title: 2014 Update of the Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception.
abstract: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU, and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world.
authors.affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA; Department of Radiology, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA; Department of Psychiatry, University of California, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, CA, USA. Electronic address: michael.weiner@ucsf.edu.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA.
authors.forename: Dallas P
authors.initials: DP
authors.lastname: Veitch
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
authors.affiliation: Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, CA, USA.
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Beckett
authors.affiliation: Knight Alzheimer's Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA; Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.affiliation: Neurology Early Clinical Development, Biogen Idec, Cambridge, MA, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Cedarbaum
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Green
authors.affiliation: Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, CA, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Harvey
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.affiliation: Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Jagust
authors.affiliation: Neuroscience Clinical Development, Neuroscience & General Medicine Product Creation Unit, Eisai Inc., Philadelphia, PA, USA.
authors.forename: Johan
authors.initials: J
authors.lastname: Luthman
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Shaw
authors.affiliation: Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Tailored Therapeutics, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Schwarz
authors.affiliation: Laboratory of Neuroimaging, Institute of Neuroimaging and Informatics, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA.
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Toga
authors.affiliation: Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Alzheimer's Disease Core Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Udall Parkinson's Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D042241:Early Diagnosis; D006801:Humans; D015337:Multicenter Studies as Topic; D018697:Nootropic Agents / Q000627:therapeutic use; D011877:Radionuclide Imaging
chemical_list: D015415:Biomarkers; D018697:Nootropic Agents
keywords: Alzheimer's disease; Amyloid; Biomarker; Mild cognitive impairment; Tau