Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers

Creators: Nho, Kwangsik; Kueider-Paisley, Alexandra; Ahmad, Shahzad; MahmoudianDehkordi, Siamak; Arnold, Matthias; Risacher, Shannon L.; Louie, Gregory; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Kastenmüller, Gabi; Trojanowski, John Q.; Shaw, Leslie M.; Weiner, Michael W.; Doraiswamy, P. Murali; van Duijn, Cornelia; Saykin, Andrew J.; Kaddurah-Daouk, Rima; Meikle, Peter; Alzheimer's Disease Neuroimaging Initiative; Alzheimer Disease Metabolomics Consortium

Abstract

Importance Increasing evidence suggests an important role of liver function in the pathophysiology of Alzheimer disease (AD). The liver is a major metabolic hub; therefore, investigating the association of liver function with AD, cognition, neuroimaging, and CSF biomarkers would improve the understanding of the role of metabolic dysfunction in AD. Objective To examine whether liver function markers are associated with cognitive dysfunction and the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD. Design, Setting, and Participants In this cohort study, serum-based liver function markers were measured from September 1, 2005, to August 31, 2013, in 1581 AD Neuroimaging Initiative participants along with cognitive measures, cerebrospinal fluid (CSF) biomarkers, brain atrophy, brain glucose metabolism, and amyloid-β accumulation. Associations of liver function markers with AD-associated clinical and A/T/N biomarkers were assessed using generalized linear models adjusted for confounding variables and multiple comparisons. Statistical analysis was performed from November 1, 2017, to February 28, 2019. Exposures Five serum-based liver function markers (total bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase) from AD Neuroimaging Initiative participants were used as exposure variables. Main Outcomes and Measures Primary outcomes included diagnosis of AD, composite scores for executive functioning and memory, CSF biomarkers, atrophy measured by magnetic resonance imaging, brain glucose metabolism measured by fludeoxyglucose F 18 (¹⁸F) positron emission tomography, and amyloid-β accumulation measured by [¹⁸F]florbetapir positron emission tomography. Results Participants in the AD Neuroimaging Initiative (n = 1581; 697 women and 884 men; mean [SD] age, 73.4 [7.2] years) included 407 cognitively normal older adults, 20 with significant memory concern, 298 with early mild cognitive impairment, 544 with late mild cognitive impairment, and 312 with AD. An elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio and lower levels of ALT were associated with AD diagnosis (AST to ALT ratio: odds ratio, 7.932 [95% CI, 1.673-37.617]; P = .03; ALT: odds ratio, 0.133 [95% CI, 0.042-0.422]; P = .004) and poor cognitive performance (AST to ALT ratio: β [SE], −0.465 [0.180]; P = .02 for memory composite score; β [SE], −0.679 [0.215]; P = .006 for executive function composite score; ALT: β [SE], 0.397 [0.128]; P = .006 for memory composite score; β [SE], 0.637 [0.152]; P < .001 for executive function composite score). Increased AST to ALT ratio values were associated with lower CSF amyloid-β 1-42 levels (β [SE], −0.170 [0.061]; P = .04) and increased amyloid-β deposition (amyloid biomarkers), higher CSF phosphorylated tau181 (β [SE], 0.175 [0.055]; P = .02) (tau biomarkers) and higher CSF total tau levels (β [SE], 0.160 [0.049]; P = .02) and reduced brain glucose metabolism (β [SE], −0.123 [0.042]; P = .03) (neurodegeneration biomarkers). Lower levels of ALT were associated with increased amyloid-β deposition (amyloid biomarkers), and reduced brain glucose metabolism (β [SE], 0.096 [0.030]; P = .02) and greater atrophy (neurodegeneration biomarkers). Conclusions and Relevance Consistent associations of serum-based liver function markers with cognitive performance and A/T/N biomarkers for AD highlight the involvement of metabolic disturbances in the pathophysiology of AD. Further studies are needed to determine if these associations represent a causative or secondary role. Liver enzyme involvement in AD opens avenues for novel diagnostics and therapeutics.

Additional Information

© 2019 Nho K et al. This is an open access article distributed under the terms of the CC-BY License. Accepted for Publication: May 28, 2019. Published: July 31, 2019. Author Contributions: Drs Nho and Arnold had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Nho and Kueider-Paisley and Mr Ahmad contributed equally. Concept and design: Nho, Kueider-Paisley, Ahmad, Trojanowski, Doraiswamy, Kaddurah-Daouk. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Nho, Kueider-Paisley, Ahmad, MahmoudianDehkordi, Louie, Trojanowski, Kaddurah-Daouk. Critical revision of the manuscript for important intellectual content: Nho, Kueider-Paisley, Ahmad, Arnold, Risacher, Blach, Baillie, Han, Kastenmüller, Trojanowski, Shaw, Weiner, Doraiswamy, van Duijn, Saykin, Kaddurah-Daouk. Statistical analysis: Nho, MahmoudianDehkordi, Trojanowski, van Duijn. Obtained funding: Nho, Arnold, Weiner, van Duijn, Saykin, Kaddurah-Daouk. Administrative, technical, or material support: Arnold, Louie, Blach, Han, Doraiswamy, Saykin. Supervision: Nho, Arnold, Kastenmüller, Shaw, Kaddurah-Daouk. Conflict of Interest Disclosures: Mr Louie reported receiving grants from the NIA during the conduct of the study. Dr Baillie reported receiving a salary from Rosa & Co outside the submitted work. Dr Kastenmüller reported receiving grants from NIH/NIA during the conduct of the study. Dr Trojanowski reported that he may accrue revenue in the future on patents submitted by the University of Pennsylvania wherein he is a coinventor; and receiving revenue from the sale of Avid to Eli Lily as a coinventor on imaging-related patents submitted by the University of Pennsylvania. Dr Shaw reported receiving research funding from the Michael J. Fox Foundation for PD Research; receiving grants from the National Institutes of Health/National Institute on Aging (NIH/NIA) during the conduct of the study; serving as a consultant for Eli Lilly, Novartis, and Roche; and providing quality control oversight for the Roche Elecsys immunoassay as part of responsibilities for the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Dr Weiner reported having stock and stock options from Elan and Synarc; receiving travel expenses from Novartis, Tohoku University, Fundacio Ace, Travel eDreams, MCI Group, NSAS, Danone Trading, ANT Congress, NeuroVigil, CHRU-Hopital Roger Salengro, Siemens, AstraZeneca, Geneva University Hospitals, Lilly, University of California, San Diego–ADNI, Paris University, Institut Catala de Neurociencies Aplicades, University of New Mexico School of Medicine, Ipsen, Clinical Trials on Alzheimer's Disease, Pfizer, and AD PD meeting; receiving grants and personal fees from the NIH; receiving grants from the Department of Defense, Johnson & Johnson, GE, the Patient-Centered Outcomes Research Institute, California Department of Public Health, Vanderbilt University Medical Center, University of Missouri, Australian Catholic University, Hillblom Foundation, Alzheimer's Association, Stroke Foundation, Veterans Administration, Siemens; and personal fees from Bioclinica, Cerecin/Accera, Genentech/Roche, Indiana University, Eli Lilly, Lynch Group GLC, Dolby Family Ventures, Nestec/Nestle, Health & Wellness Partners, Decision Resources LLC, Minds + Assembly, Japan Agency for Medical Research & Development, NYU Langone, Merck, Bionest Partners, and from Alzheon Inc outside the submitted work. Dr Doraiswamy reported receiving grants from the NIA and ADNI during the conduct of the study; receiving grants from the NIH, the Department of Defense, Lilly/Avid, Alzheimer's Drug Discovery Foundation, the Karen L. Wrenn Trust, ASNR Foundation, Avanir; and Salix; serving on boards of Apollo Health and Baycrest; being a minor shareholder in Evidation Health, Turtle Shell, Advera Health Analytics, and Anthrotronix; receiving advisory fees from Cogniciti, Neuronix, NeuroPro, Anthrotronix, Verily, Apollo, Genomind, and Clearview outside the submitted work; being a coinventor, through Duke, on patent applications on metabolomics for Alzheimer disease, novel treatments of Alzheimer's pending and computational models of dementia that are unlicensed. Dr Saykin reported receiving grants from the NIH during the conduct of the study; receiving grants from the NIH; receiving nonfinancial support from Avid Radiopharmaceuticals; receiving investigator-initiated research support from Eli Lilly unrelated to the work reported here; receiving consulting fees and travel expenses from Eli Lilly and Siemens Healthcare; serving as a consultant to Arkley BioTek; and receiving support from Springer-Nature publishing as Editor-In-Chief of Brain Imaging and Behavior. Dr Kaddurah-Daouk reported being an inventor on key patents (7947453, 7910301, 7682783, 7682784, 7635556, 7553616, 7550258, 7550260, 7329489, 7005255, and 6706764) in the field of metabolomics including applications for Alzheimer disease. No other disclosures were reported. Funding for the ADMC (Alzheimer Disease Metabolomics Consortium, led by Dr Kaddurah-Daouk at Duke University) was provided by grant R01AG046171 from the NIA, a component of the Accelerated Medicines Partnership for AD (AMP-AD) Target Discovery and Preclinical Validation Project, and grant RF1 AG0151550 from the NIA, a component of the M2OVE-AD Consortium (Molecular Mechanisms of the Vascular Etiology of AD–Consortium). Data collection and sharing for this project was funded by ADNI (NIH grant U01 AG024904) and Department of Defense ADNI (Department of Defense award W81XWH-12-2-0012). ADNI is funded by the NIA, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Araclon Biotech, BioClinica Inc, Biogen, Bristol-Myers Squibb Co, CereSpir Inc, Eisai Inc, Elan Pharmaceuticals Inc, Eli Lilly and Co, EuroImmun, F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc, Fujirebio, GE Healthcare, IXICO Ltd, Janssen Alzheimer Immunotherapy Research & Development LLC, Johnson & Johnson Pharmaceutical Research & Development LLC, Lumosity, Lundbeck, Merck & Co Inc, Meso Scale Diagnostics LLC, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corp, Pfizer Inc, Piramal Imaging, Servier, Takeda Pharmaceutical Co, and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health. The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The work of various consortium investigators are also supported by various NIA grants (U01AG024904-09S4, P50NS053488, R01AG19771, P30AG10133, P30AG10124, K01AG049050, and R03 AG054936), the National Library of Medicine (grants R01LM011360 and R01LM012535), and the National Institute of Biomedical Imaging and Bioengineering (grant R01EB022574). Additional support came from Helmholtz Zentrum, the Alzheimer's Association, the Indiana Clinical and Translational Science Institute, and the Indiana University-IU Health Strategic Neuroscience Research Initiative. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Group Information: Alzheimer's Disease Neuroimaging Initiative-I, ADNI-GO, ADNI-II, and ADNI-III investigators include Part A: Leadership and Infrastructure Principal Investigator (PI): Michael W. Weiner, MD, University of California San Francisco; ATRI PI and Director of Coordinating Center Clinical Core: Paul Aisen, MD, University of Southern California; Executive Committee: Michael Weiner, MD, University of California San Francisco; Paul Aisen, MD, University of Southern California; Ronald Petersen, MD, PhD, Mayo Clinic, Rochester, NY; Clifford R. Jack Jr, MD, Mayo Clinic, Rochester, NY; William Jagust, MD, University of California Berkeley; John Q. Trojanowki, MD, PhD, University of Pennsylvania; Arthur W. Toga, PhD, University of Southern California; Laurel Beckett, PhD, University of California Davis; Robert C. Green, MD, MPH, Brigham and Women's Hospital/Harvard Medical School; Andrew J. Saykin, PsyD, Indiana University; John Morris, MD, Washington University St Louis; and Leslie M. Shaw, University of Pennsylvania. ADNI External Advisory Board members include Zaven Khachaturian, PhD, Prevent Alzheimer's Disease 2020 (Chair); Greg Sorensen, MD, Siemens; Maria Carrillo, PhD, Alzheimer's Association; Lew Kuller, MD, University of Pittsburgh; Marc Raichle, MD, Washington University, St Louis; Steven Paul, MD, Cornell University; Peter Davies, MD, Albert Einstein College of Medicine of Yeshiva University; Howard Fillit, MD, AD Drug Discovery Foundation; Franz Hefti, PhD, Acumen Pharmaceuticals; David Holtzman, MD, Washington University, St Louis; M. Marcel Mesulam, MD, Northwestern University; William Potter, MD, National Institute of Mental Health; and Peter Snyder, PhD, Brown University. ADNI-3 Private Partner Scientific Board: Veronika Logovinsky, MD, PhD, Eli Lilly (Chair). Data and Publications Committee members include Robert C. Green, MD, MPH, BWH/HMS (Chair) Resource Allocation Review Committee; Tom Montine, MD, PhD, University of Washington (Chair); Clinical Core Leaders: Ronald Petersen, MD, PhD, Mayo Clinic, Rochester (Core PI); Paul Aisen, MD, University of Southern California Clinical Informatics and Operations; Gustavo Jimenez, MBS, University of Southern California; Michael Donohue, PhD, University of Southern California; Devon Gessert, BS, University of Southern California; Kelly Harless, BA, University of Southern California; Jennifer Salazar, MBS, University of Southern California; Yuliana Cabrera, BS, University of Southern California; Sarah Walter, MSc, University of Southern California; and Lindsey Hergesheimer, BS, University of Southern California. Biostatistics Core Leaders and Key Personnel: Laurel Beckett, PhD, University of California Davis (Core PI); Danielle Harvey, PhD, University of California Davis; and Michael Donohue, PhD, University of California San Diego. MRI Core Leaders and Key Personnel: Clifford R. Jack Jr, MD, Mayo Clinic, Rochester (Core PI); Matthew Bernstein, PhD, Mayo Clinic, Rochester; Nick Fox, MD, University of London; Paul Thompson, PhD, University of California Los Angeles School of Medicine; Norbert Schuff, PhD, University of California San Francisco MRI; Charles DeCarli, MD, University of California Davis; Bret Borowski, RT, Mayo Clinic; Jeff Gunter, PhD, Mayo Clinic; Matt Senjem, MS, Mayo Clinic; Prashanthi Vemuri, PhD, Mayo Clinic; David Jones, MD, Mayo Clinic; Kejal Kantarci, Mayo Clinic; and Chad Ward, Mayo Clinic. PET Core Leaders and Key Personnel: William Jagust, MD, University of California Berkeley (Core PI); Robert A. Koeppe, PhD, University of Michigan; Norm Foster, MD, University of Utah; Eric M. Reiman, MD, Banner Alzheimer's Institute; Kewei Chen, PhD, Banner Alzheimer's Institute; Chet Mathis, MD, University of Pittsburgh; and Susan Landau, PhD, University of California Berkeley. Neuropathology Core Leaders include John C. Morris, MD, Washington University, St Louis; Nigel J. Cairns, PhD, FRCPath, Washington University, St Louis; Erin Franklin, MS, CCRP, Washington University, St Louis; and Lisa Taylor-Reinwald, BA, HTL, Washington University, St Louis. American Society for Clinical Pathology (ASCP)–Past Investigator: Biomarkers Core Leaders and Key Personnel: Leslie M. Shaw, PhD, University of Pennsylvania School of Medicine; John Q. Trojanowki, MD, PhD, Unversity of Pennsylvania School of Medicine; Virginia Lee, PhD, MBA, Unversity of Pennsylvania School of Medicine; Magdalena Korecka, PhD, Unversity of Pennsylvania School of Medicine; and Michal Figurski, PhD, Unversity of Pennsylvania School of Medicine. Informatics Core Leaders and Key Personnel: Arthur W. Toga, PhD, University of Southern California (Core PI); Karen Crawford, University of Southern California; and Scott Neu, PhD, University of Southern California. Genetics Core Leaders and Key Personnel: Andrew J. Saykin, PsyD, Indiana University; Tatiana M. Foroud, PhD, Indiana University; Steven Potkin, MD, University of California Irvine; Li Shen, PhD, Indiana University; Kelley Faber, MS, CCRC, Indiana University; Sungeun Kim, PhD, Indiana University; and Kwangsik Nho, PhD, Indiana University. Initial Concept Planning & Development: Michael W. Weiner, MD, University of California San Francisco; Lean Thal, MD, University of California San Diego; and Zaven Khachaturian, PhD, Prevent Alzheimer's Disease 2020. Early Project Proposal Development: Leon Thal, MD, University of California San Diego; Neil Buckholtz, National Institute on Aging; Michael W. Weiner, MD, University of California San Francisco; Peter J. Snyder, PhD, Brown University; William Potter, MD, National Institute of Mental Health; Steven Paul, MD, Cornell University; Marilyn Albert, PhD, Johns Hopkins University; Richard Frank, MD, PhD, Richard Frank Consulting; Zaven Khachaturian, PhD, Prevent Alzheimer's Disease 2020; and John Hsiao, MD, National Institute on Aging. Part B: Investigators by Site: Oregon Health & Science University: Joseph Quinn, MD; Lisa C. Silbert, MD; Betty Lind, BS; Jeffrey A. Kaye, MD, (Past Investigator); Raina Carter, BA (Past Investigator); and Sara Dolen, BS (Past Investigator). University of Southern California: Lon S. Schneider, MD; Sonia Pawluczyk, MD; Mauricio Becerra, BS; Liberty Teodoro, RN; and Bryan M. Spann, DO, PhD (Past Investigator). University of California–San Diego: James Brewer, MD, PhD; Helen Vanderswag, RN; and Adam Fleisher, MD (Past Investigator). University of Michigan: Jaimie Ziolkowski, MA, BS, TLLP; Judith L. Heidebrink, MD, MS; and Joanne L. Lord, LPN, BA, CCRC (Past Investigator). Mayo Clinic, Rochester: Ronald Petersen, MD, PhD; Sara S. Mason, RN; Colleen S. Albers, RN; David Knopman, MD; and Kris Johnson, RN (Past Investigator). Baylor College of Medicine: Javier Villanueva-Meyer, MD; Valory Pavlik, PhD; Nathaniel Pacini, MA; Ashley Lamb, MA; Joseph S. Kass, MD, LD, FAAN; Rachelle S. Doody, MD, PhD (Past Investigator); Victoria Shibley, MS (Past Investigator); Munir Chowdhury, MBBS, MS (Past Investigator); Susan Rountree, MD (Past Investigator); and Mimi Dang, MD (Past Investigator). Columbia University Medical Center: Yaakov Stern, PhD; Lawrence S. Honig, MD, PhD; Karen L. Bell, MD; and Randy Yeh, MD. Washington University in St Louis: Beau Ances, MD, PhD, MSc; John C. Morris, MD; David Winkfield, BS; Maria Carroll, RN, MSN, GCNS-BC; Angela Oliver, RN, BSN, MSG; Mary L. Creech, RN, MSW (Past Investigator); Mark A. Mintun, MD (Past Investigator); and Stacy Schneider, APRN, BC, GNP (Past Investigator). University of Alabama–Birmingham: Daniel Marson, JD, PhD; David Geldmacher, MD; Marissa Natelson Love, MD; Randall Griffith, PhD, ABPP (Past Investigator); David Clark, MD (Past Investigator); and John Brockington, MD (Past Investigator). Mount Sinai School of Medicine: Hillel Grossman, MD; and Effie Mitsis, PhD (Past Investigator). Rush University Medical Center: Raj C. Shah, MD; Melissa Lamar, PhD; and Patricia Samuels. Wien Center: Ranjan Duara, MD; Maria T. Greig-Custo, MD; and Rosemarie Rodriguez, PhD. Johns Hopkins University: Marilyn Albert, PhD; Chiadi Onyike, MD; Daniel D'Agostino II, BS; and Stephanie Kielb, BS (Past Investigator). New York University: Martin Sadowski, MD, PhD; Mohammed O. Sheikh, MD; Jamika Singleton-Garvin, CCRP; Anaztasia Ulysse; and Mrunalini Gaikwad. Duke University Medical Center: P. Murali Doraiswamy, MBBS, FRCP; Jeffrey R. Petrella, MD; Olga James, MD; Salvador Borges-Neto, MD; Terence Z. Wong, MD (Past Investigator); and Edward Coleman (Past Investigator). University of Pennsylvania: Jason H. Karlawish, MD; David A. Wolk, MD; Sanjeev Vaishnavi, MD; Christopher M. Clark, MD (Past Investigator); and Steven E. Arnold, MD (Past Investigator). University of Kentucky: Charles D. Smith, MD; Greg Jicha, MD; Peter Hardy, PhD; Riham El Khouli, MD; Elizabeth Oates, MD; and Gary Conrad, MD. University of Pittsburgh: Oscar L. Lopez, MD; MaryAnn Oakley, MA; and Donna M. Simpson, CRNP, MPH. University of Rochester Medical Center: Anton P. Porsteinsson, MD; Kim Martin, RN; Nancy Kowalksi, MS, RNC; Melanie Keltz, RN; Bonnie S. Goldstein, MS, NP (Past Investigator); Kelly M. Makino, BS (Past Investigator); M. Saleem Ismail, MD (Past Investigator); and Connie Brand, RN (Past Investigator). University of California Irvine IMIND: Gaby Thai, MD; Aimee Pierce, MD; Beatriz Yanez, RN; Elizabeth Sosa, PhD; and Megan Witbracht, PhD. University of Texas Southwestern Medical School: Kyle Womack, MD; Dana Mathews, MD, PhD; and Mary Quiceno, MD. Emory University: Allan I. Levey, MD, PhD; James J. Lah, MD, PhD; and Janet S. Cellar, DNP, PMHCNS-BC. University of Kansas Medical Center: Jeffrey M. Burns, MD; Russell H. Swerdlow, MD; and William M. Brooks, PhD. University of California, Los Angeles: Ellen Woo, PhD; Daniel H.S. Silverman, MD, PhD; Edmond Teng, MD, PhD; Sarah Kremen, MD; Liana Apostolova, MD (Past Investigator); Kathleen Tingus, PhD (Past Investigator); Po H. Lu, PsyD (Past Investigator); and George Bartzokis, MD (Past Investigator). Mayo Clinic, Jacksonville: Neill R Graff-Radford, MBBCH, FRCP (London); Francine Parfitt, MSH, CCRC; and Kim Poki-Walker, BA. Indiana University: Martin R. Farlow, MD; Ann Marie Hake, MD; Brandy R. Matthews, MD (Past Investigator); Jared R. Brosch, MD; and Scott Herring, RN, CCRC. Yale University School of Medicine: Christopher H. van Dyck, MD; Richard E. Carson, PhD; and Pradeep Varma, MD. McGill University, Montreal-Jewish General Hospital: Howard Chertkow, MD; Howard Bergman, MD; and Chris Hosein, Med. Sunnybrook Health Sciences, Ontario: Sandra Black, MD, FRCPC; Bojana Stefanovic, PhD; and Chris (Chinthaka) Heyn, BSC, PhD, MD, FRCPC. U.B.C. Clinic for AD & Related Disorders: Ging-Yuek Robin Hsiung, MD, MHSc, FRCPC; Benita Mudge, BS; Vesna Sossi, PhD; Howard Feldman, MD, FRCPC (Past Investigator); and Michele Assaly, MA (Past Investigator). Cognitive Neurology - St Joseph's, Ontario: Elizabeth Finger, MD; Stephen Pasternack, MD, PhD; William Pavlosky, MD; Irina Rachinsky, MD (Past Investigator); Dick Drost, PhD (Past Investigator); and Andrew Kertesz, MD (Past Investigator). Cleveland Clinic Lou Ruvo Center for Brain Health: Charles Bernick, MD, MPH; and Donna Munic, PhD. Northwestern University: Marek-Marsel Mesulam, MD; Emily Rogalski, PhD; Kristine Lipowski, MA; Sandra Weintraub, PhD; Borna Bonakdarpour, MD; Diana Kerwin, MD (Past Investigator); Chuang-Kuo Wu, MD, PhD (Past Investigator); and Nancy Johnson, PhD (Past Investigator). Premiere Research Inst (Palm Beach Neurology): Carl Sadowsky, MD; and Teresa Villena, MD. Georgetown University Medical Center: Raymond Scott Turner, MD, PhD; Kathleen Johnson, NP; and Brigid Reynolds, NP. Brigham and Women's Hospital: Reisa A. Sperling, MD; Keith A. Johnson, MD; and Gad A. Marshall, MD. Stanford University: Jerome Yesavage, MD; Joy L. Taylor, PhD; Steven Chao, MD, PhD; Barton Lane, MD (Past Investigator); Allyson Rosen, PhD (Past Investigator); and Jared Tinklenberg, MD (Past Investigator). Banner Sun Health Research Institute: Edward Zamrini, MD; Christine M. Belden, PsyD; and Sherye A. Sirrel, CCRC. Boston University: Neil Kowall, MD; Ronald Killiany, PhD; Andrew E. Budson, MD; Alexander Norbash, MD (Past Investigator); and Patricia Lynn Johnson, BA (Past Investigator). Howard University: Thomas O. Obisesan, MD, MPH; Ntekim E. Oyonumo, MD, PhD; Joanne Allard, PhD; and Olu Ogunlana, BPharm. Case Western Reserve University: Alan Lerner, MD; Paula Ogrocki, PhD; Curtis Tatsuoka, PhD; and Parianne Fatica, BA, CCRC. University of California, Davis–Sacramento: Evan Fletcher, PhD; Pauline Maillard, PhD; John Olichney, MD; Charles DeCarli, MD; and Owen Carmichael, PhD (Past Investigator). Neurological Care of CNY: Smita Kittur, MD (Past Investigator). Parkwood Institute: Michael Borrie, MB ChB; T-Y Lee, PhD; and Rob Bartha, PhD. University of Wisconsin: Sterling Johnson, PhD; Sanjay Asthana, MD; and Cynthia M. Carlsson, MD, MS. Banner Alzheimer's Institute: Pierre Tariot, MD; Anna Burke, MD; Joel Hetelle, BS; Kathryn DeMarco, BS; Nadira Trncic, MD, PhD, CCRC (Past Investigator); Adam Fleisher, MD (Past Investigator); and Stephanie Reeder, BA (Past Investigator). Dent Neurologic Institute: Vernice Bates, MD; Horacio Capote, MD; and Michelle Rainka, PharmD, CCRP. The Ohio State University: Douglas W. Scharre, MD; Maria Kataki, MD, PhD; and Rawan Tarawneh, MD. Albany Medical College: Earl A. Zimmerman, MD; Dzintra Celmins, MD; and David Hart, MD. Hartford Hospital, Olin Neuropsychiatry Research Center: Godfrey D. Pearlson, MD; Karen Blank, MD; and Karen Anderson, RN. Dartmouth-Hitchcock Medical Center: Laura A. Flashman, PhD; Marc Seltzer, MD; Mary L. Hynes, RN, MPH; and Robert B. Santulli, MD (Past Investigator). Wake Forest University Health Sciences: Kaycee M. Sink, MD, MAS; Mia Yang, MD; and Akiva Mintz, MD, PhD. Rhode Island Hospital: Brian R. Ott, MD; Geoffrey Tremont, PhD; and Lori A. Daiello, PharmD, ScM. Butler Hospital: Courtney Bodge, PhD; Stephen Salloway, MD, MS; Paul Malloy, PhD; Stephen Correia, PhD; and Athena Lee, PhD. University of California San Francisco: Howard J. Rosen, MD; Bruce L. Miller, MD; and David Perry, MD. Medical University of South Carolina: Jacobo Mintzer, MD, MBA; Kenneth Spicer, MD, PhD; and David Bachman, MD. St Joseph's Health Care: Elizabeth Finger, MD; Stephen Pasternak, MD; Irina Rachinsky, MD; John Rogers, MD; Andrew Kertesz, MD (Past Investigator); and Dick Drost, MD (Past Investigator). Nathan Kline Institute: Nunzio Pomara, MD; Raymundo Hernando, MD; and Antero Sarrael, MD. University of Iowa College of Medicine: Delwyn D. Miller, PharmD, MD; Karen Ekstam Smith, RN; Hristina Koleva, MD; Ki Won Nam, MD; Hyungsub Shim, MD; and Susan K. Schultz, MD (Past Investigator). Cornell University: Norman Relkin, MD, PhD; Gloria Chiang, MD; Michael Lin, MD; and Lisa Ravdin, PhD. University of South Florida Health Byrd Alzheimer's Institute: Amanda Smith, MD; Christi Leach, MD; Balebail Ashok Raj, MD (Past Investigator); and Kristin Fargher, MD (Past Investigator). DOD ADNI investigators include Part A: Leadership and Infrastructure Principal Investigator: Michael W. Weiner, MD, University of California, San Francisco; ATRI PI and Director of Coordinating Center Clinical Core: Paul Aisen, MD, University of Southern California; Executive Committee: Michael Weiner, MD, University of California San Francisco; Paul Aisen, MD, University of Southern California; Ronald Petersen, MD, PhD, Mayo Clinic, Rochester; Robert C. Green, MD, MPH, Brigham and Women's Hospital/Harvard Medical School; Danielle Harvey, PhD, University of California Davis; Clifford R. Jack Jr, MD, Mayo Clinic, Rochester; William Jagust, MD, University of California Berkeley; John C. Morris, MD, Washington University, St Louis; Andrew J. Saykin, PsyD, Indiana University; Leslie M. Shaw, PhD, Perelman School of Medicine, Unversity of Pennsylvania; Arthur W. Toga, PhD, University of Southern California; John Q. Trojanowki, MD, PhD, Perelman School of Medicine, University of Pennsylvania; Psychological Evaluation/PTSD Core: Thomas Neylan, MD, University of California San Francisco; Traumatic Brain Injury/TBI Core: Jordan Grafman, PhD, Rehabilitation Institute of Chicago, Feinberg School of Medicine, Northwestern University; Data and Publication Committee: Robert C. Green, MD, MPH BWH/HMS (Chair); Resource Allocation Review Committee: Tom Montine, MD, PhD, University of Washington (Chair); Clinical Core Leaders: Michael Weiner MD, Core PI; Ronald Petersen, MD, PhD, Mayo Clinic, Rochester (Core PI); Paul Aisen, MD, University of Southern California; Clinical Informatics and Operations: Gustavo Jimenez, MBS, University of Southern California; Michael Donohue, PhD, University of Southern California; Devon Gessert, BS, University of Southern California; Kelly Harless, BA, University of Southern California; Jennifer Salazar, MBS, University of Southern California; Yuliana Cabrera, BS, University of Southern California; Sarah Walter, MSc, University of Southern California; Lindsey Hergesheimen, BS, University of Southern California; San Francisco Veterans Affairs Medical Center; Thomas Neylan, MD, University of California San Francisco; Jacqueline Hayes, University of California San Francisco; Shannon Finley, University of California San Francisco; Biostatistics Core Leaders and Key Personnel: Danielle Harvey, PhD, University of California Davis (Core PI); Michael Donohue, PhD, University of California San Diego; MRI Core Leaders and Key Personnel: Clifford R. Jack Jr, MD, Mayo Clinic, Rochester (Core PI); Matthew Bernstein, PhD, Mayo Clinic, Rochester; Bret Borowski, RT, Mayo Clinic; Jeff Gunter, PhD, Mayo Clinic; Matt Senjem, MS, Mayo Clinic; Kejal Kantarci, Mayo Clinic; Chad Ward, Mayo Clinic; PET Core Leaders and Key Personnel: William Jagust, MD, University of California Berkeley (Core PI); Robert A. Koeppe, PhD, University of Michigan; Norm Foster, MD, University of Utah; Eric M. Reiman, MD, Banner Alzheimer's Institute; Kewei Chen, PhD, Banner Alzheimer's Institute; Susan Landau, PhD, University of California Berkeley; Neuropathology Core Leaders: John C. Morris, MD, Washington University, St Louis; Nigel J. Cairns, PhD, FRCPath, Washington University, St Louis; Erin Householder, MS, Washington University, St Louis; Biomarkers Core Leaders and Key Personnel: Leslie M. Shaw, PhD, Perelman School of Medicine, University of Pennsylvania; John Q. Trojanowki, MD, PhD, Perelman School of Medicine, University of Pennsylvania; Virginia Lee, PhD, MBA, Perelman School of Medicine, University of Pennsylvania; Magdalena Korecka, PhD, Perelman School of Medicine, University of Pennsylvania; Michal Figurski, PhD, Perelman School of Medicine, University of Pennsylvania; Informatics Core Leaders and Key Personnel: Arthur W. Toga, PhD, University of Southern California (Core PI); Karen Crawford, University of Southern California; Scott Neu, PhD, University of Southern California; Genetics Core Leaders and Key Personnel: Andrew J. Saykin, PsyD, Indiana University; Tatiana M. Foroud, PhD, Indiana University; Steven Potkin, MD, University of California Irvine; Li Shen, PhD, Indiana University; Kelley Faber, MS, CCRC, Indiana University; Sungeun Kim, PhD, Indiana University; Kwangsik Nho, PhD, Indiana University; Initial Concept Planning & Development: Michael W. Weiner, MD, University of California San Francisco; Karl Friedl, Department of Defense (retired). Part B: Investigators by Site: University of Southern California: Lon S. Schneider, MD, MS; Sonia Pawluczyk, MD; and Mauricio Becerra. University of California, San Diego: James Brewer, MD, PhD; and Helen Vanderswag, RN. Columbia University Medical Center: Yaakov Stern, PhD; Lawrence S. Honig, MD, PhD; and Karen L. Bell, MD. Rush University Medical Center: Debra Fleischman, PhD; Konstantinos Arfanakis, PhD; and Raj C. Shah, MD. Wien Center: Ranjan Duara, MD (PI); Daniel Varon, MD (Co-PI); and Maria T Greig, HP (Coordinator). Duke University Medical Center: P. Murali Doraiswamy, MBBS; Jeffrey R. Petrella, MD; and Olga James, MD. University of Rochester Medical Center: Anton P. Porsteinsson, MD (director); Bonnie Goldstein, MS, NP (coordinator); and Kimberly S. Martin, RN. University of California, Irvine: Steven G. Potkin, MD; Adrian Preda, MD; and Dana Nguyen, PhD. Medical University of South Carolina: Jacobo Mintzer, MD, MBA; Dino Massoglia, MD, PhD; and Olga Brawman-Mintzer, MD. Premiere Research Inst (Palm Beach Neurology): Carl Sadowsky, MD; Walter Martinez, MD; and Teresa Villena, MD. University of California, San Francisco: William Jagust MD; Susan Landau PhD; Howard Rosen, MD; and David Perry. Georgetown University Medical Center: Raymond Scott Turner, MD, PhD; Kelly Behan; and Brigid Reynolds, NP. Brigham and Women's Hospital: Reisa A. Sperling, MD; Keith A. Johnson, MD; and Gad Marshall, MD. Banner Sun Health Research Institute: Marwan N. Sabbagh, MD; Sandra A. Jacobson, MD; and Sherye A. Sirrel, MS, CCRC. Howard University: Thomas O. Obisesan, MD, MPH; Saba Wolday, MSc; and Joanne Allard, PhD. University of Wisconsin: Sterling C. Johnson, PhD; J. Jay Fruehling, MA; and Sandra Harding, MS. University of Washington: Elaine R. Peskind, MD; Eric C. Petrie, MD, MS; and Gail Li, MD, PhD. Stanford University: Jerome A. Yesavage, MD; Joy L. Taylor, PhD; Ansgar J. Furst, PhD; and Steven Chao, MD. Cornell University: Norman Relkin, MD, PhD; Gloria Chiang, MD; and Lisa Ravdin, PhD. ADNI Depression: Part A: Leadership and Infrastructure Principal Investigator: Scott Mackin, PhD, University of California San Francisco; ATRI PI and Director of Coordinating Center Clinical Core: Paul Aisen, MD, University of Southern California; Rema Raman, PhD, University of Southern California. Executive Committee: Scott Mackin, PhD, University of California San Francisco; Michael Weiner, MD, University of California San Francisco; Paul Aisen, MD, University of Southern California; Rema Raman, PhD, University of Southern California; Clifford R. Jack Jr, MD, Mayo Clinic, Rochester; Susan Landau, PhD, University of California Berkeley; Andrew J. Saykin, PsyD, Indiana University; Arthur W. Toga, PhD, University of Southern California; Charles DeCarli, MD, University of California Davis; Robert A. Koeppe, PhD, University of Michigan; Data and Publication Committee: Robert C. Green, MD, MPH, BWH/HMS (Chair); Erin Drake, MA, BWM/HMS (Director); Clinical Core Leaders: Michael Weiner, MD (Core PI); Paul Aisen, MD, University of Southern California; Rema Raman, PhD, University of Southern California; Mike Donohue, PhD, University of Southern California; Clinical Informatics, Operations and Regulatory Affairs: Gustavo Jimenez, MBS, University of Southern California; Devon Gessert, BS, University of Southern California; Kelly Harless, BA, University of Southern California; Jennifer Salazar, MBS, University of Southern California; Yuliana Cabrera, BS, University of Southern California; Sarah Walter, MSc, University of Southern California; Lindsey Hergesheimer, BS, University of Southern California; Elizabeth Shaffer, BS; Psychiatry Site Leaders and Key Personnel: Scott Mackin, PhD, University of California San Francisco; Craig Nelson, MD, University of California San Francisco; David Bickford, BA, University of California San Francisco; Meryl Butters, PhD, University of Pittsburgh; and Michelle Zmuda, MA, University of Pittsburgh. MRI Core Leaders and Key Personnel: Clifford R. Jack Jr, MD, Mayo Clinic, Rochester (Core PI); Matthew Bernstein, PhD, Mayo Clinic, Rochester; Bret Borowski, RT, Mayo Clinic, Rochester; Jeff Gunter, PhD, Mayo Clinic, Rochester; Matt Senjem, MS, Mayo Clinic, Rochester; Kejal Kantarci, MD, Mayo Clinic, Rochester; Chad Ward, BA, Mayo Clinic, Rochester; Denise Reyes, BS, Mayo Clinic, Rochester; PET Core Leaders and Key Personnel: Robert A. Koeppe, PhD, University of Michigan; Susan Landau, PhD, University of California Berkeley; Informatics Core Leaders and Key Personnel: Arthur W. Toga, PhD, University of Southern California (Core PI); Karen Crawford, University of Southern California; Scott Neu, PhD, University of Southern California. Genetics Core Leaders and Key Personnel: Andrew J. Saykin, PsyD, Indiana University; Tatiana M. Foroud, PhD, Indiana University; Kelley M. Faber, MS, CCRC, Indiana University; Kwangsik Nho, PhD, Indiana University; Kelly N. Nudelman, Indiana University. Part B: Investigators by Site: University of California San Francisco: Scott Mackin, PhD; Howard Rosen, MD; Craig Nelson, MD; David Bickford, BA; Yiu Ho Au, BA; Kelly Scherer, BS; Daniel Catalinotto, BA; Samuel Stark, BA; Elise Ong, BA; and Dariella Fernandez, BA. University of Pittsburgh: Meryl Butters, PhD; Michelle Zmuda, MA; Oscar L. Lopez, MD; MaryAnn Oakley, MA; and Donna M. Simpson, CRNP, MPH. Alzheimer's Disease Metabolomics Consortium Team Members: Indiana University: Andrew Saykin (PI) & Team (ADNI Genomics Core Leader); and Kwangsi K Nho. Helmholtz Zentrum Muenchen: Gabi Kastenmüller (PI); and Matthias Arnold (Co-PI). University of Arkansas: Sudeepa Bhattacharyya. University of Texas Health Science Center San Antonio: Xianlin Han (PI). West Coast Metabolomics Center: Oliver Fiehn (PI) & Team, Dinesh Barupal. Baker Heart and Diabetes Institute: Peter Meikle (PI). CalTech: Sarkis Mazmanian (PI). PO Metabolomics: Suzana Petanceska (NIH/NIA: 3 U01AG024904-09S4; 1R01AG046171-01). PO ADNI: John Hsiao (NIH/NIA/ERP); Michael Weiner and leadership of ADNI. University of Pennsylvania: Mitchel Kling (PI) & Team; John Toledo; Leslie Shaw (ADNI BiomarkerCore); and JohnTrojanowski (ADNI Biomarker Core). University of Oxford: Cornelia van Duijin (PI); and Shazad Ahmad (Erasmus). Leiden University Metabolomics Center: Thomas Hankemeier (Pl) & Team. National University of Ireland–Galway: Ines Thiele (PI); Almut Heinken (Luxembourg). Institute for Systems Biology: Nathan Price (PI) & Team; Cory Funk; and Priyanka Baloni. University of Hawaii: Wei Jia (PI) & Team. The Metabolomics Innovation Centre Canada tTMICl: David Wishart (PI) & Team. AMP-AD Collaborations: Rush University (David Bennen); Emory University (Allan Levey); SUNY (Herman Moreno); Columbia (Jose Luchsinger and Phil DeJager); Mt Sinai (Bin Zhang); Mayo-Florida (Nilufer Taner). University of Arizona: Roberta Brinton (PI) and Team; Rui Chang. Boston University: Lindsay Farrer (PI); Rhoda Au and Team. Biocrates Inc Metabolomics: Research Team. Nightingale Health: Peter Wurtz and Research Team. SAGE Networks: Lara Mangravire (PQ) and Team. Cornell University: Jan Krumsiek and Team. USDA: John Newman & Team. Duke University Medical Center, Psychiatry, Metabolomics Core and Statistics (Coordinating Center): Rima Kaddurah-Daouk (Overall PI); Alexandra Kueider-Paisley; P. Murali Doraiswamy (AD clinician); Colette Blach (Database); Art Moseley (Duke Proteomics and Metabolomics Core PI); Will Thompson, (Duke Proteomics and Metabolomics Core, Metabolomics Leader); Siamak Mahmoudiandehkordi (Statistics); Rebecca Baillie (Lipidmetabolism); KathleenWelsh-Bohmer; and Brenda Plassman. Additional Contributions: Lisa Howerton, Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina, provided administrative support. No compensation was received outside of usual salary. We also thank the numerous ADNI study volunteers and their families. Additional Information: Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this article. Researchers can apply for ADNI data at http://adni.loni.usc.edu/data-samples/access-data/.

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