High-dose docosahexaenoic acid (DHA), an omega-3 fatty acid, can penetrate the brain in both APOE4 carriers and non-carriers before the onset of dementia, according to the placebo-controlled PreventE4 trial. The study, presented at the Clinical Trials on Alzheimer's Disease (CTAD) annual meeting, suggests a potential cognitive benefit for individuals with a genetic risk of Alzheimer's disease.
Hussein Yassine, MD, of the Keck School of Medicine at the University of Southern California in Los Angeles, noted that while the treatment did not influence hippocampal volume, increases in brain DHA in both the treatment and placebo arms were associated with better cognitive measures in APOE4 carriers. "Omega-3s are good for the APOE4 brain when started before dementia symptoms," Yassine stated, contrasting this with findings in dementia patients where APOE4 carriers show a lower increase in brain DHA after supplementation compared to non-carriers.
Key Findings from the PreventE4 Trial
The PreventE4 trial enrolled cognitively unimpaired individuals with at least one vascular dementia risk factor and limited seafood consumption. Half of the study population had at least one APOE4 allele. Participants were randomized to 2 g/day of DHA supplements or placebo for 2 years, along with a vitamin B complex supplement. The primary outcome was the ratio of DHA to arachidonic acid (AA) in cerebrospinal fluid (CSF) at 6 months. Secondary outcomes included MRI data, with exploratory analyses assessing cognition at 24 months using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).
The study demonstrated that the intervention increased CSF DHA/AA ratios in cognitively unimpaired people, independent of APOE genotype. Exploratory analyses revealed that changes in CSF DHA/AA ratios correlated with changes in RBANS scores at 24 months in APOE4 carriers, a finding not observed in APOE4 non-carriers.
Implications for APOE4 Carriers
Lower blood omega-3 levels have been previously correlated with worse cognitive function, particularly among APOE4 carriers. Yassine highlighted that earlier studies indicated that the brains of young, cognitively normal APOE4 carriers were more dependent on circulating DHA than non- APOE4 brains. "This means that the APOE4 brain is taking more DHA from plasma into the brain for its normal biological processes," Yassine explained. "It consumes more DHA, like a specific engine that requires a specific oil to function."
This dependence suggests that APOE4 carriers may be more vulnerable to a low DHA diet. The current findings underscore the potential of early DHA supplementation as a preventive strategy for this population.
Future Research Directions
While the PreventE4 trial provides valuable insights, Yassine acknowledged that the study was not powered to assess cognition definitively. Further analyses of structural and functional connectivity data are ongoing. Additional research is needed to elucidate how APOE4 might affect the DHA/AA balance and the potential role of the gut microbiome. Yassine also emphasized the importance of exploring personalized approaches to DHA supplementation in APOE4 carriers to maximize potential benefits.
