Effects of 24-Month Supplementation of Epa and Dha on Hippocampal Spontaneous Neuroactivity in Mild Cognitive Impairment and Dementia: A Resting-State Fmri Study

Background Emerging evidence suggests that omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may provide neuroprotective benefits in individuals with cognitive impairment and dementia. These fatty acids are hypothesized to influence brain function through anti-inflammatory, antioxidative, and membrane-stabilizing effects. Resting-state functional MRI (rs-fMRI) offers a non-invasive approach to investigate spontaneous brain activity, and the amplitude of low-frequency fluctuations (ALFF) has been validated as a robust metric for assessing neural activity. Aims & Objectives This study investigates whether a 24-month intervention with EPA, DHA, or their combination can modulate hippocampal ALFF in individuals with mild cognitive impairment (MCI) or dementia. Method Participants (n=59) were randomized into four groups: (1) EPA 0.8 g/day + DHA 0.35 g/day (n=13), (2) EPA 0.8 g/day (n=15), (3) DHA 0.35 g/day (n=17), and (4) placebo (n=14). Resting-state fMRI scans were acquired at baseline and after 24 months. Alzheimer's Disease Assessment Scale–Cognitive (ADAS-cog) was used to evaluate cognitive function. ALFF was calculated for the left and right hippocampal regions of interest (ROIs) using standard preprocessing pipelines of the conn toolbox. Repeated measures ANOVA, adjusted for age, was conducted to analyze changes in hippocampal ALFF within and between groups. Partial correlation analyses, controlling for age, examined the relationship between changes in ALFF and ADAS-cog scores. Results No significant differences in age, years of education, or baseline ADAS-cog scores existed between the groups (all p > 0.05). Furthermore, no significant group-by-time interaction effects were observed for hippocampal ALFF changes (Right: F = 0.0145, p = 0.998; Left: F = 0.407, p = 0.748). However, partial correlation analyses revealed significant positive associations between changes in ADAS-cog scores (24-month minus baseline) and changes in hippocampal ALFF (Right: r = 0.274, p = 0.047; Left: r = 0.367, p = 0.007). Discussion & Conclusions These findings suggest that 24-month supplementation with EPA, DHA, or their combination does not significantly influence hippocampal ALFF in individuals with MCI or dementia. This absence of modulation implies that the neuroprotective effects of omega-3 fatty acids may not operate through alterations in spontaneous neuroactivity of the hippocampus, as measured by ALFF. Interestingly, the observed positive correlations between increasing ALFF and higher ADAS-cog scores, which indicate more profound cognitive impairment, highlight a potential compensatory mechanism, where heightened spontaneous neuroactivity in the hippocampus may reflect the brain’s attempt to counteract cognitive decline. This compensatory process aligns with prior studies suggesting that increased neural activity in the hippocampus may be a response to pathological stress, such as beta-amyloid accumulation or synaptic dysfunction. Despite these intriguing correlations, the lack of significant group effects underscores the need for further research to explore other neural mechanisms by which omega-3 fatty acids may exert neuroprotective effects. Future studies should also investigate whether specific subpopulations or alternative biomarkers may demonstrate differential responses to omega-3 supplementation.