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

Nho, Kwangsik; Kueider‐Paisley, Alexandra; MahmoudianDehkord, Siamak; Arnold, Matthias; Risacher, Shannon L.; Louie, Gregory; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Kastenmueller, Gabi; Wang, Jia; Xie, Guoxiang; Ahmad, Shahzad; Hankemeier, Thomas; Duijn, Cornelia M. van; Trojanowski, John Q.; Shaw, Leslie M.; Weiner, Michael W.; Doraiswamy, P. Murali; Saykin, Andrew J.; Kaddurah‐Daouk, Rima; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1101/284141

Cited by 54 publications

(68 citation statements)

References 85 publications

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“…The ratio of primary conjugated and secondary bile acids with respect to cholic acid (CA) showed that deoxycholic acid (DCA), lithocholic acid (LCA), glycochenodeoxycholate (GCDCA), chenodeoxycholic acid (CDCA), taurodeoxycholic acid (TDCA), glycodeoxycholic acid (GDCA), ursodeoxycholic acid (UDCA), allolithocholate (alloLCA) and taurocholic acid (TCA) were higher in individuals with AD (CERAD score 1-3) compared to controls ( Figure 4). Similar results were reported in the serum metabolomics samples of AD and CN individuals 7,10 . Allo-cholic acid (ACA) is a steroid bile acid has been studied in the context of signaling mechanisms related to differentiation, proliferation or apoptosis of hepatocytes 30 .…”

Section: Cytotoxic Bile Acidssupporting

confidence: 88%

“…Bile acids are derived from cholesterol and their synthesis is regulated by complex feedback mechanisms 12,18 . Recent studies have identified bile acids in brain samples and linked them with cognitive decline in AD 7,10,19 . To understand the physiological role of bile acids in the brain of AD and CN individuals, we analyzed transcriptome data from post-mortem brain samples obtained from three independent cohorts and identified genes involved in the alternative bile acid pathway were expressed compared to the classical pathway in the brain.…”

Section: Role Of Bile Acids In Ad Pathophysiology and Use Of Genome-smentioning

confidence: 99%

“…Interest in the transport of biochemical compounds between the brain and the gut and their possible role in regulating metabolic changes centrally and peripherally has increased recently across several neurodegenerative diseases 8,9 . There is increasing evidence to suggest a role in AD for primary and secondary bile acids 7,10,11 . Bile acids are amphipathic molecules and primary bile acids are derived from cholesterol mostly in the liver, whereas secondary bile acids are typically produced by bacteria in the gut 12 .…”

Section: Introductionmentioning

confidence: 99%

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Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions

Baloni

Funk

Yan

et al. 2019

Preprint

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Alzheimer's disease (AD) is the leading cause of dementia, with metabolic dysfunction seen years before the emergence of clinical symptoms. Increasing evidence suggests a role for primary and secondary bile acids, the end-product of cholesterol metabolism, influencing pathophysiology in AD. In this study, we analyzed transcriptomes from 2114 post-mortem brain samples from three independent cohorts and identified that the genes involved in alternative bile acid synthesis pathway was expressed in brain compared to the classical pathway. These results were supported by targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals. We reconstructed brain region-specific metabolic networks using data from three independent cohorts to assess the role of bile acid metabolism in AD pathophysiology. Our metabolic network analysis suggested that taurine transport, bile acid synthesis and cholesterol metabolism differed in AD and cognitively normal individuals. Using the brain transcriptional regulatory network, we identified putative transcription factors regulating these metabolic genes and influencing altered metabolism in AD. Intriguingly, we find bile acids from the brain metabolomics whose synthesis cannot be explained by enzymes we find in the brain, suggesting they may originate from an external source such as the gut microbiome. These findings motivate further research into bile acid metabolism and transport in AD to elucidate their possible connection to cognitive decline.

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Section: Cytotoxic Bile Acidssupporting

confidence: 88%

Section: Role Of Bile Acids In Ad Pathophysiology and Use Of Genome-smentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions

Baloni

Funk

Yan

et al. 2019

Preprint

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“…In total, 73 cortical thickness measures and 26 volume measures from different brain regions were extracted. 20 of them presented in Table 1 were found to be highly relevant to AD [27] and were used as quantitative traits in this analysis. analysis after performing standard quality control procedures for genetic markers and subjects.…”

Section: Mri Imaging Processingmentioning

confidence: 99%

Functional biological paths altered in Alzheimer’s disease: from genes to bile acids

Gorijala¹,

Nho

Risacher

et al. 2020

Preprint

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Large-scale genome wide association studies (GWASs) have been performed in search for risk genes for Alzheimer's disease (AD). Despite the significant progress, replicability of genetic findings and their translation into targetable mechanisms related to the disease pathogenesis remains a challenge. Given that bile acids have been suggested in recent metabolic studies as potential age-related metabolic factors associated with AD, we integrated genomic and metabolomic data together with heterogeneous biological networks and investigated the potential cascade of effect of genetic variations to proteins, bile acids and ultimately AD brain phenotypes.Particularly, we leveraged functional protein interaction networks and metabolic networks and focused on the genes directly interacting with AD-altered bile acids and their functional regulators.We examined the association of all the SNPs located in those candidate genes with AD brain imaging phenotypes, and identified multiple AD risk SNPs whose downstream genes and bile acids were also found to be altered in AD. These AD related markers span from genetics to metabolomics, forming functional biological paths connecting across multiple-omics layers, and give valuable insights into the underlying mechanism of AD.

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“…This profiling technology has already been used to identify differential metabolites that can distinguish mild cognitive impairment (MCI) subjects who will develop AD from stable MCI 9 . Mounting evidence suggests that AD is closely accompanied with the abnormal bile acid (BA) metabolism [10][11][12][13] , free fatty acid (FFA) metabolism 14,15,26 , lipid metabolism 16,17 and neurotransmitter metabolism 18 . BAs are increasingly recognized as important metabolic signaling molecules that modulate lipid, glucose, and energy metabolism 19 .…”

Section: Introductionmentioning

confidence: 99%

Peripheral Serum Metabolomic Profiles Inform Antecedent Central Cognitive Impairment in Older Adults

Wang

Wei

Xie

et al. 2019

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The incidence of Alzheimer's disease (AD) increases with age and is a significant cause of worldwide morbidity and mortality. However, the metabolic perturbations behind the onset of AD remains unclear. In this study, we performed metabolite profiling in both brain (n = 109) and matching serum samples (n = 566) to identify differentially expressed metabolites and metabolic pathways associated with neuropathology and cognitive performance and to identify individuals at high risk of developing cognitive impairment. The abundances of six metabolites, GLCA, petroselinic acid, linoleic acid, myristic acid, palmitic acid, and palmitoleic acid as well as the DCA/CA ratio, along with the dysregulation scores of three metabolic pathways, primary bile acid biosynthesis, fatty acid biosynthesis, and biosynthesis of unsaturated fatty acids showed significant differences in diagnostic groups across both brain and serum (P-value < 0.05).Significant associations were observed between the levels of differential metabolites/pathways and cognitive performance, neurofibrillary tangles, and neuritic plaque burden. Metabolites abundances and personalized metabolic pathways scores were used to derive machine learning models that could be used to differentiate cognitively impaired persons from those without cognitive impairment (median of AUC = 0.772 for the metabolite level model; median of AUC = 0.731 for the pathway level model). Utilizing these two models on the entire baseline control group, we identified those who experienced cognitive decline (AUC = 0.804, sensitivity = 0.722, specificity = 0.749 for the metabolite level model; AUC = 0.778, sensitivity = 0.633, specificity = 0.825 for the pathway level model) and demonstrated their pre-AD onset prediction potentials.Our study provides a proof-of-concept that it is possible to discriminate antecedent cognitive impairment in older adults before the onset of overt clinical symptoms using metabolomics. Our findings, if validated in future studies, could enable the earlier detection and intervention of cognitive impairment that may halt its progression.

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

Cited by 54 publications

References 85 publications

Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions

Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions

Functional biological paths altered in Alzheimer’s disease: from genes to bile acids

Peripheral Serum Metabolomic Profiles Inform Antecedent Central Cognitive Impairment in Older Adults

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