Role of Brain Age Gap as a Mediator in the Relationship Between Cognitive Impairment Risk Factors and Cognition.

Background And Objectives: Cerebrovascular disease (CeVD) and cognitive impairment risk factors contribute to cognitive decline, but the role of brain age gap (BAG) in mediating this relationship remains unclear, especially in Southeast Asian populations. This study investigated the influence of cognitive impairment risk factors on cognition and examined how BAG mediates this relationship, particularly in individuals with varying CeVD burden.

Methods: This cross-sectional study analyzed Singaporean community and memory clinic participants. Cognitive impairment risk factors were assessed using the Cognitive Impairment Scoring System (CISS), encompassing 11 sociodemographic and vascular factors. Cognition was assessed through a neuropsychological battery, evaluating global cognition and 6 cognitive domains: executive function, attention, memory, language, visuomotor speed, and visuoconstruction. Brain age was derived from structural MRI features using ensemble machine learning model. Propensity score matching balanced risk profiles between model training and the remaining sample. Structural equation modeling examined the mediation effect of BAG on CISS-cognition relationship, stratified by CeVD burden (high: CeVD+, low: CeVD-).

Results: The study included 1,437 individuals without dementia, with 646 in the matched sample (mean age 66.4 ± 6.0 years, 47% female, 60% with no cognitive impairment). Higher CISS was consistently associated with poorer cognitive performance across all domains, with the strongest negative associations in visuomotor speed (β = -2.70, < 0.001) and visuoconstruction (β = -3.02, < 0.001). Among the CeVD+ group, BAG significantly mediated the relationship between CISS and global cognition (proportion mediated: 19.95%, = 0.01), with the strongest mediation effects in executive function (34.1%, = 0.03) and language (26.6%, = 0.008). BAG also mediated the relationship between CISS and memory (21.1%) and visuoconstruction (14.4%) in the CeVD+ group, but these effects diminished after statistical adjustments.

Discussion: Our findings suggest that BAG is a key intermediary linking cognitive impairment risk factors to cognitive function, particularly in individuals with high CeVD burden. This mediation effect is domain-specific, with executive function, language, and visuoconstruction being the most vulnerable to accelerated brain aging. Limitations of this study include the cross-sectional design, limiting causal inference, and the focus on Southeast Asian populations, limiting generalizability. Future longitudinal studies should verify these relationships and explore additional factors not captured in our model.