MASLD, MetALD Associated with Accelerated Brain Aging, Study Finds

New research is shedding light on a significant association between metabolic dysfunction-associated steatotic liver disease (MASLD) and accelerated brain aging, suggesting the potential benefit of MASLD-focused anti-inflammatory interventions for promoting brain health.1

Leveraging data for > 30,000 UK Biobank participants, the study found MASLD, MASLD with increased alcohol intake (MetALD), and MASLD with other combined etiology were linked to older brain age compared to chronological age. Of note, this finding was consistent regardless of age, sex, and APOE ɛ4.1

“MASLD is considered not only a hepatic but also a systemic inflammatory disease, and inflammation is an important mechanism underlying brain ageing,” Jiao Wang, of the National Clinical Research Center for Geriatrics at Sichuan University in China and the Aging Research Center at Karolinska Institutet in Sweden, and colleagues wrote.1 “However, to the best of our knowledge, no studies have yet examined whether inflammation could act as a mediator in the effects of MASLD on brain ageing.”

Mounting evidence suggests people with MASLD are at an increased risk of cognitive impairment and dementia.2,3 Identifying accelerated brain aging and related risk factors can inform early intervention for brain health, but MASLD’s role in this context is not well understood.1

To address this gap in research, investigators assessed neuroimaging data for 30,386 UK Biobank participants with complete brain MRI data. They classified these patients into MASLD/related SLD (n = 7360) and no MASLD/related SLD (n = 19,351) groups, defining SLD as Fatty Liver Index ≥ 60 and MASLD as the presence of SLD with ≥ 1 cardiometabolic risk factor.1

Brain age was estimated using machine learning by 1079 brain MRI phenotypes. Additionally, brain age gap (BAG) was calculated as the difference between brain age and chronological age.1

Investigators also assessed the role of low-grade inflammation in the association between MASLD and brain aging. They calculated a composite score for low-grade inflammation based on white blood cell count, platelet, neutrophil granulocyte to lymphocyte ratio, and C-reactive protein, with higher scores indicating higher levels of inflammation.1

Among the cohort, the mean age was 54.73 ± 7.48 years and the majority (53.4%) of participants were female. In total, 5227 (17.0%) participants had MASLD, 2104 (6.9%) had MetALD, and 29 (0.11%) had MASLD with other combined etiology at enrollment.1

Compared to participants without MASLD/related SLD, investigators noted those with MASLD/related SLD had significantly increased BAG (β = 0.86; 95% CI, 0.70-1.02), as well as those with MASLD (β = 0.59; 95% CI, 0.41-0.77) or MetALD (β = 1.57; 95% CI, 1.31-1.83).1

Further analysis revealed the association between MASLD/related SLD and larger BAG was significant across patients < 60 years of age and those ≥ 60 years of age, males and females, and APOE ɛ4 carriers and non-carriers.1

Additionally, mediation analysis showed low-grade inflammation partly mediated the association of MASLD/related SLD, MASLD and MetALD with BAG, with mediation proportions of 13.53%, 20.14% and 7.13%, respectively.1

“The present study provides evidence that MASLD/related SLD (including MASLD and MetALD) may contribute to accelerated brain ageing even in middle-aged adults and APOE ɛ4 non-carriers,” investigators concluded.1 “Our findings highlight the need for managing MASLD in adults of any age, sex and genetic background, for promoting brain health.”

References

1. Wang J, Yang R, Miao Y, Zhang X, Paillard-Borg S, Fang Z, Xu W. Metabolic Dysfunction-Associated Steatotic Liver Disease Is Associated With Accelerated Brain Ageing: A Population-Based Study. Liver Int. 2025 Jun;45(6):e70109. doi:10.1111/liv.70109

2. Meroni M, Longo M, Paolini E, Dongiovanni P. A narrative review about cognitive impairment in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Another matter to face through a holistic approach. J Adv Res. doi:10.1016/j.jare.2024.02.007

3. Bao X, Kang L, Yin S, et al. Association of MAFLD and MASLD with all-cause and cause-specific dementia: a prospective cohort study. Alzheimers Res Ther. doi:10.1186/s13195-024-01498-5