Association Between Non-alcoholic Fatty Liver Disease and the Risk of Dementia

A Nationwide Cohort Study

Gi-Ae Kim; Chi Hyuk Oh; Jung Wook Kim; Su Jin Jeong; In-Hwan Oh; Jin San Lee; Key-Chung Park; Jae-Jun Shim


Liver International. 2022;42(5):1027-1036. 

In This Article

Abstract and Introduction


Background and Aims: Little is known about the association between non-alcoholic fatty liver disease (NAFLD) and dementia. Given that hepatic steatosis is linked to abnormal fat metabolism, and fat dysregulation in the brain is related to dementia, we aimed to investigate whether NAFLD is associated with an increased risk of dementia.

Methods: We conducted a nationwide cohort study involving 4 031 948 subjects aged 40–69 years who underwent ≥2 health check-ups provided by the National Health Insurance Service in Korea between January 2004 and December 2007. Based on the hepatic steatosis index (HSI), subjects were categorized into non-NAFLD (HSI <30 at all check-ups) and NAFLD (HSI >36 at one or more check-ups). Dementia defined by ICD-10 codes with prescription data was followed up until December 2017. Cox proportional hazards regression models analysed the dementia risk.

Results: At baseline, 31.3% had NAFLD. During the median follow-up of 9.5 years, 138 424 in NAFLD group and 69 982 in non-NAFLD group developed dementia. NAFLD group was associated with a higher risk of dementia than non-NAFLD group on multivariable-adjusted analysis (hazard ratio [HR], 1.05; p < .001), competing risk analysis (HR, 1.08; p < .001) and propensity-score matched analysis (HR, 1.09; p < .001). The association between NAFLD and dementia risk was more prominent among females (HR, 1.16; p < .001). The association was stronger among non-obese NAFLD subjects (BMI <25 kg/m2, HR, 1.09; p < .001) than obese NAFLD subjects.

Conclusions: This nationwide study found that NAFLD is associated with an increased risk of dementia. The association was prominent among females and non-obese NAFLD subjects.


Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide with an estimated prevalence of 25%.[1–5] The global burden of NAFLD is on the rise coinciding with the increasing prevalence of obesity and metabolic diseases.[6–8] As a multisystem disease, NAFLD is closely associated with extrahepatic manifestations, such as cardiovascular disease, chronic kidney disease, sleep apnoea and cancers.[9–11]

In recent years, accumulating evidence indicates that NAFLD can be associated with conditions related to brain ageing. A study found that NAFLD is linked to cognitive impairment and decreased brain activity independent of cardiovascular disease.[12] The results of a study which demonstrated that NAFLD patients had smaller total cerebral brain volume suggest a possible association between NAFLD and brain ageing.[13] While an advanced stage of NAFLD was found to be related to poor cognitive function,[14] the association of NAFLD with dementia specifically has not been actively explored.

Dementia is a neurodegenerative or vascular disorder associated with the deterioration of behaviour, cognition and emotion. An estimated 50 million people worldwide suffer from dementia, and its prevalence is expected to triple by 2050.[15] Lipids play a pivotal role in maintaining the physiological functions of the brain; however, the precise mechanism requires further investigation.[15–19] Peroxisome proliferator-activated receptor α (PPARα) was found to be a master metabolic regulator in fatty acid catabolism, and PPARα signalling can be a crosstalk between liver steatosis and brain function, such as learning and memory.[15,20] A recent study in mice showed that the liver inflammation caused by NAFLD induced signs of Alzheimer's disease.[21] Given that hepatic steatosis is one of the abnormal fat metabolisms in the body and fat dysregulation in the brain is related to dementia, it would be reasonable to investigate the potential link between NAFLD and dementia.

Thus, in this large nationwide population-based observational study, we aimed to investigate whether NAFLD is associated with an increased risk of dementia. These findings may help clinicians develop better treatment strategies for NAFLD patients.