Folate, related B-vitamins and omega-3 fatty acids, and their interaction, in relation to the ageing brain

Abstract

Dementia and mental health disorders, such as depression and anxiety are a leading cause of ill-health and disability in older age. Therefore, public health strategies to improve both cognitive and mental health in ageing are an urgent priority for countries globally. Certain nutritional factors are associated with better brain health, but the majority of the evidence is observational, which limits the ability to determine whether a causal relationship exists. Therefore, in order to more fully investigate diet-brain relationships, a comprehensive systematic review and meta-analysis of randomised controlled trials (RCTs) was conducted to investigate the effect of interventions with certain dietary patterns or specific nutrients on depression and anxiety in adults. The results indicated a significant benefit of vitamin D supplementation in reducing symptoms of depression. In relation to B vitamins and omega-3 fatty acids, the results were inconclusive and reflected a limited body of available evidence and relative lack of studies that reported data in a format suitable for inclusion in the meta-analysis. Folate and the related B vitamins (B12, B6 and riboflavin) and omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are considered to have key roles in supporting cognitive and mental health in older adults. Therefore, a critical narrative review of the emerging evidence was subsequently conducted to evaluate the totality of evidence linking B vitamins and omega-3 fatty acids with cognitive dysfunction and depression and to examine their impacts on the ageing brain. The results indicated beneficial effects of supplementation with both B vitamins and omega-3 fatty acids on brain health. In addition, some evidence emerged of an interactive effect between B vitamins and omega3 fatty acids, suggesting potential benefits of combined nutritional strategies aimed at achieving better mental health in ageing. The review however identified some inconsistencies in the literature, and it was unclear whether B vitamin supplementation was more beneficial in those with better or poorer omega-3 fatty acid status. Therefore, the role of baseline omega-3 fatty acids status in determining the effect of B vitamin supplementation on cognitive function was investigated using available data from the BrainHOP trial, a two year RCT of B vitamin supplementation on cognitive outcomes in community-dwelling older adults. The results showed that intervention with B vitamins resulted in improved cognition in the visuospatial sub-domain in participants with higher total omega-3 fatty acids status and DHA concentrations at baseline. Another objective of the thesis was to establish the folate microbiological assay at this centre and validate its performance using stored blood samples collected from three previously conducted RCTs. Once the method was established, the results showed that intervention with low iii dose folic acid for two years resulted in marked increases in serum and red blood cell (RBC) folate concentrations, by 130% and 124%, respectively. Additionally, reported dietary intake was found to be positively correlated with both serum and RBC folate and inversely correlated with homocysteine concentrations. In conclusion, the findings of this thesis suggest that optimising folate, the related B vitamins and omega-3 fatty acid status through food fortification or supplementation, may be important for maintaining cognitive and mental health outcomes in older adults, particularly those who are at risk of nutritional deficiency. Further, well-defined RCTs, particularly targeting those at greater risk, would help to inform public health strategies in order to reduce the risk of adverse brain outcomes in ageing.

Thesis is embargoed until 30th June 2028

Date of Award	Jun 2026
Original language	English
Supervisor	Mary Ward (Supervisor), Catherine Hughes (Supervisor), Helene McNulty (Supervisor) & Leane Hoey (Supervisor)