A poor B-vitamin and omega-3 fatty acid (FA) status and are both associated with cognitive decline and dementia. Post-hoc analyses of clinical trial data and experimental work indicate that B-vitamins and omega-3 fatty acids (FAs) may exert synergistic benefits on processes related to brain health and cognition. However, this combination has not been tested directly in humans. In the BOOMERANG project, we will study effects of jointly supplementing B-vitamins and a highly bioavailable omega-3 FA supplement, LYSOVETA, on a biomarker of brain atrophy, neurofilament light chain, for 3 months in a randomized controlled trial (RCT) in older adults. To complement our novel RCT and support clinical relevance, we will use dietary, biomarker, epigenetic and genetic data from pre-existing RCTs (with B-vitamin interventions only), and multiple cohorts (total n > 50,000) to study the interaction of B-vitamin and omega-3 FAs on cognitive function and long-term cognitive decline and brain atrophy (follow-up time 3 to 10+ years). Finally, through experimental in vivo and in vitro studies we will study effects of this 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 from five countries (Norway, Ireland, The Netherlands, Germany, Northern Ireland-UK), we expect robust results supporting the causal interaction effects of B-vitamins and omega-3 FA on brain health, and the application of B-vitamin and omega-3 FA in long-term studies on cognitive decline. The implications of our expected results are affordable and immediately available preventive strategies for cognitive decline and dementia, and results can also be used to inform policy-making and new guidelines related to diet and brain health.