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

Article type: Research Article

Authors: Weinstein, Galit^{a; *} | O’Donnell, Adrienne^{b; c} | Davis-Plourde, Kendra^{b; c} | Zelber-Sagi, Shira^{a; d} | Ghosh, Saptaparni^{c; e} | DeCarli, Charles S.^f | Thibault, Emma G.^g | Sperling, Reisa A.^{g; h} | Johnson, Keith A.^{g; h} | Beiser, Alexa S.^{b; c; e} | Seshadri, Sudha^{c; e; i}

Affiliations: [a] School of Public Health, University of Haifa, Haifa, Israel | [b] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA | [c] The Framingham Study, Framingham, MA, USA | [d] Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv, Israel | [e] Department of Neurology, Boston University School of Medicine, Boston, MA, USA | [f] Department of Neurology, School of Medicine & Imaging of Dementia and Aging Laboratory, Center for Neuroscience, University of California Davis, Davis, CA, USA | [g] Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA | [h] Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA | [i] Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA

Correspondence: [*] Correspondence to: Galit Weinstein, PhD, School of Public Health, University of Haifa, 199 Aba Khoushy Ave., Mount Carmel, Haifa, 3498838, Israel. Tel.: +972 4 828 8675; Fax: +972 4 8288637; E-mail: gweinstei@univ.haifa.ac.il.; ORCID: 0000-0002-1316-4448

Abstract: 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.

Keywords: Alzheimer’s disease, amyloid-β, liver fibrosis, non-alcoholic fatty liver disease, positron emission tomography

DOI: 10.3233/JAD-215409

Journal: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1371-1383, 2022