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JAMA Network Open has just published the results of a randomized and quadruple-blinded clinical trial conducted at the Oregon Health & Science University, evaluating the use of omega-3 supplementation on the progression of white matter lesions (WMLs) and neuronal integrity breakdown among older adults. One-hundred and two participants aged 75 or older were included as part of the Polyunsaturated Fatty Acids for the Prevention of Cerebral Small Vessel Disease and Inflammation in Aging (PUFA) trial. The study participants were cognitively intact or had mild cognitive impairment, but not dementia, as defined by both the Clinical Dementia Rating (CDR) and the Mini-Mental State Examination (MMSE). However, brain MRI scans indicated the presence of WMLs (greater than or equal to 5 cm3), as well as suboptimal plasma levels of omega-3 fatty acids (less 5.5% of total fatty acids) in all participants, both factors raising the risk for cognitive decline and progression of WMLs.
Participants in this 3-year clinical trial received either a total daily dose of 1.65 g omega-3s (975 mg EPA and 675 mg DHA) in a triacylglycerol emulsion or a placebo comprised of soybean oil. The primary outcome was WML progression, and secondary outcomes included whole-brain diffusion tensor imaging of fractional anisotropy (DTI-FA), an indicator of white matter microstructural integrity, previously shown to be a potential early indicator of underlying Alzheimer’s disease (AD) pathology, particularly among people carrying an APOE ε4 allele. It’s worth noting that the ε4 allele is the best-established risk factor for late-onset AD, present in 40% of people with AD; one copy is associated with a roughly 3-fold higher risk and two copies with approximately a 15-fold higher risk for developing AD. 28% of participants in this trial carried at least one copy.
Regarding the primary study outcome, although people receiving omega-3 supplementation had a reduced progression of WMLs, this difference was not statistically significant. Additionally, although a similar lower decline in DTI-FA was observed with omega-3 supplementation (indicative of less breakdown of neuronal integrity), this also was not significantly different from the placebo group.
However, when stratified by APOE Genotype, significant differences were observed. The mean annual decline in DTI-FA among those with an APOE ε4 allele was lower in the group receiving omega-3 supplementation (−0.0016 mm2/s) compared to those receiving placebo (−0.0047 mm2/s), a statistically significant difference. No adverse events or serious adverse events were attributed to either placebo or omega-3 supplementation, and did not differ between groups. Overall, although no difference was observed in the primary outcome, people carrying at least 1 ε4 allele had significant reductions in the breakdown of neuronal integrity which became apparent within the first year of the study.
The authors point out that the study may have been underpowered (i.e., not enough participants) to demonstrate efficacy for the primary outcome. One reason for this is that the WML progression observed in this trial was less than expected from previous trial data, requiring a larger sample size and/or a longer duration to notice differences between groups. Thus, it’s possible that the reduction in WML progression (and other secondary outcomes) observed with omega-3 supplementation would have reached significance with an adequately powered study.
The authors also indicate that existing omega-3 supplementation trials lasting longer than 18 months (for cognitive decline or for AD prevention) and using doses greater than 1g per day, used either only DHA or DHA with very low amounts of EPA, and had generally disappointing results. In contrast, this study used a larger proportion of EPA, which, as the authors point out, is more abundant than DHA in the microglia and more able to prevent glial activation and the release of inflammatory compounds. Results of this study, in combination with previous ones, suggest the possibility that an EPA-rich formulation may have more benefit for APOE ε4 carriers without AD (but with WMLs), while a DHA-rich formulation may be more appropriate for non-carriers with mild to moderate dementia.
In controlled trials, omega 3s have previously been shown to improve perfusion in regions of the brain most affected by mild cognitive impairment, and to have beneficial effects on white matter microstructural integrity that were associated with improved brain function in healthy older adults. Additionally, in the large community-based Cardiovascular Health Study, a higher plasma omega-3 content was associated with a lower prevalence of subclinical infarcts and better white matter grade on MRI, indicating both a cardiovascular and cognitive protective effect. A higher plasma level of omega-3s has been associated with more protection against white matter-mediated executive decline, and the dose utilized in this study (1.65 g per day) was chosen to achieve a protective omega-3 threshold of 11.0 mg/dL in the plasma.
On a final note, it’s also worth noting that while controlled trials are needed to evaluate the effect size of therapies in isolation, a large evidence base suggests that multiple nutrient deficiencies may play a role in neurodegeneration in the real world. The journal Alzheimer’s & Dementia just recently published an analysis suggesting that suboptimal status of three nutrients together, omega-3s, vitamin D, and (elevated) homocysteine, had a nearly 5-fold increase in risk for dementia, a greater magnitude than other known factors, including both diabetes and the presence of an APOE ε4 allele.
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