Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to cognitive decline and dementia risk. We aimed to investigate the association between MASLD and brain ageing and explore the role of low-grade inflammation.

Methods: Within the UK Biobank, 30 386 chronic neurological disorders-free participants who underwent brain magnetic resonance imaging (MRI) scans were included. Individuals were categorised into no MASLD/related SLD and MASLD/related SLD (including subtypes of MASLD, MASLD with increased alcohol intake [MetALD] and MASLD with other combined aetiology). Brain age was estimated using machine learning by 1079 brain MRI phenotypes. Brain age gap (BAG) was calculated as the difference between brain age and chronological age. Low-grade inflammation (INFLA) was calculated based on white blood cell count, platelet, neutrophil granulocyte to lymphocyte ratio and C-reactive protein. Data were analysed using linear regression and structural equation models.

Results: At baseline, 7360 (24.2%) participants had MASLD/related SLD. Compared to participants with no MASLD/related SLD, those with MASLD/related SLD had significantly larger BAG (beta = 0.86, 95% CI = 0.70, 1.02), as well as those with MASLD (beta = 0.59, 95% CI = 0.41, 0.77) or MetALD (beta = 1.57, 95% CI = 1.31, 1.83). The association between MASLD/related SLD and larger BAG was significant across middle-aged (< 60) and older (>= 60) adults, males and females, and APOE epsilon 4 carriers and non-carriers. INFLA mediated 13.53% of the association between MASLD/related SLD and larger BAG (p < 0.001).

Conclusion: MASLD/related SLD, as well as MASLD and MetALD, is associated with accelerated brain ageing, even among middle-aged adults and APOE epsilon 4 non-carriers. Low-grade systemic inflammation may partially mediate this association.