Omega-3 fatty acids show potential in protecting brain health in older adults

A recent one JAMA network opened study assesses the role of ω-3 polyunsaturated fatty acids (PUFAs) in reducing white matter lesion (WML) accumulation and degeneration of neuronal integrity in older adults.

Study: ω-3 PUFA for secondary prevention of white matter lesions and neuronal integrity breakdown in older adults: a randomized clinical trial. Image credits: Bk87 / Shutterstock.com

What is WML accumulation?

Cerebral WML accumulation is associated with an increased risk of cognitive decline and Alzheimer’s disease (AD). The pathophysiological mechanisms involved in this association include the reduced regenerative capacity of oligodendrocytes, cerebral hypoperfusion, degeneration of the blood-brain barrier and activation of endothelial cells. Although periventricular WMLs may suggest microglial activation, the deeper subcortical tissue WMLs may be more indicative of progressive myelin loss, astrogliosis, and axonal degeneration.

Reduced WML burden has been associated with dietary-derived bioactive lipids, such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and ω-3 PUFAs. The ω-3 PUFAs can act as lipophilic, inflammasome-resolving substrates for metabolite synthesis, thereby shifting metabolism and cell signaling toward a reduced inflammatory state. Previous studies have demonstrated the ability of ω-3 PUFAs to reduce the expression of endothelial and immune cell surface protein CD54, which may increase blood-brain barrier permeability and release of microglial cytokines.

Meta-analyses of clinical trials have shown that plasma ω-3 levels may be directly associated with up to 25% of WML variations. Furthermore, higher levels of ω-3 PUFAs have been associated with a 40% reduction in the risk of WML in older adults. Therefore, it is critical to clarify whether the ω-3 treatment offered to individuals with WML accumulation and suboptimal ω-3 status can attenuate the progression of WML and the breakdown of neuronal integrity.

About the study

The current placebo-controlled, quadruple-blind and randomized clinical trial was conducted on Oregon Health and Science University between 2014 and 2019. Treatment stratification was performed using the apolipoprotein E ε4 allele (APOE*E4) carrier status, and all results were compared to a placebo group.

The primary study outcome was annual WML progression measured by magnetic resonance imaging (MRI). Diffusion tensor imaging of fractional anisotropy (DTI-FA) was also used to assess neuronal integrity degradation.

The study cohort consisted of persons aged 75 years and older without dementia. Study participants also had suboptimal plasma ω-3 PUFA levels less than 5.5 percent by weight of total, as well as WMLs greater than or equal to 5 cm.³.

A three-year treatment with 1.65 g of ω-3 PUFA, consisting of 975 mg EPA and 650 mg DHA, was administered, along with a soybean oil placebo matched in appearance, taste and odor.

Findings of the study

The ω-3 treatment group showed less annual crude WML progression compared to the placebo group; however, this difference was not statistically significant. These results were similar for neuronal integrity degradation, with the ω-3 group showing less, but not statistically significant, DTI-FA decrease. The mean annual change in ventricular volume and total change in brain volume were not different between groups.

The average annual increase in WMLs in APOE*E4 carriers who received the ω-3 treatment was lower than in the placebo group, but not statistically significant. For APOE*E4 in noncarriers, no difference in the mean annual increase in WML was observed in the ω-3 and placebo groups.

In the midst of APOE*E4 carriers, the The mean annual DTI-FA reduction of the treatment group was significantly lower than that of the placebo group. Similarly, mean annual DTI-FA reduction for non-carriers of APOE*E4 was not different between treated and control groups.

Adverse events (AEs) or serious adverse events (SAEs) did not differ between groups. Sixteen study participants experienced SAEs in the two study groups, and 26 participants were hospitalized, including 12 and 14 individuals from the treatment and placebo groups, respectively. Five deaths were recorded in the ω-3 group and one in the placebo group.

Adverse events occurred in 44 and 41 participants in the ω-3 and placebo groups, respectively. Side effects include harmful falls, gastrointestinal disorders, and musculoskeletal and connective tissue disorders.

The mean annual increase in subcortical and periventricular WML was lower in the ω-3 group compared with the control group. This pattern was similar for mean annual DTI radial diffusivity and mean DTI diffusivity increase. For executive cognitive function z-scores, no differences were observed between the treatment and control groups.

Conclusions

The research results indicate this ω-3 treatment was well tolerated and safe but ineffective in achieving a significant reduction in WML progression and neuronal integrity degradation in individuals at risk for dementia. However, for APOE*E4 carriers, the reduction in neuronal integrity degradation was significant, suggesting the enhanced effects of ω-3 for these individuals.