medRxiv · Jan 9, 2026
Integrating lifestyle, vascular, brain and cognitive markers: an exploratory multimodal approach to brain aging
By van Loenen MR, Remie LB, van Trijp MPH et al.
ABSTRACT Background Lifestyle modifiable risk factors are promising intervention targets to delay cognitive decline and dementia in older adults. While previous studies have reported associations between lifestyle, vascular health, (MRI-based) brain health and cognition, few have considered all domains simultaneously. In this exploratory cross-sectional study, we examined pathways linking lifestyle to cognition via vascular and brain health, and identified key variables contributing to shared variance between these domains. Methods We included 176 Dutch adults, aged 60–75 years old with modifiable risk of cognitive decline. Composite domain scores for lifestyle, vascular health, (MRI-based) brain health, and cognitive functioning were calculated. We used Structural Equation Modelling (SEM) to test direct and indirect pathways between composite domain scores, Canonical Correlation Analysis (CCA) to identify individual variables driving shared variance between domains, and Pearson’s correlations to explore pairwise associations. Results SEM showed associations between lifestyle and vascular health (β = 0.23, p = 0.002), and vascular and brain health (β = 0.18, p = 0.01). No direct pathways were found between lifestyle and brain health, or between vascular health and cognitive functioning. CCA revealed vascular markers, specifically BMI (-0.837), blood pressure (-0.837), and blood lipids (-0.408 to -0.466), as the strongest drivers of shared variance with cerebral perfusion (-0.318 to -0.364). Discussion Our results indicate stepwise links between lifestyle, vascular health, and brain health. Integrating multimodal markers of all domains highlights the key role of vascular health in understanding lifestyle-related effects on brain health. HIGHLIGHTS · Brain health links to lifestyle via vascular health markers · Lifestyle or vascular health alone is not associated with cognitive functioning · BMI, blood pressure and blood lipids most strongly linked to cerebral blood flow · Multimodal designs enable analysis of multifactorial causes of cognitive decline CLINICAL TRIAL REGISTRATION HELI study ClinicalTrials.gov ID: NCT05777863 . Medical Ethics Research Committee (MREC) Oost-Nederland ToetsingOnline filenumber: NL78263.091.21. COMBI study Clinicaltrials.gov ID: NCT05675007 . MREC Oost-Nederland ToetsingOnline filenumber: NL80063.091.22.