Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-β and Tau Pathology in Middle-Aged Adults: The Framingham Study

Galit Weinstein, Adrienne O'Donnell, Kendra Davis-Plourde, Shira Zelber-Sagi, Saptaparni Ghosh, Charles S. Decarli, Emma G. Thibault, Reisa A. Sperling, Keith A. Johnson, Alexa S. Beiser, Sudha Seshadri

Research output: Contribution to journalArticlepeer-review


Background: Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimer's disease pathology is unclear. Objective: To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-β (Aβ) and tau pathology. Methods: The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011-2014) and 2 (2008-2011), respectively. Participants underwent 11C-Pittsburgh Compound-B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aβ, adjusting for potential confounders and multiple comparisons. Results: Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 > 1.3). Prevalent NAFLD was not associated with Aβ or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (β= 1.03±0.33, p = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (β= 2.01±0.47, p < 0.001; β= 1.60±0.53, p = 0.007, and β= 1.59±0.47, p = 0.003 and β= 1.60±0.42, p = 0.001, respectively) and to Aβ deposition overall and in the inferior temporal and parahippocampal regions (β= 1.93±0.47, p < 0.001; β= 1.59±0.38, p < 0.001, and β= 1.52±0.54, p = 0.008, respectively). Conclusion: This study suggests a possible association between liver fibrosis and early Alzheimer's disease pathology, independently of cardio-metabolic risk factors.

Original languageEnglish
Pages (from-to)1371-1383
Number of pages13
JournalJournal of Alzheimer's Disease
Issue number3
StatePublished - 2022

Bibliographical note

Publisher Copyright:
© 2022 - IOS Press. All rights reserved.


  • Alzheimer's disease
  • amyloid-β
  • liver fibrosis
  • non-alcoholic fatty liver disease
  • positron emission tomography
  • Liver Cirrhosis/diagnostic imaging
  • Humans
  • Middle Aged
  • Male
  • tau Proteins
  • Non-alcoholic Fatty Liver Disease/diagnostic imaging
  • Amyloid beta-Peptides
  • Female
  • Alzheimer Disease/diagnostic imaging
  • Positron-Emission Tomography/methods

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Clinical Psychology
  • General Neuroscience


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