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Mediation Analyses Link Cardiometabolic Factors and Liver Fat With White Matter Hyperintensities and Cognitive
Daniel E Askeland-Gjerde1,2, Lars T Westlye1,3,4, Patrik Andersson5
1Section for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Insights
Non-alcoholic fatty liver disease is linked to cerebrovascular disease and cognitive decline. Liver fat mediates the relationship between cardiometabolic risk factors and white matter hyperintensities, which in turn affect cognitive performance.
Area of Science:
- Cardiology
- Neurology
- Hepatology
- Radiology
Background:
- Non-alcoholic fatty liver disease (NAFLD) is associated with cardiometabolic diseases, cerebrovascular disease, and dementia.
- Cerebrovascular disease, particularly white matter hyperintensities (WMHs) visible on MRI, is a common cause of dementia.
- The precise role of liver fat in the interplay between cardiometabolic risk, WMHs, and cognitive function remains unclear.
Purpose of the Study:
- To investigate the associations between cardiometabolic factors, liver fat, WMHs, and cognitive performance.
- To determine if liver fat mediates the relationship between cardiometabolic factors and WMHs.
- To examine if WMHs mediate the relationship between liver fat and cognitive performance.
Main Methods:
- Utilized data from the UK Biobank cohort (N=32,461) with a mean follow-up of 9.3 years.
- Employed linear regression to assess associations between baseline cardiometabolic factors and follow-up measurements of liver fat, WMHs, and cognitive performance.
- Applied structural equation modeling to explore mediation pathways involving liver fat and WMHs.
Main Results:
- Nearly all cardiometabolic factors were significantly associated with both liver fat and WMHs.
- Liver fat showed significant associations with WMHs (r=0.11) and cognitive performance (r=-0.03).
- Liver fat mediated the association between cardiometabolic factors and WMHs, while WMHs mediated the association between liver fat and cognitive performance.
Conclusions:
- Liver fat plays a mediating role in the pathway from cardiometabolic factors to cerebrovascular disease (WMHs).
- White matter hyperintensities mediate the impact of liver fat on cognitive performance.
- Targeting liver fat may be crucial for preventing cognitive impairment linked to vascular factors.
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, p mediation = 1.9 × 10-8 to 0), and WMHs mediated the associations between liver fat and cognitive performance (βmediation = -0.01, p mediation = 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.
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