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Articles
December 1, 2010

Genome-wide association study of CSF biomarkers Aβ1-42, t-tau, and p-tau181p in the ADNI cohort

January 4, 2011 issue
76 (1) 69-79

Abstract

Objectives:

CSF levels of Aβ1-42, t-tau, and p-tau181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (Aβ1-42, t-tau, p-tau181p, p-tau181p/Aβ1-42, and t-tau/Aβ1-42).

Methods:

A total of 374 non-Hispanic Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p < 0.01 (uncorrected p < 3.10 × 10−8) and secondarily examined SNPs with uncorrected p values less than 10−5 to identify potential candidates.

Results:

Four SNPs in the regions of the APOE, LOC100129500, TOMM40, and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134, ABCG2, SREBF2, and NFATC4, although not reaching genome-wide significance, were identified as potential candidates.

Conclusions:

In addition to known candidate genes, APOE, TOMM40, and one hypothetical gene LOC100129500 partially overlapping APOE; one novel gene, EPC2, and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.

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Supplementary Material

File (figure_e-1.pdf)
File (figure_e-2.pdf)
File (kim.pdf)
File (table_e-1.pdf)

COINVESTIGATORS

Clifford R. Jack, Jr., MD (Mayo Clinic, Rochester, Core PI MRI, Executive Committee); William Jagust, MD (UC Berkeley, Core PI PET, Executive Committee); Arthur W. Toga, PhD (UCLA, Core PI Informatics, Executive Committee); Laurel Beckett, PhD (UC Davis, Core PI Biostatistics, Executive Committee); Anthony Gamst, PhD (UC San Diego, Clinical Informatics and Operations, Executive Committee); Holly Soares, PhD (Pfizer, Chair, Industry Scientific Advisory Board [iSAB]); Robert C. Green, MD, MPH (Boston University, Chair, Data and Publication Committee [DPC]); Tom Montine, MD, PhD (University of Washington, Chair, Resource Allocation Review Committee); Ronald G. Thomas, PhD (UC San Diego, Clinical Informatics and Operations); Michael Donohue, PhD (UC San Diego, Clinical Informatics and Operations); Sarah Walter, MSc (UC San Diego, Clinical Informatics and Operations); Anders Dale, PhD (UC San Diego, MRI); Matthew Bernstein, PhD (Mayo Clinic, Rochester, MRI); Joel Felmlee, PhD (Mayo Clinic, Rochester, MRI); Nick Fox, MD (University of London, MRI); Paul Thompson, PhD (UCLA School of Medicine, MRI); Norbert Schuff, PhD (UCSF MRI, MRI); Gene Alexander, PhD (Banner Alzheimer's Institute, MRI); Charles DeCarli, MD (UC Davis, MRI); Dan Bandy, MS, CNMT (Banner Alzheimer's Institute, PET); Kewei Chen, PhD (Banner Alzheimer's Institute, PET); Robert A. Koeppe, PhD (University of Michigan, PET); Norm Foster, MD (University of Utah, PET); Eric M. Reiman, MD (Banner Alzheimer's Institute, PET); Chet Mathis, MD (University of Pittsburgh, PET); John Morris, MD (Washington University, St. Louis, Neuropathology, Executive Committee); Nigel J. Cairns, PhD, MRCPath (Washington University, St. Louis, Neuropathology); Lisa Taylor-Reinwald, BA, HTL (ASCP) (Washington University, St. Louis, Neuropathology); Virginia M.-Y. Lee, PhD, MBA (UPenn School of Medicine, Biomarkers); Magdalena Korecka, PhD (UPenn School of Medicine, Biomarkers); Karen Crawford (UCLA, Informatics); Scott Neu, PhD (UCLA, Informatics); Danielle Harvey, PhD (UC Davis, Biostatistics); John Kornak, PhD (UC Davis, Biostatistics); Neil Buckholtz, PhD (National Institute on Aging/NIH); Jeffrey Kaye, MD (Oregon Health and Science University, site investigator); Sara Dolen, BS (Oregon Health and Science University, site investigator); Joseph Quinn, MD (Oregon Health and Science University, site investigator); Lon Schneider, MD (University of Southern California, site investigator); Sonia Pawluczyk, MD (University of Southern California, site investigator); Bryan M. Spann, DO, PhD (University of Southern California, site investigator); James Brewer, MD, PhD (University of California–San Diego, site investigator); Helen Vanderswag, RN (University of California–San Diego, site investigator); Judith L. Heidebrink, MD, MS (University of Michigan, site investigator); Joanne L. Lord, LPN, BA, CCRC (University of Michigan, site investigator); Ronald Petersen, MD, PhD (Mayo Clinic, Rochester, site investigator); Kris Johnson, RN (Mayo Clinic, Rochester, site investigator); Rachelle S. Doody, MD, PhD (Baylor College of Medicine, site investigator); Javier Villanueva-Meyer, MD (Baylor College of Medicine, site investigator); Munir Chowdhury, MS (Baylor College of Medicine, site investigator); Yaakov Stern, PhD (Columbia University Medical Center, site investigator); Lawrence S. Honig, MD, PhD (Columbia University Medical Center, site investigator); Karen L. Bell, MD (Columbia University Medical Center, site investigator); John C. Morris, MD (Washington University, St. Louis, site investigator); Mark A. Mintun, MD (Washington University, St. Louis, site investigator); Stacy Schneider, APRN, BC, GNP (Washington University, St. Louis, site investigator); Daniel Marson, JD, PhD (University of Alabama–Birmingham, site investigator); Randall Griffith, PhD, ABPP (University of Alabama–Birmingham, site investigator); David Clark, MD (University of Alabama–Birmingham, site investigator); Hillel Grossman, MD (Mount Sinai School of Medicine, site investigator); Cheuk Tang, PhD (Mount Sinai School of Medicine, site investigator); George Marzloff, BS (Mount Sinai School of Medicine, site investigator); Leyla deToledo-Morrell, PhD (Rush University Medical Center, site investigator); Raj C. Shah, MD (Rush University Medical Center, site investigator); Ranjan Duara, MD (Wein Center, site investigator); Daniel Varon, MD (Wein Center, site investigator); Peggy Roberts, CNA (Wein Center, site investigator); Marilyn S. Albert, PhD (Johns Hopkins University, site investigator); Julia Pedroso, MA (Johns Hopkins University, site investigator); Jaimie Toroney, BA (Johns Hopkins University, site investigator); Henry Rusinek, PhD (New York University, site investigator); Mony J. de Leon, EdD (New York University, site investigator); Susan M. De Santi, PhD (New York University, site investigator); P. Murali Doraiswamy, MD (Duke University Medical Center, site investigator); Jeffrey R. Petrella, MD (Duke University Medical Center, site investigator); Marilyn Aiello, BS (Duke University Medical Center, site investigator); Christopher M. Clark, MD (University of Pennsylvania, site investigator); Cassie Pham, BS (University of Pennsylvania, site investigator); Jessica Nunez (University of Pennsylvania, site investigator); Charles D. Smith, MD (University of Kentucky, site investigator); Curtis A. Given II, MD (University of Kentucky, site investigator); Peter Hardy, PhD (University of Kentucky, site investigator); Oscar L. Lopez, MD (University of Pittsburgh, site investigator); MaryAnn Oakley, MA (University of Pittsburgh, site investigator); Donna M. Simpson, CRNP, MPH (University of Pittsburgh, site investigator); M. Saleem Ismail, MD (University of Rochester Medical Center, site investigator); Connie Brand, RN (University of Rochester Medical Center, site investigator); Jennifer Richard, BA (University of Rochester Medical Center, site investigator); Ruth A. Mulnard, DNSc, RN, FAAN (University of California, Irvine, site investigator); Gaby Thai, MD (University of California, Irvine, site investigator); Catherine McAdams-Ortiz, MSN, RN, A/GNP (University of California, Irvine, site investigator); Ramon Diaz-Arrastia, MD, PhD (University of Texas Southwestern Medical School, site investigator); Kristen Martin-Cook, MA (University of Texas Southwestern Medical School, site investigator); Michael DeVous, PhD (University of Texas Southwestern Medical School, site investigator); Allan I. Levey, MD, PhD (Emory University, site investigator); James J. Lah, MD, PhD (Emory University, site investigator); Janet S. Cellar, RN, MSN (Emory University, site investigator); Jeffrey M. Burns, MD (University of Kansas, Medical Center, site investigator); Heather S. Anderson, MD (University of Kansas, Medical Center, site investigator); Mary M. Laubinger, MPA, BSN (University of Kansas, Medical Center, site investigator); George Bartzokis, MD (University of California, Los Angeles, site investigator); Daniel H.S. Silverman, MD, PhD (University of California, Los Angeles, site investigator); Po H. Lu, PsyD (University of California, Los Angeles, site investigator); Neill R. Graff-Radford MBBCH, FRCP (London) (Mayo Clinic, Jacksonville, site investigator); Francine Parfitt, MSH, CCRC (Mayo Clinic, Jacksonville, site investigator); Heather Johnson, MLS, CCRP (Mayo Clinic, Jacksonville, site investigator); Martin Farlow, MD (Indiana University, site investigator); Scott Herring, RN (Indiana University, site investigator); Ann M. Hake, MD (Indiana University, site investigator); Christopher H. van Dyck, MD (Yale University School of Medicine, site investigator); Martha G. MacAvoy, PhD (Yale University School of Medicine, site investigator); Amanda L. Benincasa, BA (Yale University School of Medicine, site investigator); Howard Chertkow, MD (McGill University, Montreal-Jewish General Hospital, site investigator); Howard Bergman, MD (McGill University, Montreal-Jewish General Hospital, site investigator); Chris Hosein, MEd (McGill University, Montreal-Jewish General Hospital, site investigator); Sandra Black, MD FRCP(C) (Sunnybrook Health Sciences, Ontario, site investigator); Simon Graham, PhD (Sunnybrook Health Sciences, Ontario, site investigator); Curtis Caldwell, PhD (Sunnybrook Health Sciences, Ontario, site investigator); Ging-Yuek Robin Hsiung, MD, MHSc, FRCPC (U.B.C. Clinic for AD & Related, B.C., site investigator); Howard Feldman, MD FRCP(C) (U.B.C. Clinic for AD & Related, B.C., site investigator); Michele Assaly, MA (U.B.C. Clinic for AD & Related, B.C., site investigator); Andrew Kertesz, MD (Cognitive Neurology-St. Joseph's, Ontario, site investigator); John Rogers, MD (Cognitive Neurology-St. Joseph's, Ontario, site investigator); Dick Trost, PhD (Cognitive Neurology-St. Joseph's, Ontario, site investigator); Charles Bernick, MD (Cleveland Clinic Lou Ruvo Center for Brain Health, site investigator); Donna Munic, PhD (Cleveland Clinic Lou Ruvo Center for Brain Health, site investigator); Chuang-Kuo Wu, MD, PhD (Northwestern University, site investigator); Nancy Johnson, PhD (Northwestern University, site investigator); Marsel Mesulam, MD (Northwestern University, site investigator); Carl Sadowsky, MD (Premiere Research Inst [Palm Beach Neurology], site investigator); Walter Martinez, MD (Premiere Research Inst [Palm Beach Neurology], site investigator); Teresa Villena, MD (Premiere Research Inst [Palm Beach Neurology], site investigator); Raymond Scott Turner, MD, PhD (Georgetown University Medical Center, site investigator); Kathleen Johnson, NP (Georgetown University Medical Center, site investigator); Kelly E. Behan, BA (Georgetown University Medical Center, site investigator); Reisa A. Sperling, MD (Brigham and Women's Hospital, site investigator); Dorene M. Rentz, PsyD (Brigham and Women's Hospital, site investigator); Keith A. Johnson, MD (Brigham and Women's Hospital, site investigator); Allyson Rosen, PhD (Stanford University, site investigator); Jared Tinklenberg, MD (Stanford University, site investigator); Wes Ashford, MD, PhD (Stanford University, site investigator); Marwan Sabbagh, MD, FAAN, CCRI (Sun Health Research Institute, site investigator); Donald Connor, PhD, PhD (Sun Health Research Institute, site investigator); Sandra Jacobson, MD (Sun Health Research Institute, site investigator); Ronald Killiany, PhD (Boston University, site investigator); Alexander Norbash, MD (Boston University, site investigator); Anil Nair, MD (Boston University, site investigator); Thomas O. Obisesan, MD, MPH (Howard University, site investigator); Annapurni Jayam-Trouth, MD (Howard University, site investigator); Paul Wang, PhD (Howard University, site investigator); Alan Lerner, MD (Case Western Reserve University, site investigator); Leon Hudson, MPH (Case Western Reserve University, site investigator); Paula Ogrocki, PhD (Case Western Reserve University, site investigator); Charles DeCarli, MD (University of California, Davis-Sacramento, site investigator); Evan Fletcher, PhD (University of California, Davis-Sacramento, site investigator); Owen Carmichael, PhD (University of California, Davis-Sacramento, site investigator); Smita Kittur, MD (Neurological Care of CNY, site investigator); Seema Mirje, MBBS (Neurological Care of CNY, site investigator); Michael Borrie, MD (Parkwood Hospital, site investigator); T.-Y. Lee, PhD (Parkwood Hospital, site investigator); Dr. Rob Bartha, PhD (Parkwood Hospital, site investigator); Sterling Johnson, PhD (University of Wisconsin, site investigator); Sanjay Asthana, MD (University of Wisconsin, site investigator); Cynthia M. Carlsson, MD (University of Wisconsin, site investigator); Steven G. Potkin, MD (University of California, Irvine-BIC, site investigator); Adrian Preda, MD (University of California, Irvine-BIC, site investigator); Dana Nguyen, PhD (University of California, Irvine-BIC, site investigator); Pierre Tariot, MD (Banner Alzheimer's Institute, site investigator); Adam Fleisher, MD (Banner Alzheimer's Institute, site investigator); Stephanie Reeder, BA (Banner Alzheimer's Institute, site investigator); Vernice Bates, MD (Dent Neurologic Institute, site investigator); Horacio Capote, MD (Dent Neurologic Institute, site investigator); Michelle Rainka, PhD (Dent Neurologic Institute, site investigator); Barry A. Hendin, MD (Dent Neurologic Institute, site investigator); Douglas W. Scharre, MD (Ohio State University, site investigator); Maria Kataki, MD, PhD (Ohio State University, site investigator); Earl A. Zimmerman, MD (Albany Medical College, site investigator); Dzintra Celmins, MD (Albany Medical College, site investigator); Alice D. Brown, FNP (Albany Medical College, site investigator); Sam Gandy, MD, PhD, PhD (Thomas Jefferson University, site investigator); Marjorie E. Marenberg, MD (Thomas Jefferson University, site investigator); Barry W. Rovner, MD (Thomas Jefferson University, site investigator); Godfrey Pearlson, MD (Hartford Hosp, Olin Neuropsychiatry Research Center); Karen Blank, MD (Hartford Hosp, Olin Neuropsychiatry Research Center); Karen Anderson, RN (Hartford Hosp, Olin Neuropsychiatry Research Center); Andrew J. Saykin, PsyD (Dartmouth-Hitchcock Medical Center, site investigator); Robert B. Santulli, MD (Dartmouth-Hitchcock Medical Center, site investigator); Jessica Englert, PhD (Dartmouth-Hitchcock Medical Center, site investigator); Jeff D. Williamson, MD, MHS (Wake Forest University Health Sciences, site investigator); Kaycee M. Sink, MD, MS (Wake Forest University Health Sciences, site investigator); Franklin Watkins, MD (Wake Forest University Health Sciences, site investigator); Brian R. Ott, MD (Rhode Island Hospital, site investigator); Chuang-Kuo Wu, MD, PhD (Rhode Island Hospital, site investigator); Ronald Cohen, PhD (Rhode Island Hospital, site investigator); Stephen Salloway, MD, MS (Butler Hospital, site investigator); Paul Malloy, PhD (Butler Hospital, site investigator); Stephen Correia, PhD (Butler Hospital, site investigator); Howard J. Rosen, MD (UC San Francisco, site investigator); Bruce L. Miller, MD (UC San Francisco, site investigator); and Jacobo Mintzer, MD (Medical University South Carolina, site investigator).

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Information & Authors

Information

Published In

Neurology®
Volume 76Number 1January 4, 2011
Pages: 69-79
PubMed: 21123754

Publication History

Received: April 12, 2010
Accepted: August 20, 2010
Published online: December 1, 2010
Published in print: January 4, 2011

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Disclosure

Dr. Kim and S. Swaminathan reports no disclosures. Dr. Shen receives support from the NIH (NIBIB R03 EB008674 [PI], NIBIB R03 EB008674S1 [PI], and UL1 RR025761 [PI of an Indiana CTSI pilot project]). S.L. Risacher reports no disclosures. Dr. Nho receives support from the NIH (NLM T15LM07117 [trainee]). Dr. Foroud serves on the editorial boards of Psychiatric Genetics, Journal of Bone and Mineral Research, Behavior Genetics, Journal of Studies on Alcohol, Parkinsonism and Related Disorders, and Journal of Studies on Alcohol and Drugs; has served as a consultant for the Institute for Behavioral Genetics at the University of Colorado; and receives research support from the NIH (NIA 5U24AG021886 [PI], R01AR047822 [PI], R01NS037167 [PI], N01NS32357 [PI], U01AA014809 [PI], R01CA141668 [PI], and P01AG018397 [PI]), Families of Spinal Muscular Atrophy, the Muscular Dystrophy Association, HP Therapeutics Foundation, and CHDI Foundation (previously High Q Foundation). Dr. Shaw has served on a scientific advisory board for Bristol-Myers Squibb; has received funding for travel and speaker honoraria from Pfizer Inc.; serves on the editorial board of Therapeutic Drug Monitoring; may potentially receive revenue for patent pending re: O-methylated rapamycin derivatives for alleviation and inhibition of lymphoproliferative disorders, licensed by the University of Pennsylvania to Novartis; receives royalties from publication of Applied Pharmacokinetics and Pharmacodynamics: Principles of Therapeutic Drug Monitoring (Wolters Kluwer/Lippincott Williams & Wilkins, 2005); receives research support from the NIH (AG024904 [Co-PI Biomarker Core Laboratory] and 1RC 2AG-036535 (ARRA) [PI Biomarker Core Laboratory]); and receives board of directors' compensation and holds stock options in Saladax Biomedical. Dr. Trojanowski has received funding for travel and honoraria from Takeda Pharmaceutical Company Ltd.; has received speaker honoraria from Pfizer Inc.; serves as an Associate Editor of Alzheimer's & Dementia; may accrue revenue on patents re: Modified avidin-biotin technique, Method of stabilizing microtubules to treat Alzheimer's disease, Method of detecting abnormally phosphorylated tau, Method of screening for Alzheimer's disease or disease associated with the accumulation of paired helical filaments, Compositions and methods for producing and using homogeneous neuronal cell transplants, Rat comprising straight filaments in its brain, Compositions and methods for producing and using homogeneous neuronal cell transplants to treat neurodegenerative disorders and brain and spinal cord injuries, Diagnostic methods for Alzheimer's disease by detection of multiple MRNAs, Methods and compositions for determining lipid peroxidation levels in oxidant stress syndromes and diseases, Compositions and methods for producing and using homogenous neuronal cell transplants, Method of identifying, diagnosing and treating alpha-synuclein positive neurodegenerative disorders, Mutation-specific functional impairments in distinct tau isoforms of hereditary frontotemporal dementia and parkinsonism linked to chromosome-17: genotype predicts phenotype, Microtubule stabilizing therapies for neurodegenerative disorders, and Treatment of Alzheimer's and related diseases with an antibody; and receives research support from the NIH (NIA P01 AG 09215-20 [PI], NIA P30 AG 10124-18 [PI], NIA PO1 AG 17586-10 [Project 4 Leader], NIA 1PO1 AG-19724-07 [Core C Leader], NIA 1 U01 AG 024904-05 [Co-PI Biomarker Core Laboratory], NINDS P50 NS053488-02 [PI], NIA UO1 AG029213-01 [Co-I]; RC2NS069368 [PI], RC1AG035427 [PI], and NIA P30AG036468 [PI]), and from the Marian S. Ware Alzheimer Program. Dr. Potkin serves on scientific advisory boards and speakers' bureaus for and has received funding for travel and speaker honoraria from AstraZeneca, Bioline, Bristol Myers-Squibb, Cortex Pharmaceuticals, Inc., Dainippon Sumitomo Pharma, Janssen, Novartis, Merck Serono, Pfizer Inc., Otsuka Pharmaceutical Co., Ltd., Roche, and Minster Pharmaceuticals plc; serves on the editorial board of Brain Imaging and Behavior; conducts clinical procedures/imaging studies at the UCI Brain Imaging Center and Neuropsychiatric Clinical Research Division (10% effort); and receives research support from the Transdisciplinary Imaging Genetics Center (TIGC) P20 RR020837-01, and the NIH (NCRR U24 RR021992 [PI], U01 AG032984 [PI], NCIRE AG036535 [coinvestigator]). Dr. Huentelman receives research support from the NIH/NINDS (R01 N5059873 [PI]). Dr. Craig has received research support from the Arizona Science Foundation, Arizona Alzheimer's Research Center, and the NIH (U01 HL086528 [PI] and R01 MH078151 [coinvestigator]). Dr. DeChairo was an employee of Pfizer Inc. and is presently an employee of Medco Health Solutions; has received research support from Medco Health Solutions and Pfizer Inc.; and holds/has held stock in Medco Health Solutions and Pfizer Inc. Dr. Aisen serves on a scientific advisory board for NeuroPhage; serves on the editorial advisory board of Alzheimer's Research & Therapy; serves as a consultant to Elan Corporation, Wyeth, Eisai Inc., Schering-Plough Corp., Bristol-Myers Squibb, Eli Lilly and Company, NeuroPhage, Merck & Co., Roche, Amgen, Genentech, Inc., Abbott, Pfizer Inc., Novartis, Bayer Schering Pharma, Medivation, Inc., Daiichi Sankyo, Astellas Pharma Inc., Dainippon Sumitomo Pharma Company Limited, BioMarin Pharmaceutical Inc., Solvay Pharmaceuticals, Inc., Otsuka Pharmaceutical Co., Ltd., AstraZeneca, and Janssen; receives research support from Pfizer Inc., Baxter International Inc., and the NIH (NIA U01-AG10483 [PI], NIA U01-AG024904 [Coordinating Center Director], NIA R01-AG030048 [PI], and R01-AG16381 [coinvestigator]); and has received stock options from Medivation, Inc. and NeuroPhage. Dr. Petersen serves on scientific advisory boards for Elan Corporation, Wyeth, and GE Healthcare; receives royalties from publishing Mild Cognitive Impairment (Oxford University Press, 2003); and receives research support from the NIH/NIA (P50-AG16574 [PI], U01-AG06786 [PI], R01-AG11378 [coinvestigator], and U01–24904 (coinvestigator)]. Dr. Weiner serves on scientific advisory boards for Bayer Schering Pharma, Eli Lilly and Company, Nestlé, CoMentis, Inc., Neurochem Inc., Eisai Inc., Avid Radiopharmaceuticals Inc., Aegis Therapies, Genentech, Inc., Allergan, Inc., Lippincott Williams & Wilkins, Bristol-Myers Squibb, Forest Laboratories, Inc., Pfizer Inc., McKinsey & Company, Mitsubishi Tanabe Pharma Corporation, and Novartis; has received funding for travel from Nestlé and Kenes International and to attend conferences not funded by industry; serves on the editorial board of Alzheimer's & Dementia; has received honoraria from the Rotman Research Institute and BOLT International; serves as a consultant for Elan Corporation; receives research support from Merck & Co., Avid Radiopharmaceuticals Inc., the NIH (U01AG024904 [PI], P41 RR023953 [PI], R01 AG10897 [PI], P01AG19724 [coinvestigator], P50AG23501 [coinvestigator], R24 RR021992 [coinvestigator], R01 NS031966 [coinvestigator], and P01AG012435 [coinvestigator]), the US Department of Defense, the Veterans Administration, and the State of California; and holds stock in Synarc and Elan Corporation. Dr. Saykin serves as Editor-in-Chief of Brain Imaging and Behavior; has served as a consultant to Baxter International Inc., Bristol-Myers Squibb, and Pfizer Inc.; and receives research support from Eli Lilly and Company, Siemens AG, Welch Allyn Inc., the NIH (R01 CA101318 [PI], R01 AG19771 [PI], RC2 AG036535 [Core Leader], P30 AG10133–18S1 [Core Leader], and U01 AG032984 [Site PI and Chair, Genetics Working Group]), the Indiana Economic Development Corporation (IEDC #87884), and the Foundation for the NIH.

Authors

Affiliations & Disclosures

S. Kim, PhD*
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
S. Swaminathan, BTech*
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
L. Shen, PhD
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
S.L. Risacher, BS
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
K. Nho, PhD
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
T. Foroud, PhD
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
L.M. Shaw, PhD
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
J.Q. Trojanowski, MD, PhD
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
S.G. Potkin, MD
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
M.J. Huentelman, PhD
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
D.W. Craig, PhD
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
B.M. DeChairo, PhD
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
P.S. Aisen, MD
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
R.C. Petersen, MD
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
M.W. Weiner, MD
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
A.J. Saykin, PsyD For the Alzheimer's Disease Neuroimaging Initiative
From the Center for Neuroimaging, Department of Radiology and Imaging Sciences (S.K., S.S., L.S., S.L.R., K.N., T.F., A.J.S.), Center for Computational Biology and Bioinformatics (S.K., L.S., T.F., A.J.S.), and Department of Medical and Molecular Genetics (S.S., T.F., A.J.S.), Indiana University School of Medicine, Indianapolis; Regenstrief Institute (K.N.), Indianapolis, IN; Department of Laboratory Medicine (L.M.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Psychiatry and Human Behavior (S.G.P.), University of California, Irvine; The Translational Genomics Research Institute (M.J.H., D.W.C.), Phoenix, AZ; Neuroscience (B.M.D.), Molecular Medicine, Pfizer Global R&D, New London, CT; Department of Neurosciences (P.S.A.), University of California, San Diego; Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN; Department of Radiology, Medicine and Psychiatry (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.

Notes

*
These authors contributed equally to this work.
Address correspondence and reprint requests to Dr. Andrew J. Saykin, Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 950 West Walnut Street, R2 E124, Indianapolis, IN 46202 [email protected]
Data used in the preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). 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 report. For a complete list of investigators involved in ADNI, see http://www.loni.ucla.edu/ADNI/Collaboration/ADNI_Authorship_list.pdf.
Study funding: Supported by the NIH (AG024904, AG010129, AG030514, and AG032984), the Dana Foundation, and the Alzheimer's Disease Genetics Consortium. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (NIH U01 AG024904).

Author Contributions

Statistical analysis was conducted by Dr. Sungeun Kim.

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