Abstract TP106: Age-related cognitive decline is partly mediated by white matter hyperintensities

Background: White matter hyperintensities (WMH) are common imaging biomarkers indicative of cerebral small vessel disease (CSVD), stroke risk, and cognitive decline. While WMH is linked to cognitive decline and dementia pathology, the role of WMH in age-related cognitive decline is not fully understood. WMH is frequently detected in older adults and may mediate the relationship between age and cognition, as both worsen with old age. Objective: To examine the relationship between WMH, age and cognition, we performed a mediation analysis using age, WMH, cognition and vascular risk factors (VRFs) in the longitudinal study “Identify Mechanisms to Preserve Agility in Cognition and Thinking (IMPACT)”. Methods: 580 participants from the IMPACT cohort were included in the analysis. All participants completed a brain MRI, cognitive assessment and provided detailed medical history. Global cognition scores were calculated as a composite z score from individual cognitive tests (Trails A, Trails B, PSM, HVLT, Flanker, LSWM, PCPS, Digit Span). A mediation model was developed with global cognition score as the outcome variable, WMH as the mediating variable, and age as the exposure variable. The following confounding variables were included as covariates: sex, education, race, diabetes, hypertension, hyperlipidemia, and smoking. Data analysis was conducted using the lavaan package in R. Results: All VRFs were individually associated with cognition, but when combined in the model, diabetes and hypertension were the only two risk factors that remained significantly associated with worse cognition. Our mediation analysis shows that 14.5% of the effect of age on cognition was mediated through WMH (p < 0.001). Conclusion: While WMH burden is associated with cognitive function, WMH plays a partial mediating role in age-related cognitive impairment. Our ongoing work will assess regional effects of WMH on specific white matter tracts using diffusion tensor imaging (DTI) as well as examine functional connectivity to determine the combined contribution of all age-related imaging variables to cognitive function. These findings will expand the repertoire of structural and functional changes that link age to cognitive decline and identify potential targets for intervention.