A poor nutrition status is a modifiable risk factor for cognitive decline and dementia. In particular, evidence links low status of certain B-vitamins and ω-3 fatty acids (ω-3 FA) with a greater risk of cognitive decline and dementia. Although these dietary components are typically investigated separately, post-hoc analyses of existing clinical trial data and experimental work indicate that B-vitamins and ω-3 FA may exert synergistic beneficial effects on processes related to brain health and cognition. However, this combination has not been tested directly in humans. In the proposed BOOMERANG project, we will study the effects of jointly supplementing with B-vitamins and a highly bioavailable ω-3 FA supplement, Lysoveta, on a robust biomarker of brain atrophy, the neurofilament light chain, in a double-blinded randomized controlled trial (RCT) over 3 months in older adults. To complement our novel RCT, support its relevance in practice and provide mechanistic insights, we will use dietary, biomarker, epigenetic and genetic data from multiple pre-existing RCTs (with B-vitamin interventions only) and cohorts (total n > 50,000), to study the interaction of B-vitamins and ω3 FA on cognitive function (cross-sectional), long-term cognitive decline (follow-up periods of 3 to 10+ years) and brain atrophy. Finally, through experimental in vivo and in vitro studies, we will study the effects of this nutritional combination on mechanisms related to neuronal ageing including cell death, mitochondrial metabolism, DNA methylation and histone deacetylation. By using multiple lines of evidence generated from six partners and collaborators (University of Oslo, Aker BioMarine, Norway; Trinity College Dublin, Ireland; Maastricht University, The Netherlands; Leibniz Research Institute for Environmental Medicine, Germany; Ulster University, Northern Ireland-UK), we expect robust results supporting the causal interactive effects of B-vitamins and ω-3 FA on brain health outcomes, and the application of this combination in long-term studies on cognitive decline. The expected outcomes of our research will be affordable and immediately available prevention strategies for cognitive decline and dementia. The results can also be used to inform policy-making and generate new dietary and clinical guidelines for better brain health.