from aquaculture (i.e. farmed seafoods). Farmed salmon were traditionally fed a diet with high levels of the marine ingredients – fish oil and fishmeal. These are increasingly being replaced by seed-oils (e.g rapeseed oil) with a consequence of an increase in omega-6 fatty acid (O6 FA) as well as a ≥50% reduction in the EPA and DHA levels (2). Remember, O6FA is pro-inflammatory and O3FA is anti-inflammatory. The consequences of this shift in O6:O3 ratios is unknown.

What do DHA and EPA do in the brain?

DHA is a major fatty acid in membrane phospholipids in the grey matter of the brain and makes up approximately 25% of total fatty acids in the human cerebral cortex and 50% of all PUFA in the central nervous system. DHA is transported into the brain in the form of lyso-phosphatidyl-choline by the major facilitator superfamily domain-containing protein 2a (Mfsd2a) [3]. Mfsd2a knockout mice had 50% lower levels of DHA in brains with consequent cognitive deficits and neuronal cell loss in hippocampus and cerebellum, providing strong support for the role of DHA in cognitive function. The only source of DHA is from the blood and apoE4 plays an active role in the transport (4,5).

Overall, O3FA has 3 major roles in brain function:

  1. Building and maintaining brain function – brain has a constant cell turnover or apoptosis, albeit a slow one. DHA is also needed for brain structure maintenance.
  2. Brain perfusion – Brain perfusion is distributed by arteries and arterioles, which are modulated by vasoactive molecules, some of them derivatives of EPA, and some of them derivatives of DHA.
  3. Managing inflammatory process in the brain – Both EPA and DHA reduce severity of inflammation, with mechanisms and/or metabolites mitigating development of inflammation, as well as facilitating resolution of inflammation.

What about apoE?

25% of all cholesterol in the body is found in the brain. The most recognised function of apoE is transport of cholesterol and other lipids, although apoE is also important in synaptic plasticity, signal transduction and immunomodulation [6]. An imbalance in cholesterol homeostasis is associated with an increased risk of neurodegenerative disorders such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), Niemann-Pick type C disease (NPC), and Smith–Lemli Opitz syndrome (SLOS) [6].

In humans, the apoE gene has three common alleles, ε2, ε3, and ε4. About 25% of the people in the U.S. are apoE4 carriers, and apoE4 is present in 65–80% of all AD patients. The presence of apoE4 increases the risk of developing AD by 4-fold (one allele) to 14-fold (two alleles) compared with apoE3 homozygotes. apoE2 is considered neuroprotective.

Postulated reasons for the increased risk in apoE4 carriers include defective amyloidβ (Aβ) clearance, which leads to increased deposition of Aβ in senile plaques (30], a loss of neuronal synaptic plasticity and dendrite outgrowth, neuroinflammation, blood-brain barrier dysfunction and lower brain uptake of DHA [6]

Evidence of the importance of O3FA in brain health

There is a lot of evidence out there that link maternal DHA levels in pregnancy and lactation with neural development in infants. Similarly, the links of low DHA levels and mental illness in adolescents and adults, ADHD, autism and psychopathology are increasingly being demonstrated but it is beyond the scope of this review. We will be concentrating on the links between O3FAs and adult cognitive function and dementia today.

There is definitely solid evidence albeit from small and sometimes, short duration randomised controlled trials which demonstrate the link between low fish intake and cognitive impairment. However, the results over the years have been mixed (see below to see why). Older studies stretching back to the 1990s were included in previous meta-analyses which may be the reason why we are seeing inconsistent results. Many of these were observational studies.

Over the last 5 years, there have been newer studies. Wood et al (2022) reviewed 5 prospective cohort studies in subjects >55 years old (12):

  • The Rotterdam study of 5386 individuals showed that > 18.5 g/day of fish consumption at baseline was associated with a 70% reduced risk of AD at 1.2-year follow-up [16], although a 9.6-year follow-up showed no association.
  • At 5.4-year follow-up in the Cardiovascular Health Cognition Study of 2233 individuals ≥ 65 years, consumption of > two fatty fish meals per week showed a 41% decreased risk of AD in those without the apoE4 allele compared with those eating less than once/month [8].
  • At 3.9-year follow-up In the Chicago Memory and Aging Project of 815 individuals ages 65-94 years, ≥1 fish meals per week was associated with a 60% reduction in risk of AD with those in the top three quintiles having a multivariate-adjusted relative risk as low as 0.2 [9].
  • In 9.1-year follow-up of 899 individuals in the Framingham Heart Study, those in the upper quartile of DHA in plasma phosphatidylcholine (mean DHA intake of 0.18 g/day of fish intake equating to 3 servings/week) had a significant 47% reduction in risk of developing all-cause dementia (RR= 0.53, P = 0.04) and a 39% reduction in risk of AD (RR= 0.61, P = 0.14) [10].
  • In the Rush Memory and Aging Project of 915 individuals with a mean age of 81.4 years living in retirement communities and without Alzheimer’s disease, at 4.9-year follow-up, cognitive ability showed that consumption of one seafood meal per week was associated with slower rates of decline in semantic memory and perceptual speed [11].

What about those with mild cognitive impairments (MCI)?

A review by Wood et al. (2022) of 13 RCTs of adults ≥ 50 years with MCI, supplemental O3FA had a protective effect against cognitive decline in nine studies but no effect in four studies with higher amounts showing most benefit [12]. Importantly, significant improvement occurred prior to cognitive impairment or with early and MCI, whereas those with AD had no benefit.

Kosti et al (2022) reviewed nine RCTs of which five included MCI or AD and found a dose-response relationship was found between the omega-3 index achieved and improvement in executive function but not in general cognition (13). The age range was > 50 years in seven trials but in two trials the age was > 18 years and it showed minimal benefit. A wide range in EPA and/or DHA supplementation (from 2 to 36 months) and doses (112.5-1680 mg EPA and 297-1680 mg of DHA) may also have affected outcome.

Yet, in an RCT of 60 adults between the ages of 60 – 90 years from New Zealand with MCI, supplementation with 1491 mg DHA + 351 mg EPA daily had no effect on cognition compared to a placebo (1857 mg linoleic acid) at 12 months [14].

It would seem that the effects of O3FAs supplementation in mild Alzheimer’s disease may be beneficial early in disease onset when there is slight impairment of brain function; however, there is not enough evidence to support O3FAs in the treatment of AD. Yassine et al. recommended that high-dose DHA supplementation be considered in apoE4 carriers before the onset of AD or in the early stages (15).

What about those with normal cognition?

Malik A, et al (2021) reported that 250 patients with stable clinical coronary artery disease (CAD) on statin treatment randomized to 1.8 g EPA and 1.5 g DHA daily over 30 months had significantly better scores than control (no supplementation) for verbal fluency, language and memory and two tests of visual-motor coordination respectively [16].

15 RCTs previously reported the effect of EPA and DHA on cognitive function in cognitively healthy individuals over age 50 (17). There was a wide range of trial duration and doses of O3FA. Trial duration ranged from 3 months to 5 years and total dose of EPA and DHA ranged from 285mg to 3.36 g daily. Of the 15 RCTs, seven reported benefit on cognitive function measured by neuropsychological testing, whereas eight reported no benefit.

Why the conflicting results?

  • Differences in outcomes in the trials can be due to:
  • Differences in doses of DHA and EPA
  • Whether the doses studied were based on the (inaccurate) dietary questionnaires, or plasma levels of EPA/DHA or erythrocyte DHA (Omega 3 Index)
  • Duration of the trials
  • The baseline of cognition of subjects
  • The age and sex of the subjects and the type of cognitive assessment used in the trials – men with higher O3FA levels had better executive functioning and processing speed, whereas women had better verbal and nonverbal episodic memory
  • Whether apoE4 were screened for in the trial subjects

As you can see, it’s hard for us to make up our minds as to whether we should recommend O3FAs supplements to our patients and if we do, which patient, what dose and for how long. For those patients who are already cognitively impaired where the diagnosis of AD is already made, is it too late?

A summary?

It would seem that there are credible evidence that O3FAs can improve cognitive function in patients who are either healthy or has MCI. There is conflicting evidence as to whether O3FA supplement is beneficial to those who has moderate to severe cognitive impairment. Thus, if we were to advise O3FA supplements, it should be in those >50 years old with MCI (before it’s too late) or those healthy individuals but at higher risk of dementia. These might be patients who has a family history of AD, family history of apoE4 and those with coronary artery disease.

Should we be advocating screening for apoE4?

Certainly, in those with a family history of AD or apoE4. We need to treat before significant cognitive impairment has set in. What about those without the family history? That’s the discussion we need to have with the patient in front of us. Remember, about ~20-25% the general population carry at least one allele of the apoE4 gene but ApoE4 carriers account for 50-70% with AD. Checking for apoE is not rebatable under Medicare and it costs about $180.

What dose DHA then?

The American Heart Association suggests a daily intake of 1000 mg EPA + DHA for those individuals with established cardiovascular disease (18). The European Food Safety Authority suggest that all adults should be consuming 250 mg EPA + DHA per day respectively through oily fish consumption (19), whereas the International Society for the Study of Fatty Acids and Lipids (ISSFAL) recommends a minimum daily intake of 500 mg of EPA + DHA to reduce the risk of cardiovascular disease (20)The Australian “guidelines” recommends about 160mg of total omega-3 fatty acids daily for men and 90mg per day for women (21). But have not been updated for at least 20 years. All the recommendations in the guidelines are for CV protection.

Farmed Atlantic salmon still provide a significantly higher amount of EPA + DHA than wild salmon, yielding 2.75, 2.21 and 1.36 g per 100 g ww flesh for salmon farmed in 2006, 2010 and 2015 respectively, compared to 0.76 g per 100 g ww flesh for wild salmon (2). A single 130 g portion of Scottish salmon farmed in 2006 would have been adequate to meet the 3.5 g EPA + DHA weekly intake level set by ISSFAL, whereas in 2015 this would have required two portions per week. But these recommendations are for CV benefit and not brain health which requires more.

The doses of O3FAs used in the RCTs ranged from 112.5–1680mg EPA and 297–1680mg of DHA per day. One generic Australian brand 1000mg fish oil capsule only contains 180mg of EPA and 120mg of DHA. So, we are talking about 2 – 10 capsules per day for brain health.

References:

  1. https://en.wikipedia.org/wiki/Omega-3_fatty_acid. Accessed 4th January 2025.
  2. Sprague M, Dick JR, Tocher DR. Impact of sustainable feeds on omega-3 long-chain fatty acid levels in farmed Atlantic salmon, 2006-2015. Sci Rep. 2016 Feb 22;6:21892
  3. Nguyen LN, Ma D, Shui G, et al. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 2014; 509:503–506
  4. Pontifex, M.; Vauzour, D.; Minihane, A.M. The effect of APOE genotype on Alzheimer’s disease risk is influenced by sex and docosahexaenoic acid status. Neurobiol. Aging 2018, 69, 209–220
  5. Balakrishnan, J.; Kannan, S.; Govindasamy, A. Structured form of DHA prevents neurodegenerative disorders: A better insight into the pathophysiology and the mechanism of DHA transport to the brain. Nutr. Res. 2021, 85, 119–134
  6. Lanfranco MF, Ng CA, Rebeck GW. ApoE Lipidation as a Therapeutic Target in Alzheimer’s Disease. Int J Mol Sci. 2020 Sep 1;21(17):6336.
  7. Devore EE, Grodstein F, vanRooij FJA, et al. Dietary intakeof fishandomega-3fatty acids in relation to long-term dementia risk. Am J Clin Nutr 2009; 90:170–176.
  8. Huang TL, Zandi PP, Tucker KL, et al. Benefits of fatty fish on dementia risk are stronger for those without APOE e4. Neurology 2005; 65:1409–1414.
  9. 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.
  10. 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.
  11. van de Rest O, Wang Y, Barnes LL, et al. APOE e4 and the associations of seafood and long-chain omega-3 fatty acids with cognitive decline. Neurology 2016; 86:2063–2070
  12. Wood AHR, Chappell HF, Zulyniak MA. Dietary and supplemental long-chain omega-3 fatty acids as moderators of cognitive impairment and Alzheimer’s disease. Eur J Nutr 2022; 61:589–604.
  13. Kosti RI, Kasdagli MI, Kyrozis A, et al. Fish intake, n-3 fatty acid body status, and risk of cognitive decline: a systematic reviewand a dose-response meta-analysis of observational and experimental studies. Nutr Rev 2022; 80:1445–1458.
  14. Mengelberg A, Leathem J, Podd J, et al. The effects of docosahexaenoic acid supplementation on cognition and well being in mild cognitive impairment: a 12-month randomised controlled trial. Int J Geriatr Psychiatry 2022; 37:1–12.
  15. Yassine HN, Finch CE. APOE Alleles and diet in brain aging and Alzheimer’s disease. Front Aging Neurosci 2020; 12:150.
  16. Malik A, Ramadan A, Vemuri B, et al. v-3 Ethyl ester results in better cognitive function at 12 and 30 months than control in cognitively healthy subjects with coronary artery disease: a secondary analysis of a randomized clinical trial. Am J Clin Nutr 2021; 113:1168–1176.
  17. Welty FK. Omega-3 fatty acids and cognitive function. Curr Opin Lipidol. 2023 Feb 1;34(1):12-21.
  18. Kris-Etherton PM, Harris WS, Appel LJ; American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002 Nov 19;106(21):2747-57.
  19. EFSA, European Food Safety Authority. Scientific opinion on dietary reference values for fats, including saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans fatty acids, and cholesterol. EFSA panel on dietetic products, nutrition and allergies (NDA). EFSA J. 8, 1461 (2010).
  20. International Society for the Study of Fatty Acids and Lipids (ISSFAL). Report of the sub-committee on: Recommendations for intake of polyunsaturated fatty acids in healthy adults. (ISSFAL, Brighton, 2004).
  21. https://www.eatforhealth.gov.au/nutrient-reference-values/nutrients/fats-total-fat-fatty-acids. Accessed 8th January 2025.