Epidemiological research highlights the role of lifestyle, particularly diet, in cognitive decline and dementia. However, controversies persist regarding the effectiveness of dietary interventions for cognitive aging. A better understanding of underlying mechanisms and decisive modifiers of the brain´s response to dietary and lifestyle interventions is thus needed to develop better intervention strategies.

A game changer towards delivering more precise diets could lie in accounting for the crucial role of the gut microbiome in mediating diet-related brain changes, for example through (anti-)inflammatory signalling. The applicants provided early data in support, showing that microbial metabolites predicted steeper cognitive decline in the 3-City cohort, and prebiotics modulated neural correlates of higher cognition. Also, faecal microbiome transplantation improved metabolic response to diet interventions in participants at risk for cognitive decline. Thus, targeting microbiome-related mechanisms of diet-brain communication offers a promising lever towards more effective interventions. Yet, a systematic development of nutrition strategies to modify the microbiota, modulate the inflammatory milieu, and prevent cognitive decline is lacking.

We therefore aim to develop a microbiome-healthy diet to improve brain ageing by joint analysis of unique human data. To this end, we plan (1) to test how microbiome-changing diets affect markers of neuroinflammation and brain ageing in interventional studies, (2) to decipher targets and pathways of the diet-microbiota-neuroinflammation-brain axis across ageing in epidemiological cohorts, and (3) to identify predispositions such as age, sex, and cardiometabolic disease that affect the responsiveness to diets. Combining unique data and multidisciplinary expertise, we hope to establish a better understanding on effective mechanisms and modifiers of diets on brain health, paving the way to personalised nutrition.