Multiomics analysis to explore blood metabolite biomarkers in an Alzheimer’s Disease Neuroimaging Initiative cohort

Takaki Oka; Yuki Matsuzawa; Momoka Tsuneyoshi; Yoshitaka Nakamura; Ken Aoshima; Hiroshi Tsugawa; Michael Weiner; Paul Aisen; Ronald Petersen; Clifford R. Jack; William Jagust; John Q. Trojanowki; Arthur W. Toga; Laurel Beckett; Robert C. Green; Andrew J. Saykin; John Morris; Leslie M. Shaw; Enchi Liu; Tom Montine; Ronald G. Thomas; Michael Donohue; Sarah Walter; Devon Gessert; Tamie Sather; Gus Jiminez; Danielle Harvey; Michael Donohue; Matthew Bernstein; Nick Fox; Paul Thompson; Norbert Schuff; Charles DeCArli; Bret Borowski; Jeff Gunter; Matt Senjem; Prashanthi Vemuri; David Jones; Kejal Kantarci; Chad Ward; Robert A. Koeppe; Norm Foster; Eric M. Reiman; Kewei Chen; Chet Mathis; Susan Landau; Nigel J. Cairns; Erin Householder; Lisa Taylor Reinwald; Virginia Lee; Magdalena Korecka; Michal Figurski; Karen Crawford; Scott Neu; Tatiana M. Foroud; Steven Potkin; Li Shen; Faber Kelley; Sungeun Kim; Kwangsik Nho; Zaven Kachaturian; Richard Frank; Peter J. Snyder; Susan Molchan; Jeffrey Kaye; Joseph Quinn; Betty Lind; Raina Carter; Sara Dolen; Lon S. Schneider; Sonia Pawluczyk; Mauricio Beccera; Liberty Teodoro; Bryan M. Spann; James Brewer; Helen Vanderswag; Adam Fleisher; Judith L. Heidebrink; Joanne L. Lord; Ronald Petersen; Sara S. Mason; Colleen S. Albers; David Knopman; Kris Johnson; Rachelle S. Doody; Javier Villanueva Meyer; Munir Chowdhury; Susan Rountree; Mimi Dang; Yaakov Stern; Lawrence S. Honig; Karen L. Bell; Beau Ances; John C. Morris; Maria Carroll; Sue Leon; Erin Householder; Mark A. Mintun; Stacy Schneider; Angela Oliver; Daniel Marson; Randall Griffith; David Clark; David Geldmacher; John Brockington; Erik Roberson; Hillel Grossman; Effie Mitsis; Leyla de Toledo-Morrell; Raj C. Shah; Ranjan Duara; Daniel Varon; Maria T. Greig; Peggy Roberts; Marilyn Albert; Chiadi Onyike; Daniel D’Agostino; Stephanie Kielb; James E. Galvin; Dana M. Pogorelec; Brittany Cerbone; Christina A. Michel; Henry Rusinek; Mony J. de Leon; Lidia Glodzik; Susan De Santi; P. Murali Doraiswamy; Jeffrey R. Petrella; Terence Z. Wong; Steven E. Arnold; Jason H. Karlawish; David Wolk; Charles D. Smith; Greg Jicha; Peter Hardy; Partha Sinha; Elizabeth Oates; Gary Conrad; Oscar L. Lopez; Mary Ann Oakley; Donna M. Simpson; Anton P. Porsteinsson; Bonnie S. Goldstein; Kim Martin; Kelly M. Makino; M. Saleem Ismail; Connie Brand; Ruth A. Mulnard; Gaby Thai; Catherine Mc Adams Ortiz; Kyle Womack; Dana Mathews; Mary Quiceno; Ramon Diaz Arrastia; Richard King; Myron Weiner; Kristen Martin Cook; Michael DeVous; Allan I. Levey; James J. Lah; Janet S. Cellar; Jeffrey M. Burns; Heather S. Anderson; Russell H. Swerdlow; Liana Apostolova; Kathleen Tingus; Ellen Woo; Daniel H.S. Silverman; Po H. Lu; George Bartzokis; Neill R. Graff Radford; Francine Parfitt; Tracy Kendall; Heather Johnson; Martin R. Farlow; Ann Marie Hake; Brandy R. Matthews; Scott Herring; Cynthia Hunt; Christopher H. van Dyck; Richard E. Carson; Martha G. MacAvoy; Howard Chertkow; Howard Bergman; Chris Hosein; Sandra Black; Bojana Stefanovic; Curtis Caldwell; Ging Yuek Robin Hsiung; Howard Feldman; Benita Mudge; Michele Assaly; Andrew Kertesz; John Rogers; Dick Trost; Charles Bernick; Donna Munic; Diana Kerwin; Marek Marsel Mesulam; Kristine Lipowski; Chuang Kuo Wu; Nancy Johnson; Carl Sadowsky; Walter Martinez; Teresa Villena; Raymond Scott Turner; Kathleen Johnson; Brigid Reynolds; Reisa A. Sperling; Keith A. Johnson; Gad Marshall; Meghan Frey; Jerome Yesavage; Joy L. Taylor; Barton Lane; Allyson Rosen; Jared Tinklenberg; Marwan N. Sabbagh; Christine M. Belden; Sandra A. Jacobson; Sherye A. Sirrel; Neil Kowall; Ronald Killiany; Andrew E. Budson; Alexander Norbash; Patricia Lynn Johnson; Thomas O. Obisesan; Saba Wolday; Joanne Allard; Alan Lerner; Paula Ogrocki; Leon Hudson; Evan Fletcher; Owen Carmichael; John Olichney; Charles DeCarli; Smita Kittur; Michael Borrie; T. Y. Lee; Rob Bartha; Sterling Johnson; Sanjay Asthana; Cynthia M. Carlsson; Steven G. Potkin; Adrian Preda; Dana Nguyen; Pierre Tariot; Adam Fleisher; Stephanie Reeder; Vernice Bates; Horacio Capote; Michelle Rainka; Douglas W. Scharre; Maria Kataki; Anahita Adeli; Earl A. Zimmerman; Dzintra Celmins; Alice D. Brown; Godfrey D. Pearlson; Karen Blank; Karen Anderson; Robert B. Santulli; Tamar J. Kitzmiller; Eben S. Schwartz; Kaycee M. Sink; Jeff D. Williamson; Pradeep Garg; Franklin Watkins; Brian R. Ott; Henry Querfurth; Geoffrey Tremont; Stephen Salloway; Paul Malloy; Stephen Correia; Howard J. Rosen; Bruce L. Miller; Jacobo Mintzer; Kenneth Spicer; David Bachman; Elizabether Finger; Stephen Pasternak; Irina Rachinsky; John Rogers; Andrew Kertesz; Dick Drost; Nunzio Pomara; Raymundo Hernando; Antero Sarrael; Susan K. Schultz; Laura L.Boles Ponto; Hyungsub Shim; Karen Elizabeth Smith; Norman Relkin; Gloria Chaing; Lisa Raudin; Amanda Smith; Kristin Fargher; Balebail Ashok Raj

doi:10.1038/s41598-024-56837-1

Multiomics analysis to explore blood metabolite biomarkers in an Alzheimer’s Disease Neuroimaging Initiative cohort

Takaki Oka, Yuki Matsuzawa, Momoka Tsuneyoshi, Yoshitaka Nakamura, Ken Aoshima, Hiroshi Tsugawa^*, Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Enchi Liu, Tom MontineRonald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Danielle Harvey, Michael Donohue, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, Nigel J. Cairns, Erin Householder, Lisa Taylor Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Faber Kelley, Sungeun Kim, Kwangsik Nho, Zaven Kachaturian, Richard Frank, Peter J. Snyder, Susan Molchan, Jeffrey Kaye, Joseph Quinn, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Beccera, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Ronald Petersen, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva Meyer, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, John C. Morris, Maria Carroll, Sue Leon, Erin Householder, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, Randall Griffith, David Clark, David Geldmacher, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Leyla de Toledo-Morrell, Raj C. Shah, Ranjan Duara, Daniel Varon, Maria T. Greig, Peggy Roberts, Marilyn Albert, Chiadi Onyike, Daniel D’Agostino, Stephanie Kielb, James E. Galvin, Dana M. Pogorelec, Brittany Cerbone, Christina A. Michel, Henry Rusinek, Mony J. de Leon, Lidia Glodzik, Susan De Santi, P. Murali Doraiswamy, Jeffrey R. Petrella, Terence Z. Wong, Steven E. Arnold, Jason H. Karlawish, David Wolk, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, Mary Ann Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Ruth A. Mulnard, Gaby Thai, Catherine Mc Adams Ortiz, Kyle Womack, Dana Mathews, Mary Quiceno, Ramon Diaz Arrastia, Richard King, Myron Weiner, Kristen Martin Cook, Michael DeVous, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Heather S. Anderson, Russell H. Swerdlow, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H.S. Silverman, Po H. Lu, George Bartzokis, Neill R. Graff Radford, Francine Parfitt, Tracy Kendall, Heather Johnson, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Scott Herring, Cynthia Hunt, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging Yuek Robin Hsiung, Howard Feldman, Benita Mudge, Michele Assaly, Andrew Kertesz, John Rogers, Dick Trost, Charles Bernick, Donna Munic, Diana Kerwin, Marek Marsel Mesulam, Kristine Lipowski, Chuang Kuo Wu, Nancy Johnson, Carl Sadowsky, Walter Martinez, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Meghan Frey, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Leon Hudson, Evan Fletcher, Owen Carmichael, John Olichney, Charles DeCarli, Smita Kittur, Michael Borrie, T. Y. Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Steven G. Potkin, Adrian Preda, Dana Nguyen, Pierre Tariot, Adam Fleisher, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Anahita Adeli, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Robert B. Santulli, Tamar J. Kitzmiller, Eben S. Schwartz, Kaycee M. Sink, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Henry Querfurth, Geoffrey Tremont, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, Jacobo Mintzer, Kenneth Spicer, David Bachman, Elizabether Finger, Stephen Pasternak, Irina Rachinsky, John Rogers, Andrew Kertesz, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Laura L.Boles Ponto, Hyungsub Shim, Karen Elizabeth Smith, Norman Relkin, Gloria Chaing, Lisa Raudin, Amanda Smith, Kristin Fargher, Balebail Ashok Raj

^*Corresponding author for this work

Neurology

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

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that commonly causes dementia. Identifying biomarkers for the early detection of AD is an emerging need, as brain dysfunction begins two decades before the onset of clinical symptoms. To this end, we reanalyzed untargeted metabolomic mass spectrometry data from 905 patients enrolled in the AD Neuroimaging Initiative (ADNI) cohort using MS-DIAL, with 1,304,633 spectra of 39,108 unique biomolecules. Metabolic profiles of 93 hydrophilic metabolites were determined. Additionally, we integrated targeted lipidomic data (4873 samples from 1524 patients) to explore candidate biomarkers for predicting progressive mild cognitive impairment (pMCI) in patients diagnosed with AD within two years using the baseline metabolome. Patients with lower ergothioneine levels had a 12% higher rate of AD progression with the significance of P = 0.012 (Wald test). Furthermore, an increase in ganglioside (GM3) and decrease in plasmalogen lipids, many of which are associated with apolipoprotein E polymorphism, were confirmed in AD patients, and the higher levels of lysophosphatidylcholine (18:1) and GM3 d18:1/20:0 showed 19% and 17% higher rates of AD progression, respectively (Wald test: P = 3.9 × 10^–8 and 4.3 × 10^–7). Palmitoleamide, oleamide, diacylglycerols, and ether lipids were also identified as significantly altered metabolites at baseline in patients with pMCI. The integrated analysis of metabolites and genomics data showed that combining information on metabolites and genotypes enhances the predictive performance of AD progression, suggesting that metabolomics is essential to complement genomic data. In conclusion, the reanalysis of multiomics data provides new insights to detect early development of AD pathology and to partially understand metabolic changes in age-related onset of AD.

Original language	English (US)
Article number	6797
Journal	Scientific reports
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41598-024-56837-1
State	Published - Dec 2024

Funding

The study represents a portion of the dissertation submitted by Takaki Oka to the Tokyo University of Agriculture and Technology, in partial fulfillment of the requirement for his Ph.D. This work was supported by JSPS KAKENHI (21K18216 to Hiroshi T.), the National Cancer Center Research and Development Fund (2020-A-9, Hiroshi T.), AMED Japan Program for Infectious Diseases Research and Infrastructure (21wm0325036h0001, Hiroshi T.), AMED Brain/MINDS (JP15dm0207001, Hiroshi T.), JST National Bioscience Database Center (JPMJND2305, Hiroshi T.), and JST ERATO Grant (JPMJER2101 to Hiroshi T.). Data used in preparation of this article were generated by the Alzheimer’s Disease Metabolomics Consortium. The study represents a portion of the dissertation submitted by Takaki Oka to the Tokyo University of Agriculture and Technology, in partial fulfillment of the requirement for his Ph.D. This work was supported by JSPS KAKENHI (21K18216 to Hiroshi T.), the National Cancer Center Research and Development Fund (2020-A-9, Hiroshi T.), AMED Japan Program for Infectious Diseases Research and Infrastructure (21wm0325036h0001, Hiroshi T.), AMED Brain/MINDS (JP15dm0207001, Hiroshi T.), JST National Bioscience Database Center (JPMJND2305, Hiroshi T.), and JST ERATO Grant (JPMJER2101 to Hiroshi T.).

ASJC Scopus subject areas

General

Access to Document

10.1038/s41598-024-56837-1

Cite this

Oka, T., Matsuzawa, Y., Tsuneyoshi, M., Nakamura, Y., Aoshima, K., Tsugawa, H., Weiner, M., Aisen, P., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J. Q., Toga, A. W., Beckett, L., Green, R. C., Saykin, A. J., Morris, J., Shaw, L. M., Liu, E., ... Raj, B. A. (2024). Multiomics analysis to explore blood metabolite biomarkers in an Alzheimer’s Disease Neuroimaging Initiative cohort. Scientific reports, 14(1), Article 6797. https://doi.org/10.1038/s41598-024-56837-1

@article{c0e8dff86bf4480784b3aab3b32adc0b,

title = "Multiomics analysis to explore blood metabolite biomarkers in an Alzheimer{\textquoteright}s Disease Neuroimaging Initiative cohort",

abstract = "Alzheimer's disease (AD) is a neurodegenerative disease that commonly causes dementia. Identifying biomarkers for the early detection of AD is an emerging need, as brain dysfunction begins two decades before the onset of clinical symptoms. To this end, we reanalyzed untargeted metabolomic mass spectrometry data from 905 patients enrolled in the AD Neuroimaging Initiative (ADNI) cohort using MS-DIAL, with 1,304,633 spectra of 39,108 unique biomolecules. Metabolic profiles of 93 hydrophilic metabolites were determined. Additionally, we integrated targeted lipidomic data (4873 samples from 1524 patients) to explore candidate biomarkers for predicting progressive mild cognitive impairment (pMCI) in patients diagnosed with AD within two years using the baseline metabolome. Patients with lower ergothioneine levels had a 12% higher rate of AD progression with the significance of P = 0.012 (Wald test). Furthermore, an increase in ganglioside (GM3) and decrease in plasmalogen lipids, many of which are associated with apolipoprotein E polymorphism, were confirmed in AD patients, and the higher levels of lysophosphatidylcholine (18:1) and GM3 d18:1/20:0 showed 19% and 17% higher rates of AD progression, respectively (Wald test: P = 3.9 × 10–8 and 4.3 × 10–7). Palmitoleamide, oleamide, diacylglycerols, and ether lipids were also identified as significantly altered metabolites at baseline in patients with pMCI. The integrated analysis of metabolites and genomics data showed that combining information on metabolites and genotypes enhances the predictive performance of AD progression, suggesting that metabolomics is essential to complement genomic data. In conclusion, the reanalysis of multiomics data provides new insights to detect early development of AD pathology and to partially understand metabolic changes in age-related onset of AD.",

author = "Takaki Oka and Yuki Matsuzawa and Momoka Tsuneyoshi and Yoshitaka Nakamura and Ken Aoshima and Hiroshi Tsugawa and Michael Weiner and Paul Aisen and Ronald Petersen and Jack, {Clifford R.} and William Jagust and Trojanowki, {John Q.} and Toga, {Arthur W.} and Laurel Beckett and Green, {Robert C.} and Saykin, {Andrew J.} and John Morris and Shaw, {Leslie M.} and Enchi Liu and Tom Montine and Thomas, {Ronald G.} and Michael Donohue and Sarah Walter and Devon Gessert and Tamie Sather and Gus Jiminez and Danielle Harvey and Michael Donohue and Matthew Bernstein and Nick Fox and Paul Thompson and Norbert Schuff and Charles DeCArli and Bret Borowski and Jeff Gunter and Matt Senjem and Prashanthi Vemuri and David Jones and Kejal Kantarci and Chad Ward and Koeppe, {Robert A.} and Norm Foster and Reiman, {Eric M.} and Kewei Chen and Chet Mathis and Susan Landau and Cairns, {Nigel J.} and Erin Householder and Reinwald, {Lisa Taylor} and Virginia Lee and Magdalena Korecka and Michal Figurski and Karen Crawford and Scott Neu and Foroud, {Tatiana M.} and Steven Potkin and Li Shen and Faber Kelley and Sungeun Kim and Kwangsik Nho and Zaven Kachaturian and Richard Frank and Snyder, {Peter J.} and Susan Molchan and Jeffrey Kaye and Joseph Quinn and Betty Lind and Raina Carter and Sara Dolen and Schneider, {Lon S.} and Sonia Pawluczyk and Mauricio Beccera and Liberty Teodoro and Spann, {Bryan M.} and James Brewer and Helen Vanderswag and Adam Fleisher and Heidebrink, {Judith L.} and Lord, {Joanne L.} and Ronald Petersen and Mason, {Sara S.} and Albers, {Colleen S.} and David Knopman and Kris Johnson and Doody, {Rachelle S.} and Meyer, {Javier Villanueva} and Munir Chowdhury and Susan Rountree and Mimi Dang and Yaakov Stern and Honig, {Lawrence S.} and Bell, {Karen L.} and Beau Ances and Morris, {John C.} and Maria Carroll and Sue Leon and Erin Householder and Mintun, {Mark A.} and Stacy Schneider and Angela Oliver and Daniel Marson and Randall Griffith and David Clark and David Geldmacher and John Brockington and Erik Roberson and Hillel Grossman and Effie Mitsis and {de Toledo-Morrell}, Leyla and Shah, {Raj C.} and Ranjan Duara and Daniel Varon and Greig, {Maria T.} and Peggy Roberts and Marilyn Albert and Chiadi Onyike and Daniel D{\textquoteright}Agostino and Stephanie Kielb and Galvin, {James E.} and Pogorelec, {Dana M.} and Brittany Cerbone and Michel, {Christina A.} and Henry Rusinek and {de Leon}, {Mony J.} and Lidia Glodzik and {De Santi}, Susan and Doraiswamy, {P. Murali} and Petrella, {Jeffrey R.} and Wong, {Terence Z.} and Arnold, {Steven E.} and Karlawish, {Jason H.} and David Wolk and Smith, {Charles D.} and Greg Jicha and Peter Hardy and Partha Sinha and Elizabeth Oates and Gary Conrad and Lopez, {Oscar L.} and Oakley, {Mary Ann} and Simpson, {Donna M.} and Porsteinsson, {Anton P.} and Goldstein, {Bonnie S.} and Kim Martin and Makino, {Kelly M.} and Ismail, {M. Saleem} and Connie Brand and Mulnard, {Ruth A.} and Gaby Thai and {Mc Adams Ortiz}, Catherine and Kyle Womack and Dana Mathews and Mary Quiceno and Arrastia, {Ramon Diaz} and Richard King and Myron Weiner and Cook, {Kristen Martin} and Michael DeVous and Levey, {Allan I.} and Lah, {James J.} and Cellar, {Janet S.} and Burns, {Jeffrey M.} and Anderson, {Heather S.} and Swerdlow, {Russell H.} and Liana Apostolova and Kathleen Tingus and Ellen Woo and Silverman, {Daniel H.S.} and Lu, {Po H.} and George Bartzokis and {Graff Radford}, {Neill R.} and Francine Parfitt and Tracy Kendall and Heather Johnson and Farlow, {Martin R.} and Hake, {Ann Marie} and Matthews, {Brandy R.} and Scott Herring and Cynthia Hunt and {van Dyck}, {Christopher H.} and Carson, {Richard E.} and MacAvoy, {Martha G.} and Howard Chertkow and Howard Bergman and Chris Hosein and Sandra Black and Bojana Stefanovic and Curtis Caldwell and Hsiung, {Ging Yuek Robin} and Howard Feldman and Benita Mudge and Michele Assaly and Andrew Kertesz and John Rogers and Dick Trost and Charles Bernick and Donna Munic and Diana Kerwin and Mesulam, {Marek Marsel} and Kristine Lipowski and Wu, {Chuang Kuo} and Nancy Johnson and Carl Sadowsky and Walter Martinez and Teresa Villena and Turner, {Raymond Scott} and Kathleen Johnson and Brigid Reynolds and Sperling, {Reisa A.} and Johnson, {Keith A.} and Gad Marshall and Meghan Frey and Jerome Yesavage and Taylor, {Joy L.} and Barton Lane and Allyson Rosen and Jared Tinklenberg and Sabbagh, {Marwan N.} and Belden, {Christine M.} and Jacobson, {Sandra A.} and Sirrel, {Sherye A.} and Neil Kowall and Ronald Killiany and Budson, {Andrew E.} and Alexander Norbash and Johnson, {Patricia Lynn} and Obisesan, {Thomas O.} and Saba Wolday and Joanne Allard and Alan Lerner and Paula Ogrocki and Leon Hudson and Evan Fletcher and Owen Carmichael and John Olichney and Charles DeCarli and Smita Kittur and Michael Borrie and Lee, {T. Y.} and Rob Bartha and Sterling Johnson and Sanjay Asthana and Carlsson, {Cynthia M.} and Potkin, {Steven G.} and Adrian Preda and Dana Nguyen and Pierre Tariot and Adam Fleisher and Stephanie Reeder and Vernice Bates and Horacio Capote and Michelle Rainka and Scharre, {Douglas W.} and Maria Kataki and Anahita Adeli and Zimmerman, {Earl A.} and Dzintra Celmins and Brown, {Alice D.} and Pearlson, {Godfrey D.} and Karen Blank and Karen Anderson and Santulli, {Robert B.} and Kitzmiller, {Tamar J.} and Schwartz, {Eben S.} and Sink, {Kaycee M.} and Williamson, {Jeff D.} and Pradeep Garg and Franklin Watkins and Ott, {Brian R.} and Henry Querfurth and Geoffrey Tremont and Stephen Salloway and Paul Malloy and Stephen Correia and Rosen, {Howard J.} and Miller, {Bruce L.} and Jacobo Mintzer and Kenneth Spicer and David Bachman and Elizabether Finger and Stephen Pasternak and Irina Rachinsky and John Rogers and Andrew Kertesz and Dick Drost and Nunzio Pomara and Raymundo Hernando and Antero Sarrael and Schultz, {Susan K.} and Ponto, {Laura L.Boles} and Hyungsub Shim and Smith, {Karen Elizabeth} and Norman Relkin and Gloria Chaing and Lisa Raudin and Amanda Smith and Kristin Fargher and Raj, {Balebail Ashok}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41598-024-56837-1",

language = "English (US)",

volume = "14",

journal = "Scientific reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

Oka, T, Matsuzawa, Y, Tsuneyoshi, M, Nakamura, Y, Aoshima, K, Tsugawa, H, Weiner, M, Aisen, P, Petersen, R, Jack, CR, Jagust, W, Trojanowki, JQ, Toga, AW, Beckett, L, Green, RC, Saykin, AJ, Morris, J, Shaw, LM, Liu, E, Montine, T, Thomas, RG, Donohue, M, Walter, S, Gessert, D, Sather, T, Jiminez, G, Harvey, D, Donohue, M, Bernstein, M, Fox, N, Thompson, P, Schuff, N, DeCArli, C, Borowski, B, Gunter, J, Senjem, M, Vemuri, P, Jones, D, Kantarci, K, Ward, C, Koeppe, RA, Foster, N, Reiman, EM, Chen, K, Mathis, C, Landau, S, Cairns, NJ, Householder, E, Reinwald, LT, Lee, V, Korecka, M, Figurski, M, Crawford, K, Neu, S, Foroud, TM, Potkin, S, Shen, L, Kelley, F, Kim, S, Nho, K, Kachaturian, Z, Frank, R, Snyder, PJ, Molchan, S, Kaye, J, Quinn, J, Lind, B, Carter, R, Dolen, S, Schneider, LS, Pawluczyk, S, Beccera, M, Teodoro, L, Spann, BM, Brewer, J, Vanderswag, H, Fleisher, A, Heidebrink, JL, Lord, JL, Petersen, R, Mason, SS, Albers, CS, Knopman, D, Johnson, K, Doody, RS, Meyer, JV, Chowdhury, M, Rountree, S, Dang, M, Stern, Y, Honig, LS, Bell, KL, Ances, B, Morris, JC, Carroll, M, Leon, S, Householder, E, Mintun, MA, Schneider, S, Oliver, A, Marson, D, Griffith, R, Clark, D, Geldmacher, D, Brockington, J, Roberson, E, Grossman, H, Mitsis, E, de Toledo-Morrell, L, Shah, RC, Duara, R, Varon, D, Greig, MT, Roberts, P, Albert, M, Onyike, C, D’Agostino, D, Kielb, S, Galvin, JE, Pogorelec, DM, Cerbone, B, Michel, CA, Rusinek, H, de Leon, MJ, Glodzik, L, De Santi, S, Doraiswamy, PM, Petrella, JR, Wong, TZ, Arnold, SE, Karlawish, JH, Wolk, D, Smith, CD, Jicha, G, Hardy, P, Sinha, P, Oates, E, Conrad, G, Lopez, OL, Oakley, MA, Simpson, DM, Porsteinsson, AP, Goldstein, BS, Martin, K, Makino, KM, Ismail, MS, Brand, C, Mulnard, RA, Thai, G, Mc Adams Ortiz, C, Womack, K, Mathews, D, Quiceno, M, Arrastia, RD, King, R, Weiner, M, Cook, KM, DeVous, M, Levey, AI, Lah, JJ, Cellar, JS, Burns, JM, Anderson, HS, Swerdlow, RH, Apostolova, L, Tingus, K, Woo, E, Silverman, DHS, Lu, PH, Bartzokis, G, Graff Radford, NR, Parfitt, F, Kendall, T, Johnson, H, Farlow, MR, Hake, AM, Matthews, BR, Herring, S, Hunt, C, van Dyck, CH, Carson, RE, MacAvoy, MG, Chertkow, H, Bergman, H, Hosein, C, Black, S, Stefanovic, B, Caldwell, C, Hsiung, GYR, Feldman, H, Mudge, B, Assaly, M, Kertesz, A, Rogers, J, Trost, D, Bernick, C, Munic, D, Kerwin, D, Mesulam, MM, Lipowski, K, Wu, CK, Johnson, N, Sadowsky, C, Martinez, W, Villena, T, Turner, RS, Johnson, K, Reynolds, B, Sperling, RA, Johnson, KA, Marshall, G, Frey, M, Yesavage, J, Taylor, JL, Lane, B, Rosen, A, Tinklenberg, J, Sabbagh, MN, Belden, CM, Jacobson, SA, Sirrel, SA, Kowall, N, Killiany, R, Budson, AE, Norbash, A, Johnson, PL, Obisesan, TO, Wolday, S, Allard, J, Lerner, A, Ogrocki, P, Hudson, L, Fletcher, E, Carmichael, O, Olichney, J, DeCarli, C, Kittur, S, Borrie, M, Lee, TY, Bartha, R, Johnson, S, Asthana, S, Carlsson, CM, Potkin, SG, Preda, A, Nguyen, D, Tariot, P, Fleisher, A, Reeder, S, Bates, V, Capote, H, Rainka, M, Scharre, DW, Kataki, M, Adeli, A, Zimmerman, EA, Celmins, D, Brown, AD, Pearlson, GD, Blank, K, Anderson, K, Santulli, RB, Kitzmiller, TJ, Schwartz, ES, Sink, KM, Williamson, JD, Garg, P, Watkins, F, Ott, BR, Querfurth, H, Tremont, G, Salloway, S, Malloy, P, Correia, S, Rosen, HJ, Miller, BL, Mintzer, J, Spicer, K, Bachman, D, Finger, E, Pasternak, S, Rachinsky, I, Rogers, J, Kertesz, A, Drost, D, Pomara, N, Hernando, R, Sarrael, A, Schultz, SK, Ponto, LLB, Shim, H, Smith, KE, Relkin, N, Chaing, G, Raudin, L, Smith, A, Fargher, K & Raj, BA 2024, 'Multiomics analysis to explore blood metabolite biomarkers in an Alzheimer’s Disease Neuroimaging Initiative cohort', Scientific reports, vol. 14, no. 1, 6797. https://doi.org/10.1038/s41598-024-56837-1

TY - JOUR

T1 - Multiomics analysis to explore blood metabolite biomarkers in an Alzheimer’s Disease Neuroimaging Initiative cohort

AU - Oka, Takaki

AU - Matsuzawa, Yuki

AU - Tsuneyoshi, Momoka

AU - Nakamura, Yoshitaka

AU - Aoshima, Ken

AU - Tsugawa, Hiroshi

AU - Weiner, Michael

AU - Aisen, Paul

AU - Petersen, Ronald

AU - Jack, Clifford R.

AU - Jagust, William

AU - Trojanowki, John Q.

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PY - 2024/12

Y1 - 2024/12

N2 - Alzheimer's disease (AD) is a neurodegenerative disease that commonly causes dementia. Identifying biomarkers for the early detection of AD is an emerging need, as brain dysfunction begins two decades before the onset of clinical symptoms. To this end, we reanalyzed untargeted metabolomic mass spectrometry data from 905 patients enrolled in the AD Neuroimaging Initiative (ADNI) cohort using MS-DIAL, with 1,304,633 spectra of 39,108 unique biomolecules. Metabolic profiles of 93 hydrophilic metabolites were determined. Additionally, we integrated targeted lipidomic data (4873 samples from 1524 patients) to explore candidate biomarkers for predicting progressive mild cognitive impairment (pMCI) in patients diagnosed with AD within two years using the baseline metabolome. Patients with lower ergothioneine levels had a 12% higher rate of AD progression with the significance of P = 0.012 (Wald test). Furthermore, an increase in ganglioside (GM3) and decrease in plasmalogen lipids, many of which are associated with apolipoprotein E polymorphism, were confirmed in AD patients, and the higher levels of lysophosphatidylcholine (18:1) and GM3 d18:1/20:0 showed 19% and 17% higher rates of AD progression, respectively (Wald test: P = 3.9 × 10–8 and 4.3 × 10–7). Palmitoleamide, oleamide, diacylglycerols, and ether lipids were also identified as significantly altered metabolites at baseline in patients with pMCI. The integrated analysis of metabolites and genomics data showed that combining information on metabolites and genotypes enhances the predictive performance of AD progression, suggesting that metabolomics is essential to complement genomic data. In conclusion, the reanalysis of multiomics data provides new insights to detect early development of AD pathology and to partially understand metabolic changes in age-related onset of AD.

AB - Alzheimer's disease (AD) is a neurodegenerative disease that commonly causes dementia. Identifying biomarkers for the early detection of AD is an emerging need, as brain dysfunction begins two decades before the onset of clinical symptoms. To this end, we reanalyzed untargeted metabolomic mass spectrometry data from 905 patients enrolled in the AD Neuroimaging Initiative (ADNI) cohort using MS-DIAL, with 1,304,633 spectra of 39,108 unique biomolecules. Metabolic profiles of 93 hydrophilic metabolites were determined. Additionally, we integrated targeted lipidomic data (4873 samples from 1524 patients) to explore candidate biomarkers for predicting progressive mild cognitive impairment (pMCI) in patients diagnosed with AD within two years using the baseline metabolome. Patients with lower ergothioneine levels had a 12% higher rate of AD progression with the significance of P = 0.012 (Wald test). Furthermore, an increase in ganglioside (GM3) and decrease in plasmalogen lipids, many of which are associated with apolipoprotein E polymorphism, were confirmed in AD patients, and the higher levels of lysophosphatidylcholine (18:1) and GM3 d18:1/20:0 showed 19% and 17% higher rates of AD progression, respectively (Wald test: P = 3.9 × 10–8 and 4.3 × 10–7). Palmitoleamide, oleamide, diacylglycerols, and ether lipids were also identified as significantly altered metabolites at baseline in patients with pMCI. The integrated analysis of metabolites and genomics data showed that combining information on metabolites and genotypes enhances the predictive performance of AD progression, suggesting that metabolomics is essential to complement genomic data. In conclusion, the reanalysis of multiomics data provides new insights to detect early development of AD pathology and to partially understand metabolic changes in age-related onset of AD.

UR - http://www.scopus.com/inward/record.url?scp=85189156050&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85189156050&partnerID=8YFLogxK

U2 - 10.1038/s41598-024-56837-1

DO - 10.1038/s41598-024-56837-1

M3 - Article

C2 - 38565541

AN - SCOPUS:85189156050

SN - 2045-2322

VL - 14

JO - Scientific reports

JF - Scientific reports

IS - 1

M1 - 6797

ER -

Multiomics analysis to explore blood metabolite biomarkers in an Alzheimer’s Disease Neuroimaging Initiative cohort

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