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JAMA Neurol. 2018 Jan 1;75(1):97-104. doi: 10.1001/jamaneurol.2017.3229.

Association of Nonalcoholic Fatty Liver Disease With Lower Brain Volume in Healthy Middle-aged Adults in the Framingham Study.

Author information

School of Public Health, University of Haifa, Haifa, Israel.
Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv, Israel.
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
The Framingham Study, Framingham, Massachusetts.
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts.
Department of Neurology, University of California at Davis, Sacramento.
Department of Gastroenterology, Massachusetts General Hospital, Boston.
Department of Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts.



Nonalcoholic fatty liver disease (NAFLD) is a common condition that is most often asymptomatic. It is associated with metabolic syndrome, incident diabetes, carotid atherosclerosis, and endothelial dysfunction, conditions that in turn are strongly linked with brain damage and cognitive impairment. However, it is not known whether NAFLD is associated with structural brain measures in humans.


To assess the association between prevalent NAFLD and brain magnetic resonance imaging (MRI) measures.

Design, Setting, and Participants:

The cross-sectional association between NAFLD and brain MRI measures was assessed from November 6, 2002, to March 16, 2011, in 766 individuals from the Offspring cohort of the Framingham Study. Participants were included if they did not have excessive alcohol intake and were free of stroke and dementia. Data analysis was conducted from December 30, 2015, to June 15, 2016.


Nonalcoholic fatty liver disease was assessed by multidetector computed tomographic scans of the abdomen.

Main Outcomes and Measures:

Linear or logistic regression models were used to evaluate the cross-sectional association between NAFLD and brain MRI measures, adjusting for age, sex, alcohol consumption, visceral adipose tissue, body mass index, menopausal status, systolic blood pressure, hypertension, current smoking, high-density lipoprotein and low-density lipoprotein cholesterol levels, lipid treatment, type 2 diabetes, cardiovascular disease, physical activity, insulin resistance, C-reactive protein levels, and plasma homocysteine values. Brain MRI measures included total cerebral brain volume, hippocampal and white matter hyperintensity volumes, and presence or absence of covert brain infarcts.


Of the 766 individuals in the study sample (410 women and 356 men; mean [SD] age at the time of brain MRI, 67 [9] years), 137 (17.9%) had NAFLD. Nonalcoholic fatty liver disease was significantly associated with smaller total cerebral brain volume even after adjustment for all the covariates included in the study (β [SE], -0.26 [0.11]; P = .02). Differences in total cerebral brain volume between those with and without NAFLD corresponded to 4.2 years of brain aging in the general sample and to 7.3 years in individuals younger than 60 years of age. No statistically significant associations were observed between NAFLD and hippocampal or white matter hyperintensity volumes or covert brain infarcts.

Conclusions and Relevance:

Nonalcoholic fatty liver disease is associated with a smaller total cerebral brain volume, independent of visceral adipose tissue and cardiometabolic risk factors, pointing to a possible link between hepatic steatosis and brain aging.

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