Altered Bile Acid Profile in Mild Cognitive Impairment and Alzheimer's Disease: Relationship to Neuroimaging and CSF Biomarkers

Overview

Journal Alzheimers Dement

Specialties Neurology
Psychiatry

Date 2018 Oct 20

PMID 30337152

Citations 133

Authors

Kwangsik Nho

Alexandra Kueider-Paisley

Siamak Mahmoudiandehkordi

Matthias Arnold

Shannon L Risacher

Gregory Louie

Colette Blach

Rebecca Baillie

Xianlin Han

Gabi Kastenmuller

Wei Jia

Guoxiang Xie

Shahzad Ahmad

Thomas Hankemeier

Cornelia M Van Duijn

John Q Trojanowski

Leslie M Shaw

Michael W Weiner

P Murali Doraiswamy

Andrew J Saykin

Rima Kaddurah-Daouk

Affiliations

Soon will be listed here.

Abstract

Introduction: Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer's disease (AD) including neuroinflammation and amyloid-β deposition.

Method: Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([F]FDG PET).

Results: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aβ ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05).

Discussion: This is the first study to show serum-based BA metabolites are associated with "A/T/N" AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.

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References

Ackerman H, Gerhard G . Bile Acids in Neurodegenerative Disorders. Front Aging Neurosci. 2016; 8:263. PMC: 5118426. DOI: 10.3389/fnagi.2016.00263. View

Nho K, Corneveaux J, Kim S, Lin H, Risacher S, Shen L . Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment. Mol Psychiatry. 2013; 18(7):781-7. PMC: 3777294. DOI: 10.1038/mp.2013.24. View

Santos R, Correia S, Wang X, Perry G, Smith M, Moreira P . Alzheimer's disease: diverse aspects of mitochondrial malfunctioning. Int J Clin Exp Pathol. 2010; 3(6):570-81. PMC: 2907118. View

Rodrigues C, Ma X, Fan G, Kren B, Steer C . Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation. Cell Death Differ. 1999; 6(9):842-54. DOI: 10.1038/sj.cdd.4400560. View

Vogt N, Kerby R, Dill-McFarland K, Harding S, Merluzzi A, Johnson S . Gut microbiome alterations in Alzheimer's disease. Sci Rep. 2017; 7(1):13537. PMC: 5648830. DOI: 10.1038/s41598-017-13601-y. View

Pham H, Arnhard K, Asad Y, Deng L, Felder T, John-Williams L . Inter-Laboratory Robustness of Next-Generation Bile Acid Study in Mice and Humans: International Ring Trial Involving 12 Laboratories. J Appl Lab Med. 2021; 1(2):129-142. DOI: 10.1373/jalm.2016.020537. View

Jack Jr C, Bennett D, Blennow K, Carrillo M, Dunn B, Budd Haeberlein S . NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018; 14(4):535-562. PMC: 5958625. DOI: 10.1016/j.jalz.2018.02.018. View

Markesbery W . The role of oxidative stress in Alzheimer disease. Arch Neurol. 1999; 56(12):1449-52. DOI: 10.1001/archneur.56.12.1449. View

Hansson O, Seibyl J, Stomrud E, Zetterberg H, Trojanowski J, Bittner T . CSF biomarkers of Alzheimer's disease concord with amyloid-β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement. 2018; 14(11):1470-1481. PMC: 6119541. DOI: 10.1016/j.jalz.2018.01.010. View

10.

Rodrigues C, Fan G, Ma X, Kren B, Steer C . A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation. J Clin Invest. 1998; 101(12):2790-9. PMC: 508870. DOI: 10.1172/JCI1325. View

11.

Paolo G, Kim T . Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat Rev Neurosci. 2011; 12(5):284-96. PMC: 3321383. DOI: 10.1038/nrn3012. View

12.

Risacher S, Saykin A . Neuroimaging biomarkers of neurodegenerative diseases and dementia. Semin Neurol. 2013; 33(4):386-416. PMC: 3975244. DOI: 10.1055/s-0033-1359312. View

13.

Olsson B, Lautner R, Andreasson U, Ohrfelt A, Portelius E, Bjerke M . CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. 2016; 15(7):673-684. DOI: 10.1016/S1474-4422(16)00070-3. View

14.

Dinan T, Cryan J . Gut-brain axis in 2016: Brain-gut-microbiota axis - mood, metabolism and behaviour. Nat Rev Gastroenterol Hepatol. 2017; 14(2):69-70. DOI: 10.1038/nrgastro.2016.200. View

15.

Greenberg N, Grassano A, Thambisetty M, Lovestone S, Legido-Quigley C . A proposed metabolic strategy for monitoring disease progression in Alzheimer's disease. Electrophoresis. 2009; 30(7):1235-9. DOI: 10.1002/elps.200800589. View

16.

Foster J, McVey Neufeld K . Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013; 36(5):305-12. DOI: 10.1016/j.tins.2013.01.005. View

17.

Leloup C, Magnan C, Benani A, Bonnet E, Alquier T, Offer G . Mitochondrial reactive oxygen species are required for hypothalamic glucose sensing. Diabetes. 2006; 55(7):2084-90. DOI: 10.2337/db06-0086. View

18.

Kueider A, Tanaka T, An Y, Kitner-Triolo M, Palchamy E, Ferrucci L . State- and trait-dependent associations of vitamin-D with brain function during aging. Neurobiol Aging. 2016; 39:38-45. PMC: 4773992. DOI: 10.1016/j.neurobiolaging.2015.11.002. View

19.

Moreira P, Carvalho C, Zhu X, Smith M, Perry G . Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochim Biophys Acta. 2009; 1802(1):2-10. DOI: 10.1016/j.bbadis.2009.10.006. View

20.

Luan H, Wang X, Cai Z . Mass spectrometry-based metabolomics: Targeting the crosstalk between gut microbiota and brain in neurodegenerative disorders. Mass Spectrom Rev. 2017; 38(1):22-33. DOI: 10.1002/mas.21553. View