Multimodal Brain Age Gap as a Mediating Indicator in the Relation between Modifiable Dementia Risk Factors and Cognitive Functioning

Introduction As a structural proxy for evaluating brain health, neuroimaging-based brain age gap (BAG) is presumed to link the dementia risks to cognitive changes in the premorbid phase, but this remains unclear. Methods Brain age prediction models were constructed and applied to a population-based cohort (N=371) to estimate their BAG. Further, structural equation modeling was employed to investigate the mediation effect of BAG between risk levels (assessed by 2 dementia-related risk scores) and cognitive changes (examined by 4 cognitive assessments). Results A higher burden of modifiable dementia risk factors was causally associated with a greater cognitive decline, and this was significantly mediated ( P =0.017) by a larger multimodal BAG, which indicated an older brain. Moreover, a steeper slope ( P =0.020) of association between cognitive decline and multimodal BAG was observed when individuals had higher dementia risks. Discussion Multimodal BAG is a potential mediating indicator to reflect the changes in the pathophysiological mechanism of cognitive aging. ### Competing Interest Statement The authors have declared no competing interest.