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. 2025 Mar 20;5(4):100488.
doi: 10.1016/j.bpsgos.2025.100488. eCollection 2025 Jul.

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

Daniel E Askeland-Gjerde  1   2 , Lars T Westlye  1   3   4 , Patrik Andersson  5 , Max Korbmacher  6   7   8 , Ann-Marie de Lange  3   9   10 , Dennis van der Meer  1   11 , Olav B Smeland  1 , Sigrun Halvorsen  12 , Ole A Andreassen  1   2   4 , Tiril P Gurholt  1
Affiliations

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

Daniel E Askeland-Gjerde et al. Biol Psychiatry Glob Open Sci. .

Abstract

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.

Keywords: Cerebral small vessel disease; Metabolic dysfunction–associated steatotic liver disease; Neurodegenerative diseases; Nonalcoholic fatty liver disease; Vascular cognitive impairment and dementia.

Plain language summary

The study examined links between fat stored in the liver, small brain lesions, and cognitive skills, such as memory. The results indicated that people with more liver fat had more small lesions in the brain and that they did not perform as well on cognitive tests as people with less fat in the liver. Therefore, reducing fat in the liver may be beneficial to avoid cognitive decline resulting from small brain lesions.

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Figures

Figure 1
Figure 1
Path diagram of the mediation analyses. The figure shows path diagrams of the mediation analyses with (A) white matter hyperintensities (WMHs) as outcome, liver fat as mediator, and cardiometabolic factors as predictors and with (B) general cognitive performance as outcome, WMHs as mediator, and liver fat and steatotic liver disease as predictors. (Figure created with BioRender.com.)
Figure 2
Figure 2
Linear associations between cardiometabolic factors and liver fat. The figure shows forest plots with the associations of (A) cardiometabolic risk factors and (B) cardiometabolic principal components with liver fat. The error bars correspond to 95% CIs. The regression models were adjusted for age, age2, sex, age × sex, age2 × sex, site, smoking status, and alcohol consumption. HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Figure 3
Figure 3
Linear associations between cardiometabolic factors, liver fat, and white matter hyperintensities (WMHs). The figure shows forest plots with the associations of (A) cardiometabolic risk factors, (B) cardiometabolic principal components, and (C) liver fat and steatotic liver disease with WMHs. The error bars correspond to 95% CIs. The regression models were adjusted for age, age2, sex, age × sex, age2 × sex, site, smoking status, alcohol consumption, and intracranial volume. HDL, high-density lipoprotein; LDL, low-density lipoprotein; MAFLD, metabolic dysfunction–associated fatty liver disease; MASLD, metabolic dysfunction–associated steatotic liver disease; NAFLD, nonalcoholic fatty liver disease.
Figure 4
Figure 4
Linear associations between cardiometabolic factors, liver fat, white matter hyperintensities (WMHs), and general cognitive performance. The figure shows forest plots with the associations of (A) cardiometabolic risk factors, (B) cardiometabolic principal components, (C) liver fat and steatotic liver disease, and (D) WMHs with general cognitive performance. The error bars correspond to 95% CIs. The regression models were adjusted for age, age2, sex, age × sex, age2 × sex, site, smoking status, alcohol consumption, education, and intracranial volume (only WMHs). HDL, high-density lipoprotein; LDL, low-density lipoprotein; MAFLD, metabolic dysfunction–associated fatty liver disease; MASLD, metabolic dysfunction–associated steatotic liver disease; NAFLD, nonalcoholic fatty liver disease.
Figure 5
Figure 5
Mediation analyses with white matter hyperintensities (WMHs) as the outcome and liver fat as the mediator. The figure shows forest plots with the (A) direct and (B) mediation (i.e., indirect) effects via liver fat of cardiometabolic risk factors and the (C) direct and (D) mediation effects via liver fat of cardiometabolic principal components on WMHs. Error bars correspond to standardized 95% CIs. (Illustrations created with BioRender.com.) HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Figure 6
Figure 6
Mediation analyses with white matter hyperintensities (WMHs) as the outcome and liver fat as the mediator in the total sample and in males and females separately. The figure shows forest plots with the (A) direct and (B) mediation effects via liver fat of cardiometabolic risk factors and cardiometabolic principal components on WMHs. Error bars correspond to standardized 95% CIs. (Illustrations created with BioRender.com.) LDL, low-density lipoprotein.
Figure 7
Figure 7
Mediation analyses with general cognitive performance as the outcome and white matter hyperintensities (WMHs) as the mediator. The figure shows forest plots with the (A) direct and (B) mediation effects via WMHs of liver fat and steatotic liver disease on general cognitive performance. Error bars correspond to standardized 95% CIs. (Illustrations created with BioRender.com.) MAFLD, metabolic dysfunction–associated fatty liver disease; MASLD, metabolic dysfunction–associated steatotic liver disease; NAFLD, nonalcoholic fatty liver disease.
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