Patients with metabolic dysfunction–associated steatotic liver disease (MASLD) or its more severe form, metabolic dysfunction–associated steatohepatitis (MASH), face significantly higher odds of developing mild cognitive impairment (MCI) compared to those with metabolic risk factors alone, according to a retrospective cohort study recently published in PLOS One. Researchers evaluated the long-term cognitive impact of these liver conditions, which are increasingly recognized as systemic issues that may affect brain health.
The global prevalence of MASLD has risen to approximately 30% of adults, with MASH affecting about 5% of the population. Since both conditions are linked to cardiovascular disease and diabetes, scientists have become interested in the “brain-liver axis.” This connection involves systemic inflammation, insulin resistance, and altered lipid metabolism, all of which may contribute to neurodegeneration. Previous observational studies have produced inconsistent results regarding the link between metabolic liver issues and cognitive decline, often limited by small sample sizes or short follow-up periods. To address these gaps, investigators used the TriNetX Research Network to track outcomes over extended periods.
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Using a database spanning 69 U.S. healthcare organizations, the team built two propensity-matched cohorts from adults over 50. One group included 3.5 million patients with metabolic risk factors matched against healthy controls. The second group contained 525,844 patients with MASLD or MASH compared to those with metabolic risk factors but no liver disease diagnosis. Outcomes were tracked using International Classification of Diseases, Tenth Revision codes for incident mild cognitive impairment, vascular dementia, and Alzheimer disease across 5-, 10-, 15-, and 20-year follow-up windows.
The study population consisted of three groups: a healthy control group (n = 7,228,315), a metabolic risk factor group (n = 3,648,323), and the MASLD/MASH with metabolic risk factors group (n = 525,354). The researchers noted that the cohorts were balanced regarding age, sex, race, and ethnicity. Matched analysis demonstrated that patients with metabolic risk factors alone consistently faced raised odds of developing all three cognitive disorders compared to healthy controls across all follow-up durations.
Within five years, the metabolic risk factors group had a 62% increased risk of vascular dementia (OR, 1.62; 95% CI, 1.60-1.64), a 38% increased risk of MCI (OR, 1.38; 95% CI, 1.35-1.40), and a 19% increased risk of Alzheimer disease (OR, 1.19; 95% CI, 1.16-1.21). These associations remained stable over time. At 10 years, the odds of developing vascular dementia, MCI, and Alzheimer disease among this group were 1.60 (95% CI, 1.57-1.62), 1.38 (95% CI, 1.35-1.41), and 1.17 (95% CI, 1.15-1.19), respectively. The odds increased at 15 years to 1.64 for vascular dementia (95% CI, 1.62–1.67), 1.44 for MCI (95% CI, 1.41–1.47), and 1.21 for Alzheimer disease (95% CI, 1.18–1.23). The pattern remained consistent at 20 years with ORs of 1.65 for vascular dementia, 1.45 for MCI, and 1.21 for Alzheimer disease (all P < .001).
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Compared with patients who had metabolic risk factors alone, those with MASLD/MASH “exhibited a distinct cognitive risk profile.” Within five years, patients with MASLD/MASH had a 25% lower risk of both vascular dementia (OR, 0.75; 95% CI, 0.72-0.78) and Alzheimer disease (OR, 0.75; 95% CI, 0.70-0.80) but a 35% increased risk of MCI (OR, 1.35; 95% CI, 1.28-1.43). Similarly, at 10 years, the odds of vascular dementia and Alzheimer disease remained reduced (ORs, 0.85 and 0.83, respectively) among patients with MASLD/MASH while the risk of MCI remained raised (OR, 1.42; 95% CI, 1.35-1.49). The patterns persisted through 15 and 20 years of follow-up, with risks of vascular dementia and Alzheimer disease reduced by 14% to 17%, whereas MCI risk was raised by 37% (OR, 1.37; 95% CI, 1.30-1.44 for both intervals).
The findings add to a mixed body of literature on the liver-brain axis; some prior cohort studies have linked MASLD to raised dementia risk, while others found higher MCI risk paired with neutral or reduced dementia risk, echoing the pattern in this analysis. The authors emphasized, however, that the reduced dementia odds among this group should not be read as a protective effect of liver disease. Because patients with MASLD/MASH tend to have higher rates of cardiovascular and liver-related mortality, some may not survive long enough to receive a dementia diagnosis. More frequent healthcare contact among patients already being monitored for liver disease could also mean earlier interventions or detection bias. In addition, the study could not adjust for unmeasured factors such as APOE genotype, physical activity, or medication use. Consequently, the authors called for future research using time-to-event models that can formally account for competing risks, something the TriNetX platform’s logistic regression approach could not do.
These results suggest a complex relationship between liver health and cognitive function, particularly regarding the distinction between mild impairment and dementia. While the study provides valuable long-term data, it highlights the limitations of retrospective designs and administrative data. Future research should focus on clarifying these pathways and addressing key knowledge gaps regarding the contribution of metabolic dysfunction to neurocognitive decline.
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The researchers acknowledged their study’s limitations, including inherent risks of selection bias and residual confounding, given its retrospective cohort design and reliance on administrative data. In addition, because the dataset was derived from the TriNetX Research Network, the findings may not generalize to non-U.S. populations or settings with differing socioeconomic conditions, health care access, or population health profiles. Consequently, they suggested areas for further research.
“These findings support the role of early cognitive screening in individuals with MASLD/MASH, particularly in those with coexisting metabolic comorbidities or progressive liver disease,” the authors concluded. “Future research should focus on clarifying these pathways and addressing key knowledge gaps regarding the contribution of metabolic dysfunction to neurocognitive decline.”
