Higher doses of omega-3 supplements may be needed to avert cognitive decline


For years, a scientific puzzle has occupied researchers with the aim of combating Alzheimer’s disease, a common and incurable form of dementia.

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The results of numerous laboratory and population studies demonstrate the preventive potential of omega-3 fatty acids, “good fats” that are abundant in fish. To date, the majority of studies examining omega-3 fatty acids to prevent or limit cognitive decline in human participants have shown no benefits.

Now, a small clinical study by USC provides important evidence of this discrepancy in the first Alzheimer’s prevention study, in which the omega-3 levels in the blood were compared with those in the central nervous system. The results suggest that higher doses of omega-3 supplements may be required to make a difference, as a dramatic increase in omega-3 blood levels is accompanied by a far smaller increase in the brain. Among participants who had a specific mutation that increased their risk of Alzheimer’s disease, taking the supplements increased levels of a key fatty acid far less than those without the mutation.

“Studies are based on the assumption that omega-3 fatty acids get into the brain,” said senior author Dr. Hussein Yassine, Associate Professor of Medicine and Neurology at USC’s Keck School of Medicine. “Our study was specifically designed to answer this question.”

The paper was published today in the journal EBioMedicine.

The researchers recruited 33 participants who had risk factors for Alzheimer’s but were not cognitively impaired. All participants had a family history of the disease, a sedentary lifestyle, and a low-fat diet. Fifteen carried a variant of the gene called APOE4, which is linked to inflammation in the brain and increases the risk of Alzheimer’s disease by a factor of four or more. The other 18 were not carriers.

Participants were randomly assigned to a treatment group or a control group. Treatment group members were asked to take supplements that contained more than 2 grams of omega-3 called docosahexaenoic acid (DHA) every day for six months. Members of the control group took placebos every day for the same period. Participants in both groups were also asked to take daily B-complex vitamins, which help the body process omega-3 fatty acids.

Dr. Yassine and his colleagues collected samples of blood plasma and cerebrospinal fluid – a measure of whether the omega-3 fatty acids reached the brain – from the participants at the beginning and again at the end of the study period. The scientists looked at the levels of two omega-3 fatty acids: DHA and eicosapentaenoic acid (EPA), a powerful anti-inflammatory agent that the body gets from a small portion of its DHA intake.

Higher Doses For Omega-3 Fatty Acids To Be Effective?

The researchers found that at the end of the six months, participants who took omega-3 supplements had 200 percent more DHA in their blood than participants who took placebos. In contrast, the DHA found in the cerebrospinal fluid was only 28 percent higher in the treatment group than in the control group. This result suggests that measuring omega-3 levels in the blood may not tell how much the brain is doing.

Dr. Yassine and his co-authors also report that within the treatment group, those without the high-risk APOE4 mutation showed a three-fold higher increase in EPA (anti-inflammatory omega-3 fatty acid) in their cerebrospinal fluid than previously seen in carriers of the gene.

E4 carriers had fewer omega-3 fatty acids in their brains despite the same dose. This finding suggests that EPA is either used up, lost, or not absorbed by the brain as efficiently with the E4 gene. “

Dr. Hussein Yassine, Associate Professor of Medicine and Neurology, USC’s Keck School of Medicine

Notably, the 2-gram dose of DHA in this study was well above that used in large clinical trials testing the preventive power of omega-3 fatty acids, which are typically administered 1 gram or less daily.

“If you use a lower dose, you can expect less than 10 percent increases in omega-3 fatty acids in the brain, which may not be considered useful,” said Dr. Yassine.

The victim of the study participants drives Alzheimer’s research

Investigators worked for two years to recruit participants for the study. The entry barrier was the only method that could be used to extract cerebrospinal fluid: a lumbar puncture, also known as a spinal tap. It proved difficult to find people willing to undergo this procedure, in which a hollow needle pierced the lower back twice.

Dr. Yassine praised the study participants.

“They were generous with their time and they were brave to do the lumbar punctures,” he said. “The main reason they did this was because they wanted to advance science.”

Participants’ bravery can pay off in creating even more knowledge about omega-3s and Alzheimer’s disease.

The preliminary data from the current study were so fascinating that the scientists were able to secure funding for a larger study that is currently being recruited. After 320 participants over two years, it is investigated whether high doses of omega-3 fatty acids can slow the cognitive decline of the carriers of the APOE4 gene.

Dr. Yassine believes that moving from a small study to a larger study is a good model for developing therapies and preventions that target the brain.

“These pilot studies are as important as a step toward much larger, more complicated studies,” he said. “The bottom line is that before you begin very expensive clinical trials, you have to prove the proof of concept that your drug is getting into the brain and changing the biomarkers for disease in the right direction.”


USC’s Keck School of Medicine

Journal reference:

Arellanes, IC et al. (2020) Brain Shedding of Additional Docosahexaenoic Acid (DHA): A Randomized, Placebo-Controlled Clinical Trial. EBioMedicine. doi.org/10.1016/j.ebiom.2020.102883.


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