The Effects of a Multidomain Lifestyle Intervention on Brain Function and Its Relation with Immunometabolic Markers and Intestinal Health in Older Adults at Risk of Cognitive Decline: The HELI Randomised Controlled Trial

Introduction: Multidomain lifestyle interventions may slow down cognitive decline and dementia, but the brain mechanisms underlying these effects remain unclear. We investigated brain, inflammation, cardiometabolic, and gut health changes associated with a six-month multidomain lifestyle intervention in Dutch older adults at risk for cognitive decline and dementia. Method: Participants aged 60-75 years with [≥]2 lifestyle-modifiable cardiovascular risk factors (e.g., BMI [≥]25, physical inactivity) were recruited and randomised in a 1:1 ratio to a high-intensity intervention or active control group using stratified (2,4) block-randomisation. The multidomain lifestyle intervention included five lifestyle domains (diet, physical activity, stress management and mindfulness, cognitive training, and sleep). Primary outcomes were changes in cerebral perfusion levels, brain activity during working memory, working memory performance, inflammation profile, and microbiota diversity. Secondary outcomes included lifestyle factors and markers of neuroimaging, brain health, cardiovascular and gut health, and cognitive functioning. The effects of the lifestyle intervention were investigated using linear mixed-effect models. Results: A total of 102 participants were randomised into the intervention (n=53) or active control group (n=49), of which 86 participants completed the six-month multidomain lifestyle intervention. Baseline characteristics were similar between the groups. Within the intervention group, favourable reductions in lifestyle-modifiable cardiovascular risk factors, such as BMI and blood pressure, were observed, but these were not significantly different from changes in the active control group. The intervention resulted in improved diet and sleep scores in the intervention group compared to the active control group (Beta 1.67, 95% CI 0.61;2.73, PFDR=0.01, and Beta -1.80, 95% CI -2.79;-0.81, PFDR=0.005, respectively). The intervention did not result in significant changes over time between the intervention and control group in primary and secondary outcomes. Conclusion: The HELI multidomain lifestyle was able to reduce lifestyle-modifiable cardiovascular risk factors associated with dementia, although not significant compared to the active control group. We did not observe significant intervention effects on brain, cardiometabolic, inflammatory, and gut health outcomes. These results emphasize the complexity of exploring the role of lifestyle on neurobiological brain mechanisms associated with maintaining optimal cognitive functioning in aging and their underlying peripheral (to central) mechanisms.