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

doi:10.3233/jad-215409

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

School of Public Health

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1371-1383
Number of pages	13
Journal	Journal of Alzheimer's Disease
Volume	86
Issue number	3
DOIs	https://doi.org/10.3233/jad-215409
State	Published - 2022

Bibliographical note

Funding Information:
This study was supported by grants from the National Institute on Aging (R01 AG054076, R01 AG049607, R01 AG033040, R01 AG063507, U01 AG052409, RF1 AG061872, U01 AG049505, U01 AG058589, and P30 AG066546), the National Institute of Neurological Disorders and Stroke (R01 NS017950 and UH2 NS100605), and the NHLBI contract for the Framingham Heart Study (contract no. N01-HC-25195, HHSN268201500001I, and 75N92019D00031).

Funding Information:
This study was supported by grants from the National Institute on Aging (R01 AG054076, R01 AG049607, R01 AG033040, R01 AG063507, U01 AG052409, RF1 AG061872, U01 AG049505, U01 AG058589, and P30 AG066546), the National Institute of Neurological Disorders and Stroke (R01

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

Keywords

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
Neuroscience (all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3233/jad-215409

Cite this

Weinstein, G., O'Donnell, A., Davis-Plourde, K., Zelber-Sagi, S., Ghosh, S., Decarli, C. S., Thibault, E. G., Sperling, R. A., Johnson, K. A., Beiser, A. S., & Seshadri, S. (2022). Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-β and Tau Pathology in Middle-Aged Adults: The Framingham Study. Journal of Alzheimer's Disease, 86(3), 1371-1383. https://doi.org/10.3233/jad-215409

@article{3397de3bb2c047dd80523d6e9acaa35b,

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

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, 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",

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

note = "Funding Information: This study was supported by grants from the National Institute on Aging (R01 AG054076, R01 AG049607, R01 AG033040, R01 AG063507, U01 AG052409, RF1 AG061872, U01 AG049505, U01 AG058589, and P30 AG066546), the National Institute of Neurological Disorders and Stroke (R01 NS017950 and UH2 NS100605), and the NHLBI contract for the Framingham Heart Study (contract no. N01-HC-25195, HHSN268201500001I, and 75N92019D00031). Funding Information: This study was supported by grants from the National Institute on Aging (R01 AG054076, R01 AG049607, R01 AG033040, R01 AG063507, U01 AG052409, RF1 AG061872, U01 AG049505, U01 AG058589, and P30 AG066546), the National Institute of Neurological Disorders and Stroke (R01 Publisher Copyright: {\textcopyright} 2022 - IOS Press. All rights reserved.",

year = "2022",

doi = "10.3233/jad-215409",

language = "English",

volume = "86",

pages = "1371--1383",

journal = "Journal of Alzheimer's Disease",

issn = "1387-2877",

publisher = "IOS Press",

number = "3",

}

Weinstein, G, O'Donnell, A, Davis-Plourde, K, Zelber-Sagi, S, Ghosh, S, Decarli, CS, Thibault, EG, Sperling, RA, Johnson, KA, Beiser, AS & Seshadri, S 2022, 'Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-β and Tau Pathology in Middle-Aged Adults: The Framingham Study', Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1371-1383. https://doi.org/10.3233/jad-215409

TY - JOUR

T1 - Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-β and Tau Pathology in Middle-Aged Adults

T2 - The Framingham Study

AU - Weinstein, Galit

AU - O'Donnell, Adrienne

AU - Davis-Plourde, Kendra

AU - Zelber-Sagi, Shira

AU - Ghosh, Saptaparni

AU - Decarli, Charles S.

AU - Thibault, Emma G.

AU - Sperling, Reisa A.

AU - Johnson, Keith A.

AU - Beiser, Alexa S.

AU - Seshadri, Sudha

N1 - Funding Information: This study was supported by grants from the National Institute on Aging (R01 AG054076, R01 AG049607, R01 AG033040, R01 AG063507, U01 AG052409, RF1 AG061872, U01 AG049505, U01 AG058589, and P30 AG066546), the National Institute of Neurological Disorders and Stroke (R01 NS017950 and UH2 NS100605), and the NHLBI contract for the Framingham Heart Study (contract no. N01-HC-25195, HHSN268201500001I, and 75N92019D00031). Funding Information: This study was supported by grants from the National Institute on Aging (R01 AG054076, R01 AG049607, R01 AG033040, R01 AG063507, U01 AG052409, RF1 AG061872, U01 AG049505, U01 AG058589, and P30 AG066546), the National Institute of Neurological Disorders and Stroke (R01 Publisher Copyright: © 2022 - IOS Press. All rights reserved.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - amyloid-β

KW - liver fibrosis

KW - non-alcoholic fatty liver disease

KW - positron emission tomography

KW - Liver Cirrhosis/diagnostic imaging

KW - Humans

KW - Middle Aged

KW - Male

KW - tau Proteins

KW - Non-alcoholic Fatty Liver Disease/diagnostic imaging

KW - Amyloid beta-Peptides

KW - Female

KW - Alzheimer Disease/diagnostic imaging

KW - Positron-Emission Tomography/methods

UR - http://www.scopus.com/inward/record.url?scp=85128394205&partnerID=8YFLogxK

U2 - 10.3233/jad-215409

DO - 10.3233/jad-215409

M3 - Article

C2 - 35213373

AN - SCOPUS:85128394205

SN - 1387-2877

VL - 86

SP - 1371

EP - 1383

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

IS - 3

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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