Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study
While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pat...
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| Veröffentlicht in: | PLoS medicine 2021-05, Vol.18 (5), p.e1003615-e1003615 |
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| creator | Varma, Vijay R Wang, Youjin An, Yang Varma, Sudhir Bilgel, Murat Doshi, Jimit Legido-Quigley, Cristina Delgado, João C Oommen, Anup M Roberts, Jackson A Wong, Dean F Davatzikos, Christos Resnick, Susan M Troncoso, Juan C Pletnikova, Olga O'Brien, Richard Hak, Eelko Baak, Brenda N Pfeiffer, Ruth Baloni, Priyanka Mohmoudiandehkordi, Siamak Nho, Kwangsik Kaddurah-Daouk, Rima Bennett, David A Gadalla, Shahinaz M Thambisetty, Madhav |
| description | While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis.
We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = 4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 |
| doi_str_mv | 10.1371/journal.pmed.1003615 |
| format | Article |
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We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = <0.001-0.013) in males in BLSA. In ADNI, we found a modest sex-specific effect indicating that lower serum concentrations of CA and CDCA were associated with faster brain atrophy (FDR p = 0.049) in males.Step 2: In the Clinical Practice Research Datalink (CPRD) dataset, covering >4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings.
We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.</description><identifier>ISSN: 1549-1676</identifier><identifier>ISSN: 1549-1277</identifier><identifier>EISSN: 1549-1676</identifier><identifier>DOI: 10.1371/journal.pmed.1003615</identifier><identifier>PMID: 34043628</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids ; Aged ; Aged, 80 and over ; Alzheimer's disease ; Atrophy ; Bile ; Bile acids ; Bile Acids and Salts - biosynthesis ; Bile Acids and Salts - metabolism ; Biology and Life Sciences ; Biosynthesis ; Blood-brain barrier ; Cholesterol ; Cholesterol metabolism ; Complications and side effects ; Dementia ; Dementia - epidemiology ; Dementia - metabolism ; Dementia disorders ; Development and progression ; Drug delivery ; Female ; Gene expression ; Gene Expression Profiling ; Health aspects ; Humans ; Hypercholesterolemia ; Incidence ; Male ; Medicine and Health Sciences ; Metabolites ; Metabolomics ; Middle Aged ; Molecular modelling ; Neuroimaging ; Pharmacoepidemiology ; Research and Analysis Methods ; Risk factors ; Substantia alba ; United Kingdom - epidemiology</subject><ispartof>PLoS medicine, 2021-05, Vol.18 (5), p.e1003615-e1003615</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c764t-1a3cc44cad2957f0181c64e6a4006a87ea34b55088668b72f9ce707cccf25fa13</citedby><cites>FETCH-LOGICAL-c764t-1a3cc44cad2957f0181c64e6a4006a87ea34b55088668b72f9ce707cccf25fa13</cites><orcidid>0000-0002-4463-158X ; 0000-0002-7624-3872 ; 0000-0002-3255-8143 ; 0000-0001-5042-7422 ; 0000-0002-4018-214X ; 0000-0003-1648-871X ; 0000-0002-6843-1718 ; 0000-0001-9553-6673 ; 0000-0002-3382-4941 ; 0000-0003-2231-2454 ; 0000-0001-7653-5106 ; 0000-0003-1858-5732 ; 0000-0003-3689-554X ; 0000-0001-7143-7726 ; 0000-0002-4096-4782</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158920/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158920/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34043628$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Varma, Vijay R</creatorcontrib><creatorcontrib>Wang, Youjin</creatorcontrib><creatorcontrib>An, Yang</creatorcontrib><creatorcontrib>Varma, Sudhir</creatorcontrib><creatorcontrib>Bilgel, Murat</creatorcontrib><creatorcontrib>Doshi, Jimit</creatorcontrib><creatorcontrib>Legido-Quigley, Cristina</creatorcontrib><creatorcontrib>Delgado, João C</creatorcontrib><creatorcontrib>Oommen, Anup M</creatorcontrib><creatorcontrib>Roberts, Jackson A</creatorcontrib><creatorcontrib>Wong, Dean F</creatorcontrib><creatorcontrib>Davatzikos, Christos</creatorcontrib><creatorcontrib>Resnick, Susan M</creatorcontrib><creatorcontrib>Troncoso, Juan C</creatorcontrib><creatorcontrib>Pletnikova, Olga</creatorcontrib><creatorcontrib>O'Brien, Richard</creatorcontrib><creatorcontrib>Hak, Eelko</creatorcontrib><creatorcontrib>Baak, Brenda N</creatorcontrib><creatorcontrib>Pfeiffer, Ruth</creatorcontrib><creatorcontrib>Baloni, Priyanka</creatorcontrib><creatorcontrib>Mohmoudiandehkordi, Siamak</creatorcontrib><creatorcontrib>Nho, Kwangsik</creatorcontrib><creatorcontrib>Kaddurah-Daouk, Rima</creatorcontrib><creatorcontrib>Bennett, David A</creatorcontrib><creatorcontrib>Gadalla, Shahinaz M</creatorcontrib><creatorcontrib>Thambisetty, Madhav</creatorcontrib><title>Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study</title><title>PLoS medicine</title><addtitle>PLoS Med</addtitle><description>While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis.
We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = <0.001-0.013) in males in BLSA. In ADNI, we found a modest sex-specific effect indicating that lower serum concentrations of CA and CDCA were associated with faster brain atrophy (FDR p = 0.049) in males.Step 2: In the Clinical Practice Research Datalink (CPRD) dataset, covering >4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings.
We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.</description><subject>Acids</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Alzheimer's disease</subject><subject>Atrophy</subject><subject>Bile</subject><subject>Bile acids</subject><subject>Bile Acids and Salts - biosynthesis</subject><subject>Bile Acids and Salts - metabolism</subject><subject>Biology and Life Sciences</subject><subject>Biosynthesis</subject><subject>Blood-brain barrier</subject><subject>Cholesterol</subject><subject>Cholesterol metabolism</subject><subject>Complications and side effects</subject><subject>Dementia</subject><subject>Dementia - epidemiology</subject><subject>Dementia - metabolism</subject><subject>Dementia disorders</subject><subject>Development and progression</subject><subject>Drug delivery</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Hypercholesterolemia</subject><subject>Incidence</subject><subject>Male</subject><subject>Medicine and Health Sciences</subject><subject>Metabolites</subject><subject>Metabolomics</subject><subject>Middle Aged</subject><subject>Molecular modelling</subject><subject>Neuroimaging</subject><subject>Pharmacoepidemiology</subject><subject>Research and Analysis Methods</subject><subject>Risk factors</subject><subject>Substantia alba</subject><subject>United Kingdom - epidemiology</subject><issn>1549-1676</issn><issn>1549-1277</issn><issn>1549-1676</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqVk12L1DAUhoso7rr6D0QLgijMjEmbpK0Xwrj4MbC44NdtOD1NOxnapjapOP_e1OkuU5kLpRdpm-d9z8k5OUHwmJIVjRP6ameGvoV61TWqWFFCYkH5neCccpYtqUjE3aP3s-CBtTtCooxk5H5wFjPCYhGl50HzVtcqBNRFaPet2yqr7SJsTDHU4LRpFyG0RVioRrVOw-twHTbKQW5q02hchK6H1mKvO3f4HuFuC30DaFSnvU57tNIYWjcU-4fBvRJqqx5N60Xw7f27r5cfl1fXHzaX66slJoK5JYUYkTGEIsp4UhKaUhRMCWCECEgTBTHLOSdpKkSaJ1GZoUpIgohlxEug8UXw9ODb1cbKqVJWRpzRlHORck9sDkRhYCe7XjfQ76UBLf_8MH0loXcaayUjTCEpkyLPsRwTyBF5knBRklxlSMdob6ZoQ-6bgb5UPdQz0_lOq7eyMj9lSnmaRcQbvJgMevNjUNbJRltUdQ2tMsOYd8wEjSMae_TZX-jp001UBf4Aui2Nj4ujqVwLwQSJSZp5anmCqlSrfJKmVaW_GnN-dYL3z9hmPCl4ORN4xqlfroLBWrn58vk_2E__zl5_n7PPj9itgtptramH8XLbOcgOIPbG2l6Vtw2kRI4Td1NpOU6cnCbOy54cN_9WdDNi8W8pVyWg</recordid><startdate>20210527</startdate><enddate>20210527</enddate><creator>Varma, Vijay R</creator><creator>Wang, Youjin</creator><creator>An, Yang</creator><creator>Varma, Sudhir</creator><creator>Bilgel, Murat</creator><creator>Doshi, Jimit</creator><creator>Legido-Quigley, Cristina</creator><creator>Delgado, João C</creator><creator>Oommen, Anup M</creator><creator>Roberts, Jackson A</creator><creator>Wong, Dean F</creator><creator>Davatzikos, Christos</creator><creator>Resnick, Susan M</creator><creator>Troncoso, Juan C</creator><creator>Pletnikova, Olga</creator><creator>O'Brien, Richard</creator><creator>Hak, Eelko</creator><creator>Baak, Brenda N</creator><creator>Pfeiffer, Ruth</creator><creator>Baloni, Priyanka</creator><creator>Mohmoudiandehkordi, Siamak</creator><creator>Nho, Kwangsik</creator><creator>Kaddurah-Daouk, Rima</creator><creator>Bennett, David A</creator><creator>Gadalla, Shahinaz M</creator><creator>Thambisetty, Madhav</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><scope>CZK</scope><orcidid>https://orcid.org/0000-0002-4463-158X</orcidid><orcidid>https://orcid.org/0000-0002-7624-3872</orcidid><orcidid>https://orcid.org/0000-0002-3255-8143</orcidid><orcidid>https://orcid.org/0000-0001-5042-7422</orcidid><orcidid>https://orcid.org/0000-0002-4018-214X</orcidid><orcidid>https://orcid.org/0000-0003-1648-871X</orcidid><orcidid>https://orcid.org/0000-0002-6843-1718</orcidid><orcidid>https://orcid.org/0000-0001-9553-6673</orcidid><orcidid>https://orcid.org/0000-0002-3382-4941</orcidid><orcidid>https://orcid.org/0000-0003-2231-2454</orcidid><orcidid>https://orcid.org/0000-0001-7653-5106</orcidid><orcidid>https://orcid.org/0000-0003-1858-5732</orcidid><orcidid>https://orcid.org/0000-0003-3689-554X</orcidid><orcidid>https://orcid.org/0000-0001-7143-7726</orcidid><orcidid>https://orcid.org/0000-0002-4096-4782</orcidid></search><sort><creationdate>20210527</creationdate><title>Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study</title><author>Varma, Vijay R ; Wang, Youjin ; An, Yang ; Varma, Sudhir ; Bilgel, Murat ; Doshi, Jimit ; Legido-Quigley, Cristina ; Delgado, João C ; Oommen, Anup M ; Roberts, Jackson A ; Wong, Dean F ; Davatzikos, Christos ; Resnick, Susan M ; Troncoso, Juan C ; Pletnikova, Olga ; O'Brien, Richard ; Hak, Eelko ; Baak, Brenda N ; Pfeiffer, Ruth ; Baloni, Priyanka ; Mohmoudiandehkordi, Siamak ; Nho, Kwangsik ; Kaddurah-Daouk, Rima ; Bennett, David A ; Gadalla, Shahinaz M ; Thambisetty, Madhav</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c764t-1a3cc44cad2957f0181c64e6a4006a87ea34b55088668b72f9ce707cccf25fa13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Acids</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Alzheimer's disease</topic><topic>Atrophy</topic><topic>Bile</topic><topic>Bile acids</topic><topic>Bile Acids and Salts - biosynthesis</topic><topic>Bile Acids and Salts - metabolism</topic><topic>Biology and Life Sciences</topic><topic>Biosynthesis</topic><topic>Blood-brain barrier</topic><topic>Cholesterol</topic><topic>Cholesterol metabolism</topic><topic>Complications and side effects</topic><topic>Dementia</topic><topic>Dementia - epidemiology</topic><topic>Dementia - metabolism</topic><topic>Dementia disorders</topic><topic>Development and progression</topic><topic>Drug delivery</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Hypercholesterolemia</topic><topic>Incidence</topic><topic>Male</topic><topic>Medicine and Health Sciences</topic><topic>Metabolites</topic><topic>Metabolomics</topic><topic>Middle Aged</topic><topic>Molecular modelling</topic><topic>Neuroimaging</topic><topic>Pharmacoepidemiology</topic><topic>Research and Analysis Methods</topic><topic>Risk factors</topic><topic>Substantia alba</topic><topic>United Kingdom - epidemiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Varma, Vijay R</creatorcontrib><creatorcontrib>Wang, Youjin</creatorcontrib><creatorcontrib>An, Yang</creatorcontrib><creatorcontrib>Varma, Sudhir</creatorcontrib><creatorcontrib>Bilgel, Murat</creatorcontrib><creatorcontrib>Doshi, Jimit</creatorcontrib><creatorcontrib>Legido-Quigley, Cristina</creatorcontrib><creatorcontrib>Delgado, João C</creatorcontrib><creatorcontrib>Oommen, Anup M</creatorcontrib><creatorcontrib>Roberts, Jackson A</creatorcontrib><creatorcontrib>Wong, Dean F</creatorcontrib><creatorcontrib>Davatzikos, Christos</creatorcontrib><creatorcontrib>Resnick, Susan M</creatorcontrib><creatorcontrib>Troncoso, Juan C</creatorcontrib><creatorcontrib>Pletnikova, Olga</creatorcontrib><creatorcontrib>O'Brien, Richard</creatorcontrib><creatorcontrib>Hak, Eelko</creatorcontrib><creatorcontrib>Baak, Brenda N</creatorcontrib><creatorcontrib>Pfeiffer, Ruth</creatorcontrib><creatorcontrib>Baloni, Priyanka</creatorcontrib><creatorcontrib>Mohmoudiandehkordi, Siamak</creatorcontrib><creatorcontrib>Nho, Kwangsik</creatorcontrib><creatorcontrib>Kaddurah-Daouk, Rima</creatorcontrib><creatorcontrib>Bennett, David A</creatorcontrib><creatorcontrib>Gadalla, Shahinaz M</creatorcontrib><creatorcontrib>Thambisetty, Madhav</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><collection>PLoS Medicine</collection><jtitle>PLoS medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Varma, Vijay R</au><au>Wang, Youjin</au><au>An, Yang</au><au>Varma, Sudhir</au><au>Bilgel, Murat</au><au>Doshi, Jimit</au><au>Legido-Quigley, Cristina</au><au>Delgado, João C</au><au>Oommen, Anup M</au><au>Roberts, Jackson A</au><au>Wong, Dean F</au><au>Davatzikos, Christos</au><au>Resnick, Susan M</au><au>Troncoso, Juan C</au><au>Pletnikova, Olga</au><au>O'Brien, Richard</au><au>Hak, Eelko</au><au>Baak, Brenda N</au><au>Pfeiffer, Ruth</au><au>Baloni, Priyanka</au><au>Mohmoudiandehkordi, Siamak</au><au>Nho, Kwangsik</au><au>Kaddurah-Daouk, Rima</au><au>Bennett, David A</au><au>Gadalla, Shahinaz M</au><au>Thambisetty, Madhav</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study</atitle><jtitle>PLoS medicine</jtitle><addtitle>PLoS Med</addtitle><date>2021-05-27</date><risdate>2021</risdate><volume>18</volume><issue>5</issue><spage>e1003615</spage><epage>e1003615</epage><pages>e1003615-e1003615</pages><issn>1549-1676</issn><issn>1549-1277</issn><eissn>1549-1676</eissn><abstract>While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis.
We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = <0.001-0.013) in males in BLSA. In ADNI, we found a modest sex-specific effect indicating that lower serum concentrations of CA and CDCA were associated with faster brain atrophy (FDR p = 0.049) in males.Step 2: In the Clinical Practice Research Datalink (CPRD) dataset, covering >4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings.
We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>34043628</pmid><doi>10.1371/journal.pmed.1003615</doi><orcidid>https://orcid.org/0000-0002-4463-158X</orcidid><orcidid>https://orcid.org/0000-0002-7624-3872</orcidid><orcidid>https://orcid.org/0000-0002-3255-8143</orcidid><orcidid>https://orcid.org/0000-0001-5042-7422</orcidid><orcidid>https://orcid.org/0000-0002-4018-214X</orcidid><orcidid>https://orcid.org/0000-0003-1648-871X</orcidid><orcidid>https://orcid.org/0000-0002-6843-1718</orcidid><orcidid>https://orcid.org/0000-0001-9553-6673</orcidid><orcidid>https://orcid.org/0000-0002-3382-4941</orcidid><orcidid>https://orcid.org/0000-0003-2231-2454</orcidid><orcidid>https://orcid.org/0000-0001-7653-5106</orcidid><orcidid>https://orcid.org/0000-0003-1858-5732</orcidid><orcidid>https://orcid.org/0000-0003-3689-554X</orcidid><orcidid>https://orcid.org/0000-0001-7143-7726</orcidid><orcidid>https://orcid.org/0000-0002-4096-4782</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1549-1676 |
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| subjects | Acids Aged Aged, 80 and over Alzheimer's disease Atrophy Bile Bile acids Bile Acids and Salts - biosynthesis Bile Acids and Salts - metabolism Biology and Life Sciences Biosynthesis Blood-brain barrier Cholesterol Cholesterol metabolism Complications and side effects Dementia Dementia - epidemiology Dementia - metabolism Dementia disorders Development and progression Drug delivery Female Gene expression Gene Expression Profiling Health aspects Humans Hypercholesterolemia Incidence Male Medicine and Health Sciences Metabolites Metabolomics Middle Aged Molecular modelling Neuroimaging Pharmacoepidemiology Research and Analysis Methods Risk factors Substantia alba United Kingdom - epidemiology |
| title | Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study |
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