Mediation Analyses Link Cardiometabolic Factors and Liver Fat With White Matter Hyperintensities and Cognitive Performance: A UK Biobank Study

Background: Liver fat is associated with cardiometabolic disease, cerebrovascular disease, and dementia. Cerebrovascular disease, most often cerebral small vessel disease, identified by magnetic resonance imaging as white matter hyperintensities (WMHs) often contributes to dementia. However, liver fat's role in the relationship between cardiometabolic risk, WMHs, and cognitive performance is unclear. Methods: In the UK Biobank cohort (N = 32,461, 52.6% female; mean age 64.2 ± 7.7 years; n = 23,354 in the cognitive performance subsample), we used linear regression to investigate associations between cardiometabolic factors measured at baseline and liver fat, WMHs, and cognitive performance measured at follow-up, which was 9.3 ± 2.0 years later on average. We used structural equation modeling to investigate whether liver fat mediated associations between cardiometabolic factors and WMHs and whether WMHs mediated associations between liver fat and cognitive performance. Results: Nearly all cardiometabolic factors were significantly associated with liver fat (|r| range = 0.03–0.41, p = 3.4 × 10−8 to 0) and WMHs (|r| = 0.04–0.15, p = 5.8 × 10−13 to 7.0 × 10−159) in regression models. Liver fat was associated with WMHs (r = 0.11, p = 4.3 × 10−82) and cognitive performance (r = −0.03, p = 1.6 × 10−7). Liver fat mediated the associations between cardiometabolic factors and WMHs (|βmediation| = 0.003–0.027, pmediation = 1.9 × 10−8 to 0), and WMHs mediated the associations between liver fat and cognitive performance (βmediation = −0.01, pmediation = 0). Conclusions: Our findings indicate that liver fat mediates associations between cardiometabolic factors and WMHs and that WMHs mediate the association between liver fat and cognitive performance. This suggests that liver fat may be important for understanding the effects of cardiometabolic factors on cerebrovascular disease and cognitive function. Experimental studies are warranted to determine relevant targets for preventing vascular-driven cognitive impairment.