Supplements

DHA: An Omega-3 Fatty Acid for Brain Health

by Ari Magill, MD

Docosahexaenoic acid (DHA) is one of three omega-3 fatty acids that play a role in human physiology. It is derived from marine sources, as is the second, eicosapentaenoic acid (EPA). The third one, alpha linoleic acid (ALA), is derived from plant sources. All three are polyunsaturated essential fatsa touted for their anti-inflammatory effect and for having a positive impact on cardiovascular health.

They are in short supply in the standard American diet compared to omega- 6 fatty acids, which are ubiquitously present in grocery stores and restaurants in the form of heavily processed vegetable oils (such as soybean, corn, and canola oil).

EPA is important for anti-inflammatory signaling and may have a beneficial impact on depression, while DHA plays a key structural role in the cellular membrane of neurons, the defining cells of the central nervous system, particularly in the brain and retina.

DHA aids in membrane flexibility and fluidity. For this reason, supplementation with DHA has been studied for its ability to enhance cognition and stave off cognitive decline. Overall results point to some benefit if DHA is taken before the onset of Alzheimer’s disease (AD). Multiple epidemiologic studies have pointed to a potential cognitive benefit in consuming foods high in DHA and omega-3 fatty acids.

The Takeaway:

Studies suggest that omega-3 supplementation might mitigate risk of cognitive decline in those with MCI.

Animal Studies

Hooijmans et al published a study exploring the differential influence of a typical western diet high in cholesterol (1%) vs a diet high in DHA (0.5%) using a transgenic mouse model, who were genetically engineered to develop AD were fed one of these two diets for 12 months starting at 6 months of age.1 At 18 months of age, their brains were imaged to determine cerebral blood volume and flow, and then evaluated for the presence of beta amyloid plaques. For those on the typical western diet, beta amyloid plaque burden increased in a specific area of the hippocampus, the brain’s memory center, called the dentate gyrus. Cerebral blood volume was unchanged.

By comparison, mice on the DHA-enhanced diet had increased cerebral blood volume without elevated blood flow elsewhere, implying that the blood vessels were dilated. Beta amyloid deposition was diminished. These results suggest a possible link between brain circulation changes and the progression of AD, and the favorable influence of DHA.

Kariv-Inbal et al used another mouse model to explore whether the AD-promoting effects of APOE4b can be reduced by a DHA-enhanced diet or magnified by a cholesterol-enriched diet.2 They were genetically modified to express human APOE3 or APOE4 and were given one of these two diets in a typical or stimulating environment. APOE4 status did not influence cholesterol metabolism or fatty acid levels in the hippocampus but did alter phospholipid levels (special molecules with both a water-soluble and a fat-soluble side that compose cell membranes). This alteration was augmented by high cholesterol diets and reversed by diets rich in DHA. Compared to APOE3, APOE4 boosted hippocampal beta amyloidc production in ordinary surroundings and decreased its production in stimulating conditions. Other abnormal pathologic effects of APOE4 included changes in certain neuronal transporter numbers and poorer scores on object-recognition tasks. These negative outcomes were prevented by DHA-fortified diets.

Human Studies

Zhang et al investigated the effects of fish consumption (a primary dietary source of EPA and DHA), total polyunsaturated fats, total omega-3 polyunsaturated fats, or at least one omega-3 polyunsaturated fat on the chances of developing mild cognitive impairment (MCI), cognitive decline, dementia, AD, or Parkinson disease (PD).3 Twenty-one studies were evaluated, constituting a total of 181,580 participants. A once-per-week serving of fish marginally reduced the likelihood of all-cause dementia and, specifically, AD. Isolated DHA had a more potent effect on lowering the risk of dementia and AD when it was added at increments of 0.1 grams per day.

Yurko-Mauro et al assessed the benefit of DHA supplementation on age-related cognitive decline.4 They enrolled 485 volunteers age 55 or older. For acceptance into the study, subjects had to perform within normal limits on a common cognitive screening test but score lower than younger adults on a logical memory test. They were randomly assigned to receive either 900 mg per day of DHA by mouth or placebo over 24 weeks. They were then evaluated for visuospatial learning and episodic memory.

Those given DHA scored significantly higher in tests of immediate and delayed verbal recognition memory. Neither working memory nor executive function was improved.

Yan-Ping Zhang et al studied the effects of DHA supplementation on 240 subjects with MCI.5 They were randomly assigned to receive either 2 grams of DHA per day or placebo, in the form of corn oil, for 24 months. Participants underwent cognitive testing as well as lab work to assess beta amyloid-related blood markers at baseline, 6, 12, 18, and 24 weeks. The treatment group performed significantly better on measures of full-scale IQ, verbal IQ, and subdomains of information and digit span. Blood biomarkers of beta amyloid were decreased and biomarkers of autophagyd were increased in those receiving DHA compared to placebo.

These same scientists examined those MCI participants, showing how 2 grams per day of DHA for only 12 months boosted cognitive testing scores while preserving the hippocampal volume and the cerebrum.6

Zhang X et al published a metanalysis of the cognitive effects of omega-3 long chain fatty acids on older subjects with MCI, examining a total of seven randomized clinical trials, consisting of 434 participants, of which 213 received treatment and 221 received placebo.7 An overall significant cognitive benefit was seen in the supplementation groups.

Yurko-Mauro et al published a metanalysis of clinical trials and observational studies that assessed the cognitive impact of DHA, given either alone or together with EPA, on healthy older adults of at least 18 years of age with or without mild memory complaints.8 Results showed that a combined intake of greater than 1 gram daily of supplementation improved episodic memory (but not semantic or working memory).

In contrast, DHA supplementation does not appear to ameliorate cognitive decline at all in subjects with mild-to-moderate AD at a dosage of 2 grams daily over 18 months.9 This might be at least partially explained by enhanced catabolic (breakdown) processes that occur due to neurodegeneration (the death and destruction of neurons) and toxicity from beta amyloid in AD.10 An enzyme called phospholipase A2 gets revved up, and it cuts away membrane-bound DHA, leaving free DHA within the cell body. This gets oxidized, a process called lipid peroxidation, to form a chemical product called a neuroprostane. This leads to more production of destructive free radicals, leaky cell membranes, and further neurodegeneration.

Possible Side Effects

Lenox and Bauer published a review article summarizing the potential side effects of omega-3 fatty acids on cats and dogs.11 Side effects documented in humans include increased risk of bleeding through altered platelete function, GI upset causing nausea, vomiting, and diarrhea, as well as the potential for lipid peroxidation, as described above. Interactions with medications, such as aspirin, which would further increase bleeding risk, are also possible. Since rancid fats are destructive to cells, it is particularly important to not take omega-3 fatty acid supplements past their expiration date. Vitamin E can protect against much of the oxidative damage from polyunsaturated fats and can be found in supplements to prevent spoilage.

Conclusion

Studies suggest that omega-3 supplementation might mitigate risk of cognitive decline in those with subjective cognitive complaints or MCI. It does not appear to be beneficial for those with mild-to-moderate AD.

Health food stores and Amazon sell DHA, but one serving of fish per week, focusing on SMASH (salmon, mackerel, anchovies, sardines, and herring) fish, could have similar benefit.

Notes

a Fats required from the diet because they cannot be synthesized in the body.

b APOE4, otherwise known as apolipoprotein E4, is a genetic isoform, that is recognized as the strongest genetic risk factor for sporadic AD. As the name implies APOE codes for the apolipoprotein involved in shuttling fats. One line of research suggest APOE also serves as a master transcription factor, that can turn on many other genes, including a host of pro-inflammatory ones, and that this function might explain why APOE influences the progression of AD pathology.

c Beta amyloid is one of two identified abnormal protein structures associated with the brain pathology of AD, the other being abnormal tau, in the form of tau tangles.

d Autophagy is an important “housecleaning” whereby wastes and poorly functioning cell products are degraded and removed. Impaired autophagy is now believed to play a key role in AD pathology.

e Platelets are “sticky” cells that help to form scabs and clots.

References

  1. Hooijmans CR, et al. Changes in cerebral blood volume and amyloid pathology in aged Alzheimer APP/PS1 mice on a docosahexaenoic acid (DHA) diet or cholesterol enriched Typical Western Diet (TWD). Neurobiol Dis. 2007;28(1):16-29. doi: 1016/j.nbd.2007.06.007.
  2. Kariv-Inbal Z, et al. The isoform-specific pathological effects of apoE4 in vivo are prevented by a fish oil (DHA) diet and are modified by cholesterol. J Alzheimers Dis. 2012;28(3):667-683. doi: 10.3233/JAD-2011-111265.
  3. Zhang Yu, et al. Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies–3. Am J Clin Nutr. 2015;103(2):330-340. doi: 3945/ajcn.115.124081.
  4. Yurko-Mauro K, et al. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010;6(6):456-464. doi: 1016/j.jalz.2010.01.013.
  5. Zhang YP, et al. DHA supplementation improves cognitive function via enhancing Aβ-mediated autophagy in Chinese elderly with mild cognitive impairment: a randomised placebo-controlled trial. J Neurol Neurosurg Psychiatry. 2018;89(4):382-388. doi: 1136/jnnp-2017-316176.
  6. Zhang YP, et al. Effects of DHA supplementation on hippocampal volume and cognitive function in older adults with mild cognitive impairment: a 12-month randomized, double-blind, placebo-controlled trial. J Alzheimers Dis. 2017;55(2):497-507. doi: 3233/JAD-160439.
  7. Zhang X, et al. Effect of n-3 long-chain polyunsaturated fatty acids on mild cognitive impairment: a meta-analysis of randomized clinical trials. Eur J Clin Nutr. 2020;74(4):548-554. doi: 1038/s41430-019-0544-4.
  8. Yurko-Mauro K, et al. Docosahexaenoic acid and adult memory: a systematic review and meta-analysis. PloS One. 2015;10(3):e0120391. doi: 1371/journal.pone.0120391.
  9. Quinn JF, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. 2010;304(17):1903-1911. doi: 10.1001/jama.2010.1510.
  10. Yassine HN, et al. Association of docosahexaenoic acid supplementation with Alzheimer disease stage in apolipoprotein E ε4 carriers: a review. JAMA Neurol. 2017;74(3):339-347. doi: 1001/jamaneurol.2016.4899.
  11. Lenox CE, Bauer JE. Potential adverse effects of omega‐3 fatty acids in dogs and cats. J Vet Intern Med. 2013;27(2):217-226. doi: 1111/jvim.12033.

About the Author

Dr. Ari Magill is a holistic neurologist and medical consultant based in Mesa, AZ. He received medical school training at University of Texas Southwestern in Dallas and residency training at the University of Arizona in Tucson. He is passionate about finding innovative treatments for cognitive impairment, emphasizing lifestyle change and natural supplements.