New Randomized Clinical Trial Shows Omega-3 Fatty Acids Benefit APOE-ε4 Carriers

Alzheimer’s disease is the most common form of dementia. The Centers for Disease Control and Prevention reports that in 2023 6.7 million Americans were living with Alzheimer’s and that number is expected to grow to 14 million by 2060.

Research shows that the pathological changes of Alzheimer’s occur decades before symptom onset and that the strongest risk factor for the disease is being an APOE-ε4 carrier, with the ε4 allele being the most significant.

APOE helps transport cholesterol and other fats into the blood stream and research demonstrates that impairment of the brain’s ability to process fats may play a role in the development of Alzheimer’s. In addition to lipid processing impairment, researchers also believe the underlying mechanisms between APOE-ε4 and Alzheimer’s includes β-amyloid peptide clearance, neuronal death, and tau phosphorylation.

It's estimated that about 25 percent of the general population carries at least one ε4 allele of APOE which represents a three-fold increased risk of Alzheimer’s for heterozygotes and nearly a 15-fold increased risk for homozygotes.

Omega-3s for Secondary Prevention

Newly published research from the Oregon Health & Science University found a statistically significant benefit of omega-3 fatty acid supplements for people predisposed to Alzheimer’s because of APOE-ε4. There was no statistically significant benefit to the healthy older study participants who did not carry the predisposition.

This randomized clinical trial featured 102 participants 75 years old or older and used magnetic resonance imaging (MRI) to determine white matter lesions and changes in white matter lesions after a three-year period. Half of the participants took a placebo, and half took a supplement containing 1.65 g of omega-3 featuring 975 milligrams (mg) of eicosapentaenoic acid (EPA) and 650 mg of docosahexaenoic acid (DHA). All participants had low omega-3 fatty acid levels, were considered healthy, and had relatively high levels of white matter lesions.

“While it’s disappointing that omega-3s did not attenuate the development of white matter lesions in the healthy older participants, it’s encouraging that it did so in a population at high risk of developing Alzheimer’s,” said Ronald Hoffman, MD, a pioneering integrative physician in New York. “In this study with an N of 102, it’s even more surprising that the subset with APOE-ε4 benefited.”

Regarding the omega-3 formulation that is most effective, the researchers point out that studies have produced mixed results based on the amount of EPA and DHA. They conclude that their findings along with previous research indicate that an EPA-dominant formula may provide benefit for APOE-ε4 carriers who have white matter lesions but no dementia while a DHA-dominant formula may have more benefit for non APOE-ε4 carriers with mild-to-moderate dementia.

Dr. Hoffman points out that in the introduction of the paper the researchers confirm that a diet high in omega-3s is associated with reduced white matter lesion burden. “The beneficial connection between omega-3s and brain preservation has been established retrospectively,” said Dr. Hoffman who is the host of the popular nationally-syndicated radio program Intelligent Medicine, and the Internet podcast of the same name. “This study is an attempt to advance a mere association into a plausible intervention.”

"The fact that neuronal integrity breakdown was slowed in people randomized to omega-3 treatment who are also at high risk for Alzheimer's disease is remarkable and warrants a larger clinical trial in more diverse populations in the future," said Gene Bowman, ND, MPH, part of the research team for this study and the director of clinical trials and instructor of neurology at the McCance Center for Brain Health, Massachusetts General Hospital, and Harvard Medical School.

Clinical Significance

As genetic testing becomes more advanced and available, patients are often informed of their increased risk of a variety of illnesses based on test results. This latest study adds to the growing body of evidence indicating that epigenetics can positively influence the genetic profile of a patient to help reduce predisposed risk.

“This study helps validate the proposition that our genes are not deterministic,” explained Dr. Hoffman. “Our genes are not our destiny and are more or less guided in their expression by environmental factors, which is epigenetics at work.”

What’s Dr. Hoffman’s clinical conclusion regarding omega-3s and brain function? “Based on this study and previous research, it’s clear that omega-3 intake confers brain benefits across the life cycle—in utero and from the cradle to the grave.”