Mediation analyses link cardiometabolic factors and liver fat with white matter hyperintensities and cognitive performance: A UK Biobank study
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Background
Liver fat is associated with cardiometabolic disease, cerebrovascular disease, and dementia. Cerebrovascular disease, most frequently cerebral small vessel disease, identified by MRI as white matter hyperintensities (WMH), often contributes to dementia. However, liver fat’s role in the relationship between cardiometabolic risk, WMH, and cognitive performance is unclear.
Methods
In the UK Biobank cohort (n=32,628; 52.6% female; mean age 64.2±7.7 years; n=23,467 cognitive performance subsample), we used linear regression to investigate associations between cardiometabolic factors measured at baseline and liver fat, WMH, and cognitive performance measured at follow-up, on average, 9.3±2.0 years later. We used structural equation modeling to investigate whether liver fat mediates associations between cardiometabolic factors and WMH and whether WMH mediates associations between liver fat and cognitive performance.
Results
Nearly all cardiometabolic factors were significantly associated with liver fat (|r| in [0.03,0.41], p in [1.4x10 -8 ,0〉) and WMH (|r| in [0.05,0.14], p in [1.5x10 -13 ,2.7x10 -148 ]) in regression models. Liver fat was associated with WMH (r=0.09,p=3x10 -64 ) and cognitive performance (r=-0.03,p=1.5x10 -7 ). Liver fat mediated the associations between cardiometabolic factors and WMH (|βmediation| in [0.01,0.03], pmediation in [5.7x10 -9 ,0〉) and WMH 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 WMH and that WMH mediates the association between liver fat and cognitive performance. This suggests that liver fat might 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.
