MASLD, MASH Linked to Higher Mild Cognitive Impairment Risk, Lower Dementia Odds

Patients with metabolic dysfunction–associated steatotic liver disease (MASLD) or its more severe form, metabolic dysfunction–associated steatohepatitis (MASH), had significantly higher odds of developing mild cognitive impairment (MCI) than patients with metabolic risk factors alone, according to a retrospective cohort study recently published in PLOS One.¹

Evaluating the Long-Term Cognitive Impact of MASLD/MASH

In addition to their established links with cardiovascular disease and diabetes, both MASLD and MASH are being increasingly recognized as systemic conditions that may affect cognitive health. Since the global prevalence of MASLD has risen to approximately 30% of adults, and MASH affects about 5%, researchers have become increasingly interested in the brain-liver axis, through which systemic inflammation, insulin resistance, and altered lipid metabolism may contribute to neurodegeneration.²

Although previous observational studies have examined whether metabolic risk factors and MASLD/MASH are associated with cognitive outcomes such as mild cognitive impairment (MCI), vascular dementia (VD), and Alzheimer disease (AD), results have been inconsistent and limited by small sample sizes, heterogeneous populations, and short follow-up periods.¹ To address these gaps, investigators conducted a study to evaluate the long-term associations between metabolic risk factors, MASLD/MASH, and the incidence of MCI, VD, and AD.

Using the TriNetX Research Network, a database spanning 69 US health care organizations, they built 2 propensity-matched cohorts from adults 50 years and older: 3.5 million patients with metabolic risk factors compared with matched healthy controls and 525,844 patients with MASLD or MASH compared with matched patients who had metabolic risk factors but no liver disease diagnosis. Outcomes were tracked using the International Classification of Diseases, Tenth Revision codes for incident MCI, VD, and AD across 5-, 10-, 15-, and 20-year follow-up windows.

Findings Suggest a Complex Relationship Between MASLD/MASH, Cognitive Decline

The study population consisted of 3 groups: the healthy control group (n = 7,228,315), the 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 successfully balanced regarding age, sex, race, and ethnicity.

Matched analysis demonstrated that patients with metabolic risk factors alone consistently faced elevated odds of developing all 3 cognitive disorders vs healthy controls across all follow-up durations. Within 5 years, the metabolic risk factors group had a 62% increased risk of VD (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 AD (OR, 1.19; 95% CI, 1.16-1.21).

The researchers noted that these associations remained stable over time. Specifically, at 10 years, the odds of developing VD, MCI, and AD 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 VD (95% CI, 1.62–1.67), 1.44 for MCI (95% CI, 1.41–1.47), and 1.21 for AD (95% CI, 1.18–1.23). The pattern remained consistent at 20 years with ORs of 1.65 for VD, 1.45 for MCI, and 1.21 for AD (all P < .001).

Compared with patients with metabolic risk factors alone, the researchers noted that those with MASLD/MASH “exhibited a distinct cognitive risk profile.” Within 5 years, patients with MASLD/MASH had a 25% lower risk of both VD (OR, 0.75; 95% CI, 0.72-0.78) and AD (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 VD and AD remained reduced (ORs, 0.85 and 0.83, respectively) among patients with MASLD/MASH while the risk of MCI remained elevated (OR, 1.42; 95% CI, 1.35-1.49). The patterns persisted through 15 and 20 years of follow-up, with risks of VD and AD reduced by 14% to 17%, whereas MCI risk was elevated 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 elevated 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 health care 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.

Future Research Needed to Clarify Cognitive Effects of MASLD/MASH

At the same time, 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-US 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.”

References

1. Nasir AB, Kilani Y, Aldiabat M, et al. Metabolic risk and metabolic dysfunction–associated steatotic liver disease and steatohepatitis in cognitive decline: a retrospective cohort study. PLoS One. 2026;21(7):e0353160. doi:10.1371/journal.pone.0353160
2. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023;77(4):1335-1347. doi:10.1097/HEP.0000000000000004