High-dose DHA successfully reached the brains of older adults at increased risk of Alzheimer's disease, but the two-year clinical trial found no improvements in memory or brain structure, challenging assumptions that greater omega-3 delivery alone can slow cognitive decline.
Study: CNS target engagement of high-dose DHA supplementation in older adults at risk for dementia: a randomised, double-blind, placebo-controlled trial. Image credit: PeopleImages/Shutterstock.com
A clinical trial published in eBioMedicine found that high-dose docosahexaenoic acid (DHA) supplementation successfully increased brain DHA levels in older adults at risk of dementia, including those carrying the APOE ε4 Alzheimer's risk variant. However, despite reaching the brain, the supplement did not improve cognitive performance or brain structure over two years, raising new questions about how DHA is used within the brain.
Why APOE ε4 alters brain DHA metabolism
DHA is a fatty acid that is part of the nerve cell membrane, playing a key role in synaptic function and modulating neuroinflammation. Its levels tend to be lower in the presence of dementia-linked changes like amyloid deposition and cognitive decline, and in patients with late-onset Alzheimer's disease (AD).
The APOE ε4 gene variant is the strongest genetic risk factor for AD. Previous research suggests it is associated with accelerated DHA catabolism and lower plasma and cerebrospinal fluid DHA levels in people with AD dementia compared with non-carriers.
Observational studies have suggested modest associations between higher omega-3 intake and lower risk of cognitive decline, but randomized trials have produced inconsistent results. Of 24 randomized trials in people without dementia, only five reported positive cognitive effects following DHA supplementation. Conversely, no improvement was seen in patients with AD.
Thus, two important questions remain unanswered: is early intervention necessary in patients with low omega-3 levels before dementia sets in, and are higher doses required to ensure adequate brain uptake? Previous imaging studies suggest that younger cognitively healthy carriers have increased brain DHA incorporation, which may reflect greater DHA demand, compared to non-carriers. This has not been studied in older adults prior to the onset of dementia.
In the current study, researchers investigated whether high-dose DHA supplementation could effectively raise brain DHA levels and potentially support cognitive and structural brain health in older adults with low dietary omega-3 intake before dementia develops.
Testing high-dose DHA before dementia develops
The investigators conducted a randomized, double-blind, placebo-controlled trial that enrolled 365 adults without dementia, aged 55–80 years, with low DHA intake and at least one dementia risk factor at baseline. Participants received either 2 g/day of DHA or a placebo for 24 months.
The mean participant age was 66 years, with 58% being female. Approximately 47% of the participants were APOE ε4 carriers, and 39% were Hispanic.
The participants were first classified by willingness to undergo a lumbar puncture (LP) to obtain cerebrospinal fluid (CSF) for analysis. The two groups were assessed for the CSF DHA: arachidonic acid (AA) ratio after six months, which reflects the extent to which DHA is delivered to the brain. Various brain volumes were also assessed.
Increased DHA delivery
The 365 participants were divided into two arms: 181 in the LP arm and 184 in the non-LP arm. In both arms, DHA supplementation significantly increased the CSF DHA/AA ratio at six months compared with placebo, indicating successful delivery of DHA to the brain. There was also a 17% increase in CSF DHA. The red cell omega-3 index also increased from 4.9% to 11%.
The increases in DHA delivery to the brain and in the red cells were independent of APOE ε4 status. This suggests that the gene variant did not influence this process.
However, APOE ε4 non-carriers showed greater improvement in cognitive scores than carriers, with a mean improvement of 3.8 and 1.6 in the two groups, respectively, regardless of treatment group. Importantly, the study demonstrates that inadequate brain delivery is unlikely to explain the disappointing results of previous DHA supplementation trials, because high-dose supplementation successfully increased CNS DHA levels.
The authors hypothesize that simply improving DHA delivery to the brain may not be sufficient to enhance cognitive function, given the enzymatic catabolism of DHA within synaptic membranes, which are crucial for cognitive processing.
There was no difference in brain volumes or in cognitive performance over the whole study period between the intervention and control groups. Adverse events were comparable between groups, and the treatment was generally safe and well-tolerated.
Strengths and limitations
The sample included White and Hispanic participants with a high proportion of APOE ε4 carriers. The low baseline omega-3 intake, CSF DHA measurement, and multiple outcome assessments, coupled with a stringent trial design, were among the study’s strengths.
However, it had several limitations. The participants were relatively young, well-educated, and at an early stage of disease, which might have limited their ability to detect treatment effects over just 24 months.
The study showed a relatively high dropout rate at 38%. Most of this was related to the coronavirus disease 2019 (COVID-19) pandemic. The consequent reduction in sample size might have affected its ability to detect smaller effects on cognitive function or brain structure. Those who dropped out of the study were more likely to be Hispanic, to have lower education levels and baseline cognitive scores, and to have lower plasma DHA concentrations than those who completed the study, which might have affected the generalizability of the findings.
The study used a single supplement, but the authors point out that this could be insufficient in the face of multiple disease processes affecting neuronal health and DHA metabolism in the brain. This is even more true when the participants have vascular risk factors like hypertension and physical inactivity, all of which need to be addressed simultaneously.
The current study included only cognitively healthy individuals, but future studies may benefit from testing supplementation in individuals who already have biochemical signs of early neurodegeneration, such as elevated biomarkers (phosphorylated tau in blood, advanced imaging markers) or more granular neuropsychological testing to detect small changes in executive function. This would improve the detection of treatment changes. A longer follow-up may also be necessary.
Conclusion
The findings show that high-dose DHA supplementation can substantially increase brain DHA levels within six months in older adults at risk of dementia, regardless of APOE ε4 status. Conversely, this did not translate into observable improvements in cognition or brain structure over 24 months.
These results suggest that high DHA intake alone may not be sufficient to improve cognitive outcomes or preserve brain structure in relatively healthy older adults over a 2-year period, despite adequate brain delivery. They also imply that APOE ε4 carriers experience normal DHA delivery to the brain before dementia, despite the dysregulation in established dementia reported in prior research.
Future research should focus on examining DHA metabolism in the brain rather than on additional supplementation trials. Because brain DHA delivery was successfully achieved without improving cognition, future work should focus on how DHA is processed and used within brain cells rather than simply increasing DHA intake.
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