Metabolic risk and metabolic dysfunction-associated steatotic liver disease and steatohepatitis in cognitive decline: A retrospective cohort study.

Authors

Ahmad Basil Nasir, Yassine Kilani, Mohammad Aldiabat, Omar Abdelghany, Youssef Hafez, Nitin Desai, Mahmoud Y Madi, Francis G Wade, Kamran Qureshi, Lewis J Frey, Adam D Farmer, Wing-Kin Syn

Published in

PloS one. Volume 21. Issue 7. Pages e0353160. Epub Jul 09, 2026.

Abstract

To determine whether metabolic risk factors (MRFs), metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are associated with incident mild cognitive impairment (MCI), vascular dementia (VD), and Alzheimer disease (AD).
Retrospective cohort study using TriNetX (2003-2023) with Propensity score matching.
Multicenter, population-based sample from 69 U.S. healthcare organizations in the TriNetX electronic health record.
Adults aged ≥50 years with ≥1 outpatient visit and sufficient clinical/laboratory data. Individuals with prior diagnoses of cognitive impairment, cerebrovascular disease, advanced liver disease, malignancy, schizophrenia, or substance use disorders were excluded. Two matched cohorts were constructed: one with 3,546,833 individuals with MRFs and 3,546,833 healthy controls, and another with 525,844 individuals with MASLD/MASH and 525,844 with MRFs only. Matching was based on age, sex, race, and ethnicity.
Incident MCI, VD, and AD, identified using ICD-10 codes, assessed at 5-20-year intervals. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression. Outcomes were prespecified.
Among 7,818,146 participants (mean [SD] age, 64.9 [8.8] years; 52.0% female), individuals with MRFs had higher odds of VD (OR, 1.65; 95% CI, 1.63-1.67), MCI (OR, 1.45; 95% CI, 1.42-1.48), and AD (OR, 1.21; 95% CI, 1.19-1.24) vs healthy controls. Compared to the MRF group, individuals with MASLD/MASH had lower odds of VD (OR, 0.86; 95% CI, 0.83-0.89) and AD (OR, 0.83; 95% CI, 0.78-0.88), but higher odds of MCI (OR, 1.37; 95% CI, 1.30-1.44); all p < .001.
In this large, propensity-matched retrospective cohort study, MRFs were independently associated with significantly increased long-term odds of MCI, VD, and AD. MASLD/MASH demonstrated a divergent cognitive risk profile relative to MRFs alone-characterized by higher odds of MCI but paradoxically lower odds of VD and AD, a pattern that warrants cautious interpretation given potential competing mortality risk, survivor bias, and residual confounding. These findings suggest that MASLD/MASH is associated with a distinct cognitive trajectory, highlighting the importance of early cognitive surveillance in this population.

PMID:
42424274
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.

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