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Metabolic dysfunction-associated steatotic liver disease and neurocognitive and reward circuit dysfunction: implications for mental disorders

Year: 2026
Type: article
Study design: Systematic Review
Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) (formerly known as nonalcoholic fatty liver disease) is the most prevalent liver disease globally. Emerging evidence suggests MASLD-related metabolic and inflammatory processes may disrupt frontostriatal–limbic circuits, contributing to alterations in cognitive and reward-related brain function. This systematic review aimed to examine whether MASLD is associated with changes in cognitive functioning and reward-related processes, and whether these changes correspond to structural and functional brain alterations. A systematic search of PubMed, Web of Science, and Google Scholar was conducted from inception to November 11, 2025, using terms related to MASLD, cognition, and reward. Eligible studies included adult MASLD populations and observational designs assessing cognitive and/or reward outcomes. Studies involving neuropsychiatric or neurological disorders or medications known to affect cognition were excluded. Fourteen studies (eight cross-sectional, four cohort or case–control, and two Mendelian randomization) found MASLD significantly associated with poorer attention, executive function and memory, often proportional to disease severity. Neuroimaging studies reported significant reductions in cortical thickness, hippocampal and white matter volume, increased white matter hyperintensities, and cerebrovascular dysfunction ( p < 0.05), most pronounced in executive and visuospatial regions. Limited evidence suggested alterations in small-to-moderate circuits, including nucleus accumbens dysfunction and reduced hippocampal–orbitofrontal connectivity. MASLD is associated with cognitive impairment, reward-related neural systems, and structural and cerebrovascular brain alterations. These findings reinforce its characterization as a multisystem condition affecting brain health and neuropsychiatric risk. Longitudinal studies with standardized criteria and confounder adjustment are needed to clarify causal mechanisms.
DOI: 10.1017/s1092852926100984
Authors: Nina Sachi Mollin, Gia Han Le, Christine E. Dri, Elim Yang, Folkert van Bruggen, Kangguang Lin, Stavroula Bargiota, Heidi K.Y. Lo, Roger Ho, Taeho Greg Rhee, Bing Cao, Angela T.H. Kwan, Roger S. McIntyre
Institutions: University of Toronto, Brain and Cognition Discovery Foundation, University Medical Center Groningen, Chinese University of Hong Kong, University of Thessaly, University of Hong Kong, National University of Singapore, Yale University, Southwest University
Language: English
Subfield: Hepatology
Field: Medicine
Open Access status: hybrid
Estimated APC paid: $3,550
Funders: Pfizer, Sanofi, Biogen, Patient-Centered Outcomes Research Institute, Purdue University, University of Connecticut, Sunovion, National Natural Science Foundation of China, Eisai, Novo Nordisk, H. Lundbeck A/S, Bausch Health, National Institutes of Health, Substance Abuse and Mental Health Services Administration, Institute for Collaboration on Health, Intervention, and Policy, University of Connecticut, Canadian Institutes of Health Research, National Institute on Aging, National Institute of Mental Health
OpenAlex ID: W7162446399
FWCI:
Cites: 35
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Related to: 10