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Dissection of the polygenic architecture of neuronal Aβ production using a large sample of individual iPSC lines derived from Alzheimer’s disease patients

Nature Aging volume 2, pages 125–139 (2022)Cite this article

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Abstract

Genome-wide association studies have demonstrated that polygenic risks shape Alzheimer’s disease (AD). To elucidate the polygenic architecture of AD phenotypes at a cellular level, we established induced pluripotent stem cells from 102 patients with AD, differentiated them into cortical neurons and conducted a genome-wide analysis of the neuronal production of amyloid β (Aβ). Using such a cellular dissection of polygenicity (CDiP) approach, we identified 24 significant genome-wide loci associated with alterations in Aβ production, including some loci not previously associated with AD, and confirmed the influence of some of the corresponding genes on Aβ levels by the use of small interfering RNA. CDiP genotype sets improved the predictions of amyloid positivity in the brains and cerebrospinal fluid of patients in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Secondary analyses of exome sequencing data from the Japanese ADNI and the ADNI cohorts focused on the 24 CDiP-derived loci associated with alterations in Aβ led to the identification of rare AD variants in KCNMA1.

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Fig. 1: CDiP using induced cortical neurons from human iPSCs.
Fig. 2: Genotype sets identified by CDiP can be a key clue for predicting real-world data of Alzheimer’s cohort with genetic risk for AD.

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Data availability

Data used in the preparation of this article were obtained from the ADNI database (adni.loni.usc.edu). ADNI was launched in 2003 as a public–private partnership, led by principal investigator M.W.W.. The primary goal of ADNI has been to test whether serial magnetic resonance imaging, PET, other biological markers and clinical and neuropsychological assessments can be combined to measure progression of mild cognitive impairment and early AD. SNP array data are available in the National Bioscience Database Center (data ID hum031; JGAS000383/JGAD00049). All data generated or analyzed during this study are included in this article and its Supplementary Information files.

Code availability

All code for data management and analysis is archived online at GitHub (https://github.com/HaruhisaInoue/iSNPs4ADNIpred). All other codes as described above are openly available in the developer site.

References

  1. Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006).

    Article  PubMed  Google Scholar 

  2. Andrews, S. J., Fulton-Howard, B. & Goate, A. Interpretation of risk loci from genome-wide association studies of Alzheimer’s disease. Lancet Neurol. 19, 326–335 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sims, R., Hill, M. & Williams, J. The multiplex model of the genetics of Alzheimer’s disease. Nat. Neurosci. 23, 311–322 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Dou, K. X. et al. Genome-wide association study identifies CBFA2T3 affecting the rate of CSF Aβ42 decline in non-demented elders. Aging 11, 5433–5444 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hong, S. et al. Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset. Transl. Psychiatry https://doi.org/10.1038/s41398-020-01074-z (2020).

  6. Liu, C. & Yu, J. Genome-wide association studies for cerebrospinal fluid soluble TREM2 in Alzheimer’s disease. Front. Aging Neurosci. https://doi.org/10.3389/fnagi.2019.00297 (2019).

  7. Deming, Y. et al. Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta Neuropathol. 133, 839–856 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kim, S. et al. Genome-wide association study of CSF biomarkers Aβ1-42, t-tau, and p-tau181p in the ADNI cohort. Neurology 76, 69–79 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Han, M. R., Schellenberg, G. D. & Wang, L. S. Genome-wide association reveals genetic effects on human Aβ42and τ protein levels in cerebrospinal fluids: a case control study. BMC Neurol. https://doi.org/10.1186/1471-2377-10-90 (2010).

  10. Tam, V. et al. Benefits and limitations of genome-wide association studies. Nat. Rev. Genet. 20, 467–484 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Gallagher, M. D. & Chen-Plotkin, A. S. The post-GWAS era: from association to function. Am. J. Hum. Genet. 102, 717–730 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hoffman, L. M. et al. X-inactivation status varies in human embryonic stem cell lines. Stem Cells 23, 1468–1478 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Kondo, T. et al. iPSC-based compound screening and in vitro trials identify a synergistic anti-amyloid β combination for Alzheimer’s disease. Cell Rep. 21, 2304–2312 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Selkoe, D. J. Alzheimer’s disease is a synaptic failure. Science 298, 789–791 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Gadadhar, A., Marr, R. & Lazarov, O. Presenilin-1 regulates neural progenitor cell differentiation in the adult brain. J. Neurosci. 31, 2615–2623 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Porayette, P. et al. Differential processing of amyloid-β precursor protein directs human embryonic stem cell proliferation and differentiation into neuronal precursor cells. J. Biol. Chem. 284, 23806–23817 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Araki, W. et al. Trophic effect of β-amyloid precursor protein on cerebral cortical neurons in culture. Biochem. Biophys. Res. Commun. 181, 265–271 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Freude, K. K., Penjwini, M., Davis, J. L., LaFerla, F. M. & Blurton-Jones, M. Soluble amyloid precursor protein induces rapid neural differentiation of human embryonic stem cells. J. Biol. Chem. 286, 24264–24274 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Arber, C. et al. Familial Alzheimer’s disease mutations in PSEN1 lead to premature human stem cell neurogenesis. Cell Rep. https://doi.org/10.1016/j.celrep.2020.108615 (2021).

  21. Jan, A., Gokce, O., Luthi-Carter, R. & Lashuel, H. A. The ratio of monomeric to aggregated forms of Aβ40 and Aβ42 is an important determinant of amyloid-β aggregation, fibrillogenesis, and toxicity. J. Biol. Chem. 283, 28176–28189 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zoltowska, K. M., Maesako, M. & Berezovska, O. Interrelationship between changes in the amyloid β 42/40 ratio and presenilin 1 conformation. Mol. Med. 22, 329–337 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kwak, S. S. et al. Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer’s disease. Nat. Commun. https://doi.org/10.1038/s41467-020-15120-3 (2020).

  24. Wang, C. et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat. Med. 24, 647–657 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lin, Y.-T. et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98, 1141–1154 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yasukawa, T. et al. NRBP1-containing CRL2/CRL4A regulates amyloid β production by targeting BRI2 and BRI3 for degradation. Cell Rep. 30, 3478–3491 (2020).

    Article  CAS  PubMed  Google Scholar 

  27. Davies, J. et al. Orexin receptors exert a neuroprotective effect in Alzheimer’s disease (AD) via heterodimerization with GPR103. Sci. Rep. https://doi.org/10.1038/srep12584 (2015).

  28. Ertekin-Taner, N. et al. Linkage of plasma Aβ42 to a quantitative locus on chromosome 10 in late-onset Alzheimer’s disease pedigrees. Science 290, 2303–2304 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Hoe, H. S., Tran, T. S., Matsuoka, Y., Howell, B. W. & Rebeck, G. W. DAB1 and reelin effects on amyloid precursor protein and ApoE receptor 2 trafficking and processing. J. Biol. Chem. 281, 35176–35185 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Hoe, H. S. et al. Fyn modulation of Dab1 effects on amyloid precursor protein and apoe receptor 2 processing. J. Biol. Chem. 283, 6288–6299 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Lourenço, F. C. et al. Netrin-1 interacts with amyloid precursor protein and regulates amyloid-β production. Cell Death Differ. 16, 655–663 (2009).

    Article  PubMed  CAS  Google Scholar 

  32. Rovelet-Lecrux, A. et al. A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease. Eur. J. Hum. Genet. 20, 613–617 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Logue, M. W. et al. A comprehensive genetic association study of Alzheimer disease in African Americans. Arch. Neurol. 68, 1569–1579 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Beecham, G. W. et al. Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am. J. Hum. Genet. 84, 35–43 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen, Y. C. et al. Performance metrics for selecting single nucleotide polymorphisms in late-onset Alzheimer’s disease. Sci. Rep. https://doi.org/10.1038/srep36155 (2016).

  36. Kunkle, B. W. et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat. Genet. 51, 414–430 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Scelsi, M. A. et al. Genetic study of multimodal imaging Alzheimer’s disease progression score implicates novel loci. Brain 141, 2167–2180 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Whelan, C. D. et al. Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease. Acta Neuropathol. Commun. https://doi.org/10.1186/s40478-019-0795-2 (2019).

  39. Jiang, S. et al. A systems view of the differences between APOE ε4 carriers and non-carriers in Alzheimer’s disease. Front. Aging Neurosci. https://doi.org/10.3389/fnagi.2016.00171 (2016).

  40. Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Krämer, A., Green, J., Pollard, J. & Tugendreich, S. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics 30, 523–530 (2014).

    Article  PubMed  CAS  Google Scholar 

  42. Tong, B. C. K., Wu, A. J., Li, M. & Cheung, K. H. Calcium signaling in Alzheimer’s disease & therapies. Biochim. Biophys. Acta Mol. Cell Res. 1865, 1745–1760 (2018).

    Article  CAS  PubMed  Google Scholar 

  43. Hampel, H. et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch. Gen. Psychiatry 61, 95–102 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Suárez‐Calvet, M. et al. Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer’s continuum when only subtle changes in Aβ pathology are detected. EMBO Mol. Med. https://doi.org/10.15252/emmm.202012921 (2020).

  45. Chen, J. et al. Netrin-1 prevents rat primary cortical neurons from apoptosis via the DCC/ERK pathway. Front. Cell. Neurosci. https://doi.org/10.3389/fncel.2017.00387 (2017).

  46. Gu, C. et al. ZNRF2 attenuates focal cerebral ischemia/reperfusion injury in rats by inhibiting mTORC1-mediated autophagy. Exp. Neurol. https://doi.org/10.1016/j.expneurol.2021.113759 (2021).

  47. Lim, S. et al. Amyloid-β precursor protein promotes cell proliferation and motility of advanced breast cancer. BMC Cancer https://doi.org/10.1186/1471-2407-14-928 (2014).

  48. Grubman, A. et al. A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat. Neurosci. 22, 2087–2097 (2019).

    Article  CAS  PubMed  Google Scholar 

  49. van Hengel, J. et al. Mutations in the area composita protein αT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy. Eur. Heart J. 34, 201–210 (2013).

    Article  PubMed  CAS  Google Scholar 

  50. Miller, J. P., Moldenhauer, H. J., Keros, S. & Meredith, A. L. An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy. Channels 15, 447–464 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Rask-Andersen, M., Masuram, S. & Schiöth, H. B. The druggable genome: evaluation of drug targets in clinical trials suggests major shifts in molecular class and indication. Annu. Rev. Pharmacol. Toxicol. 54, 9–26 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Hori, Y. et al. FDA approved asthma therapeutic agent impacts amyloid β in the brain in a transgenic model of Alzheimer’s disease. J. Biol. Chem. https://doi.org/10.1074/jbc.M114.586602 (2014).

  53. Klein, C. Genetics in dystonia. Parkinsonism Relat. Disord. https://doi.org/10.1016/S1353-8020(13)70033-6 (2014).

  54. Alzheimer’s Association Calcium Hypothesis Workgroup. Calcium hypothesis of Alzheimer’s disease and brain aging: a framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimers. Dement. https://doi.org/10.1016/j.jalz.2016.12.006 (2017).

  55. Klunk, W. E. et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh compound-B. Ann. Neurol. 55, 306–319 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Nordberg, A. PET imaging of amyloid in Alzheimer’s disease. Lancet Neurology 3, 519–527 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Jagust, W. J. et al. The Alzheimer’s disease neuroimaging initiative positron emission tomography core. Alzheimers Dement. 6, 221–229 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Swaminathan, S. et al. Amyloid pathway-based candidate gene analysis of [11C]PiB-PET in the Alzheimer’s disease neuroimaging initiative (ADNI) cohort. Brain Imaging Behav. 6, 1–15 (2012).

    Article  PubMed  Google Scholar 

  59. Saykin, A. J. et al. Genetic studies of quantitative MCI and AD phenotypes in ADNI: progress, opportunities, and plans. Alzheimers Dement. 11, 792–814 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Iwatsubo, T. et al. Japanese and North American Alzheimer’s disease neuroimaging initiative studies: harmonization for international trials. Alzheimers Dement. 14, 1077–1087 (2018).

    Article  PubMed  Google Scholar 

  61. De Strooper, B. & Karran, E. The cellular phase of Alzheimer’s disease. Cell 164, 603–615 (2016).

    Article  PubMed  CAS  Google Scholar 

  62. Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bryois, J. et al. Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease. Nat. Genet. 52, 482–493 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kreisl., W. C. et al. PET imaging of neuroinflammation in neurological disorders. Lancet. Neurol. 19, 940–950 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Newcombe, E. A. et al. Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease. J. Neuroinflammation https://doi.org/10.1186/s12974-018-1313-3 (2018).

  66. Onyango, I. G., Jauregui, G. V., Čarna, M., Bennett, J. P. Jr & Stokin, G. B. Neuroinflammation in Alzheimer’s disease. Biomedicines https://doi.org/10.3390/biomedicines9050524 (2021).

  67. Arboleda-Velasquez, J. F. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med. 25, 1680–1683 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Alqudah, A. M., Sallam, A., Baenziger, P. S. & Börner, A. GWAS: fast-forwarding gene identification and characterization in temperate cereals: lessons from barley—a review. J. Adv. Res. 22, 119–135 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Blennow, K. et al. Predicting clinical decline and conversion to Alzheimer’s disease or dementia using novel Elecsys Aβ(1–42), pTau and tTau CSF immunoassays. Sci. Rep. 9, 1–11 (2019).

    Article  CAS  Google Scholar 

  70. Van der Auwera, G. A. et al. From fastQ data to high-confidence variant calls: the genome analysis toolkit best practices pipeline. Curr. Protoc. Bioinformatics https://doi.org/10.1002/0471250953.bi1110s43 (2013).

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Acknowledgements

We express sincere gratitude to all our co-workers and collaborators; to H. Kobayashi, W. Shin and A. Nabetani for experimental support and intellectual debt; to T. Enami and I. Inoue for technical assistance; and to M. Iijima, M. Yasui, N. Kawabata, T. Saigo, T. Urai and M. Nagata for their valuable administrative support. This research was funded in part by a grant for Core Center for iPS Cell Research of Research Center Network for Realization of Regenerative Medicine from AMED to H.I., Uehara Memorial Foundation to H.I., KAKENHI (21H02807) to H.I., KAKENHI (17K16121) and (20K16599) to T.K., KAKENHI (18K18452) to Y.Y., T.K. and H.I., the invited Project at iACT, Kyoto University Hospital to H.I., Suzuken Memorial Foundation to H.I. and AMED (JP20dk0207045) to T.I. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (NIH) and by the National Cancer Institute, National Human Genome Research Institute, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health and National Institute of Neurological Disorders and Stroke. The data used for the analyses described in this manuscript were obtained from the GTEx portal on 6th July 2021. Data collection and sharing for this project was funded by the ADNI (NIH grant U01 AG024904) and Department of Defense ADNI (award no. W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering and through contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica; Biogen Idec; Bristol-Myers Squibb Company; Eisai; Elan Pharmaceuticals; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche and its affiliated company Genentech; Fujirebio; GE Healthcare; IXICO; Janssen Alzheimer Immunotherapy Research & Development; Johnson & Johnson Pharmaceutical Research & Development; Medpace; Merck & Co.; Meso Scale Diagnostics; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer; Piramal Imaging; Servier; Synarc and Takeda Pharmaceutical Company. 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 NIH (www.fnih.org). The grantee organization is the Northern 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. Data used in preparation of this article were obtained from the ADNI database (adni.loni.usc.edu). As such, investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. The full membership of the J-ADNI investigators is listed at https://humandbs.biosciencedbc.jp/en/hum0043-j-adni-authors.

Author information

Authors and Affiliations

  1. Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan

    Takayuki Kondo, Ayako Nagahashi & Haruhisa Inoue

  2. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan

    Takayuki Kondo, Yuichiro Yada, Kayoko Tsukita, Ayako Nagahashi & Haruhisa Inoue

  3. iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan

    Takayuki Kondo, Yuichiro Yada, Kayoko Tsukita & Haruhisa Inoue

  4. Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan

    Norikazu Hara & Takeshi Ikeuchi

  5. Unit of Statistical Genetics, Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Satoshi Koyama & Ryo Yamada

  6. Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

    Kenji Ishii

  7. Department of Psychiatry, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan

    Takashi Asada & Tetsuaki Arai

  8. Institute for Advancement of Clinical and Translational Science (iACT), Kyoto University Hospital, Kyoto, Japan

    Haruhisa Inoue

  9. Magnetic Resonance Unit at the VA Medical Center and Radiology, Medicine, Psychiatry and Neurology, University of California, San Francisco, CA, USA

    Michael W. Weiner, Sara S. Mason, Colleen S. Albers, David Knopman & Kris Johnson

  10. UC San Diego School of Medicine, University of California, La Jolla, CA, USA

    Paul Aisen

  11. Neurology, Mayo Clinic, Rochester, MN, USA

    Ronald Petersen

  12. Radiology, Mayo Clinic, Rochester, MN, USA

    Clifford R. Jack

  13. University of California, Berkeley, Berkeley, CA, USA

    William Jagust

  14. University of Pennsylvania, Philadelphia, PA, USA

    John Q. Trojanowki

  15. University of Southern California, Los Angeles, CA, USA

    Arthur W. Toga, Lon S. Schneider, Sonia Pawluczyk, Mauricio Beccera, Liberty Teodoro & Bryan M. Spann

  16. University of California, Davis, Davis, CA, USA

    Laurel Beckett

  17. Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Robert C. Green

  18. Washington University, St. Louis, MO, USA

    John Morris, Leslie M. Shaw, Beau Ances, John C. Morris, Maria Carroll, Mary L. Creech, Erin Franklin, Mark A. Mintun, Stacy Schneider & Angela Oliver

  19. Oregon Health and Science University, Portland, OR, USA

    Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter & Sara Dolen

  20. University of California, San Diego, San Diego, CA, USA

    James Brewer, Helen Vanderswag & Adam Fleisher

  21. University of Michigan, Ann Arbor, MI, USA

    Judith L. Heidebrink & Joanne L. Lord

  22. Baylor College of Medicine, Houston, TX, USA

    Rachelle S. Doody, Javier Villanueva-Meyer, Munir Chowdhury, Susan Rountree & Mimi Dang

  23. Columbia University Medical Center, New York, NY, USA

    Yaakov Stern, Lawrence S. Honig & Karen L. Bell

  24. University of Alabama, Birmingham, AL, USA

    Daniel Marson, Randall Griffith, David Clark, David Geldmacher, John Brockington, Erik Roberson & Marissa Natelson Love

  25. Mount Sinai School of Medicine, New York, NY, USA

    Hillel Grossman & Effie Mitsis

  26. Rush University Medical Center, Chicago, IL, USA

    Raj C. Shah & Leyla deToledo-Morrell

  27. Wien Center, Miami Beach, FL, USA

    Ranjan Duara, Daniel Varon, Maria T. Greig & Peggy Roberts

  28. Johns Hopkins University, Baltimore, MD, USA

    Marilyn Albert, Chiadi Onyike, Daniel D’Agostino & Stephanie Kielb

  29. New York University, New York, NY, USA

    James E. Galvin, Brittany Cerbone, Christina A. Michel, Dana M. Pogorelec, Henry Rusinek, Mony J. de Leon, Lidia Glodzik & Susan De Santi

  30. Duke University Medical Center, Durham, NC, USA

    P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong & Edward Coleman

  31. University of Kentucky, Lexington, KY, USA

    Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates & Gary Conrad

  32. University of Rochester Medical Center, Rochester, NY, USA

    Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail & Connie Brand

  33. University of California, Irvine, Irvine, CA, USA

    Ruth A. Mulnard, Gaby Thai & Catherine Mc-Adams-Ortiz

  34. University of Texas Southwestern Medical School, Dallas, TX, USA

    Kyle Womack, Dana Mathews & Mary Quiceno

  35. Emory University, Atlanta, GA, USA

    Allan I. Levey, James J. Lah & Janet S. Cellar

  36. University of Kansas Medical Center, Kansas City, KS, USA

    Jeffrey M. Burns, Russell H. Swerdlow & William M. Brooks

  37. Indiana University, Bloomington, IN, USA

    Liana Apostolova, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring & Cynthia Hunt

  38. Universityof California, Los Angeles, Los Angeles, CA, USA

    Kathleen Tingus, Ellen Woo, Daniel H. S. Silverman, Po H. Lu & George Bartzokis

  39. Mayo Clinic, Jacksonville, FL, USA

    Neill R. Graff-Radford, Francine Parfitt, Tracy Kendall & Heather Johnson

  40. Yale University School of Medicine, New Haven, CT, USA

    Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy & Pradeep Varma

  41. McGill University and Jewish General Hospital, Montreal, Quebec, Canada

    Howard Chertkow, Howard Bergman & Chris Hosein

  42. Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

    Sandra Black, Bojana Stefanovic & Curtis Caldwell

  43. UBC Clinic for Alzheimer Disease and Related Disorders, Vancouver, British Columbia, Canada

    Ging-Yuek Robin Hsiung, Howard Feldman, Benita Mudge & Michele Assaly

  44. Cognitive Neurology–St. Joseph’s, London, Ontario, Canada

    Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost & Andrew Kertesz

  45. Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA

    Charles Bernick & Donna Munic

  46. Northwestern University, Evanston, IL, USA

    Marek Marsel Mesulam, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu & Nancy Johnson

  47. Premiere Research Institute and Palm Beach Neurology, West Palm Beach, FL, USA

    Carl Sadowsky & Teresa Villena

  48. Georgetown University Medical Center, Washington, DC, USA

    Raymond Scott Turner, Kathleen Johnson & Brigid Reynolds

  49. Brigham and Women’s Hospital, Boston, MA, USA

    Reisa A. Sperling, Keith A. Johnson & Gad Marshall

  50. Stanford University, Stanford, CA, USA

    Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen & Jared Tinklenberg

  51. Banner Sun Health Research Institute, Sun City, AZ, USA

    Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson & Sherye A. Sirrel

  52. Boston University, Boston, MA, USA

    Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash & Patricia Lynn Johnson

  53. Howard University, Boston, DC, USA

    Thomas O. Obisesan, Saba Wolday & Joanne Allard

  54. Case Western Reserve University, Cleveland, OH, USA

    Alan Lerner, Paula Ogrocki, Curtis Tatsuoka & Parianne Fatica

  55. UC Davis School of Medicine, Sacramento, CA, USA

    Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli & Owen Carmichael

  56. Neurological Care of CNY, Syracuse, NY, USA

    Smita Kittur

  57. Parkwood Hospital, Philadelphia, PA, USA

    Michael Borrie, T.-Y. Lee & Rob Bartha

  58. University of Wisconsin, Madison, WI, USA

    Sterling Johnson, Sanjay Asthana & Cynthia M. Carlsson

  59. University of California, Irvine, Irvine, CA, USA

    Steven G. Potkin, Adrian Preda & Dana Nguyen

  60. Banner Alzheimer’s Institute, Phoenix, AZ, USA

    Pierre Tariot, Anna Burke, Nadira Trncic, Adam Fleisher & Stephanie Reeder

  61. DENT Neurologic Institute, New York, NY, USA

    Vernice Bates, Horacio Capote & Michelle Rainka

  62. Ohio State University, Columbus, OH, USA

    Douglas W. Scharre, Maria Kataki & Anahita Adeli

  63. Albany Medical College, Albany, NY, USA

    Earl A. Zimmerman, Dzintra Celmins & Alice D. Brown

  64. Hartford Hospital, Olin Neuropsychiatry Research Center, Hartford, CT, USA

    Godfrey D. Pearlson, Karen Blank & Karen Anderson

  65. Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

    Laura A. Flashman, Marc Seltzer, Mary L. Hynes & Robert B. Santulli

  66. Wake Forest University Health Sciences, Winston-Salem, NC, USA

    Kaycee M. Sink, Leslie Gordineer, Jeff D. Williamson, Pradeep Garg & Franklin Watkins

  67. Rhode Island Hospital, Providence, RI, USA

    Brian R. Ott, Henry Querfurth & Geoffrey Tremont

  68. Butler Hospital, Providence, RI, USA

    Stephen Salloway, Paul Malloy & Stephen Correia

  69. University of California, San Francisco, San Francisco, CA, USA

    Howard J. Rosen, Bruce L. Miller & David Perry

  70. Medical University of South Carolina, Charleston, SC, USA

    Jacobo Mintzer, Kenneth Spicer & David Bachman

  71. Nathan Kline Institute, Orangeburg, NY, USA

    Nunzio Pomara, Raymundo Hernando & Antero Sarrael

  72. Cornell University, Ithaca, NY, USA

    Norman Relkin, Gloria Chaing, Michael Lin & Lisa Ravdin

  73. USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FL, USA

    Amanda Smith, Balebail Ashok Raj & Kristin Fargher

  74. University of Tokyo, Tokyo, Japan

    Takeshi Iwatsubo

  75. Tsukuba University, Tsukuba, Japan

    Takashi Asada

  76. Tohoku University, Sendai, Japan

    Hiroyuki Arai

  77. Institute of Brain and Blood Vessels, Isesaki, Japan

    Morihiro Sugishita

  78. National Center of Neurology and Psychiatry, Kodaira, Japan

    Hiroshi Matsuda, Noriko Sato & Hajime Sato

  79. National Center of Geriatrics and Gerontology, Tokyo, Japan

    Kengo Ito, Teruhiko Kachi & Kenji Toba

  80. Institute of Biomedical Research and Innovation, Kobe, Japan

    Michio Senda

  81. Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan

    Kenji Ishii

  82. Niigata University, Niigata, Japan

    Ryozo Kuwano & Takeshi Ikeuchi

  83. Department of Neurology, Sapporo Medical University, Sapporo, Japan

    Shun Shimohama, Masaki Saitoh, Rika Yamauchi, Takashi Hayashi & Chiyoko Takanami

  84. Department of Neuropsychiatry, Sapporo Medical University, Sapporo, Japan

    Seiju Kobayashi

  85. Department of Clinical Psychology, School of Psychological Science, Health Sciences University of Hokkaido, Sapporo, Japan

    Norihito Nakano

  86. School of Psychological Science, Health Sciences University of Hokkaido, Sapporo, Japan

    Junichiro Kanazawa

  87. Graduate School of Psychological Science, Health Sciences University of Hokkaido, Sapporo, Japan

    Takeshi Ando

  88. Department of Radiology, Sapporo Medical University, Sapporo, Japan

    Masato Hareyama

  89. Division of Diagnostic Radiology, Sapporo Medical University, Sapporo, Japan

    Masamitsu Hatakenaka

  90. Social Medical Corporation Teishinkai Central CI Clinic, Sapporo, Japan

    Eriko Tsukamoto

  91. Radiology Department, Social Medical Corporation Teishinkai Central CI Clinic, Sapporo, Japan

    Shinji Ochi

  92. Department of Neurology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    Mikio Shoji, Etsuro Matsubara, Takeshi Kawarabayashi, Yasuhito Wakasaya, Takashi Nakata & Naoko Nakahata

  93. Department of Radiology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    Shuichi Ono & Yoshihiro Takai

  94. Division of Neurology and Gerontology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan

    Satoshi Takahashi, Hisashi Yonezawa, Junko Takahashi, Masako Kudoh, Kuniko Ueno, Hiromi Sakashita & Kuniko Watanabe

  95. Division of Ultrahigh Field MRI, Institute for Biomedical Sciences, Iwate Medical University, Morioka, Japan

    Makoto Sasaki

  96. Center for Radiological Sciences, Iwate Medical University, Morioka, Japan

    Yutaka Matsumura, Yohsuke Hirata, Tsuyoshi Metoki, Susumu Hayakawa, Yuichi Sato, Masayuki Takeda, Koichiro Sera & Kazunori Terasaki

  97. Cyclotron Research Center, Iwate Medical University, Morioka, Japan

    Toshiaki Sasaki

  98. Nishina Memorial Cyclotron Center, Japan Radioisotope Association, Takizawa, Japan

    Yoshihiro Saitoh & Shoko Goto

  99. Departmetnt of Neurology, Research Institute for Brain and Blood Vessels-Akita, Akita, Japan

    Ken Nagata, Yuichi Sato, Tetsuya Maeda, Yasushi Kondoh, Takashi Yamazaki, Daiki Takano, Mio Miyata, Hiromi Komatsu, Mayumi Watanabe, Tomomi Sinoda & Rena Muraoka

  100. Pharmacy, Research Institute for Brain and Blood Vessels-Akita, Akita, Japan

    Kayoko Kikuchi

  101. Medical Support Department, Research Institute for Brain and Blood Vessels-Akita, Akita, Japan

    Hitomi Ito & Aki Sato

  102. Department of Radiology, Research Institute for Brain and Blood Vessels-Akita, Akita, Japan

    Toshibumi Kinoshita, Hideyo Toyoshima, Kaoru Sato & Shigeki Sugawara

  103. Clinical Laboratory, Research Institute for Brain and Blood Vessels-Akita, Akita, Japan

    Isao Ito & Fumiko Kumagai

  104. Geriatrics and Gerontology, Tohoku University Hospital, Sendai, Japan

    Hiroyuki Arai, Katsutoshi Furukawa, Masaaki Waragai, Naoki Tomita, Mari Ootsuki, Katsumi Sugawara & Satomi Sugawara

  105. Pharamacology, Tohoku University Hospital, Sendai, Japan

    Nobuyuki Okamura

  106. RadiologyTohoku University Hospital, Sendai, Japan

    Shunji Mugikura, Atsushi Umetsu, Takanori Murata & Tatsuo Nagasaka

  107. Neuroimaging, Tohoku University Hospital, Sendai, Japan

    Yukitsuka Kudo

  108. Nuclear Medicine, Tohoku University Hospital, Sendai, Japan

    Manabu Tashiro & Shoichi Watanuki

  109. Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan

    Masatoyo Nishizawa, Takeshi Ikeuchi & Takayoshi Tokutake

  110. Department of Rehabilitation, Niigata University Medical and Dental Hospital, Niigata, Japan

    Saeri Ishikawa, Emiko Kishida & Nozomi Sato

  111. Clinical Research Center, Niigata University Medical and Dental Hospital, Niigata, Japan

    Mieko Hagiwara, Kumi Yamanaka, Takeyuki Watanabe & Taeko Takasugi

  112. Department of Radiology, Niigata University Medical and Dental Hospital, Niigata, Japan

    Shoichi Inagawa, Kenichi Naito, Masanori Awaji & Tsutomu Kanazawa

  113. Department of Neurology, Gunma University Hospital, Maebashi, Japan

    Kouiti Okamoto, Masaki Ikeda, Yuiti Tasiro, Syunn Nagamine & Sathiko Kurose

  114. Department of Health of Rehabilitation, Gunma University Hospital, Maebashi, Japan

    Tsuneo Yamazaki & Shiori Katsuyama

  115. Clinical Trial Unit, Gunma University Hospital, Maebashi, Japan

    Sayuri Fukushima & Etsuko Koya

  116. Department of Radiology, Gunma University Hospital, Maebashi, Japan

    Makoto Amanuma, Kouiti Ujita, Kazuhiro Kishi & Kazuhisa Tuda

  117. Department of Nuclear Medicine Image, Gunma University Hospital, Maebashi, Japan

    Noboru Oriuti

  118. Department of Psychiatry Division of Clinical MedicineFaculty of Medicine, University of Tsukuba, Tsukuba, Japan

    Takashi Asada, Katsuyoshi Mizukami, Tetsuaki Arai & Etsuko Nakajima

  119. Department of Radiological Technology, Tsukuba Medical Center Hospital, Tsukuba, Japan

    Katsumi Miyamoto, Tomoya Kobayashi, Saori Itoya, Jun Ookubo, Toshiya Akatsu, Yoshiko Anzai, Junya Ikegaki, Yuuichi Katou, Kaori Kimura, Hajime Saitou, Kazuya Shinoda, Satoka Someya, Hiroko Taguchi, Kazuya Tashiro, Masaya Tanaka, Tatsuya Nemoto, Ryou Wakabayashi & Daisuke Watanabe

  120. Former Department of Radiological Technology, Tsukuba Medical Center Hospital, Tsukuba, Japan

    Kousaku Saotome & Ryou Kuchii

  121. Molecular Imaging Center Molecular Neuroimaging Program, National Institute of Radiological Sciences, Chiba, Japan

    Harumasa Takano, Tetsuya Suhara, Hitoshi Shinoto, Hitoshi Shimada, Makoto Higuchi & Takaaki Mori

  122. Molecular Imaging Center Biophysics Program, National Institute of Radiological Sciences, Chiba, Japan

    Hiroshi Ito & Takayuki Obata

  123. Molecular Imaging Center Planning and Promotion Unit Clinical Research Support Section, National Institute of Radiological Sciences, Chiba, Japan

    Yoshiko Fukushima, Kazuko Suzuki & Izumi Izumida

  124. Hospital Research Center for Charged Particle Therapy Radiological Technology Section, National Institute of Radiological Sciences, Chiba, Japan

    Katsuyuki Tanimoto & Takahiro Shiraishi

  125. Asahi Hospital for Neurological Diseases and Rehabilitation, Matsudo, Japan

    Hitoshi Shinotoh, Hitoshi Shimada, Junko Shiba, Hiroaki Yano, Miki Satake, Aimi Nakui, Yae Ebihara & Tomomi Hasegawa

  126. National Hospital Organization Chiba East National Hospital, Chiba, Japan

    Yasumasa Yoshiyama, Mami Kato, Yuki Ogata & Hiroyuki Fujikawa

  127. Department of Neurology & Stroke Care Unit, Saitama Medical University Hospital, Moroyama, Japan

    Nobuo Araki, Yoshihiko Nakazato, Takahiro Sasaki, Tomokazu Shimadu & Kimiko Yoshimaru

  128. Department of Nuclear Medicine, Saitama Medical University Hospital, Moroyama, Japan

    Hiroshi Matsuda, Etsuko Imabayashi, Asako Yasuda & Keiko Ozawa

  129. Department of Rehabilitation, Saitama Medical University Hospital, Moroyama, Japan

    Etuko Yamamoto, Natsumi Nakamata & Noriko Miyauchi

  130. Central Radiology Division, Saitama Medical University Hospital, Moroyama, Japan

    Rieko Hashimoto, Taishi Unezawa, Takafumi Ichikawa, Hiroki Hayashi, Masakazu Yamagishi, Tunemichi Mihara, Masaya Hirano & Shinichi Watanabe

  131. Pharmacy Division, Saitama Medical University Hospital, Moroyama, Japan

    Junichiro Fukuhara & Hajime Matsudo

  132. SHI Accelerator Service Ltd. (SAS), Tokyo, Japan

    Nobuyuki Saito

  133. Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan

    Atsushi Iwata, Hisatomo Kowa, Toshihiro Hayashi, Ryoko Ihara, Toji Miyagawa, Mizuho Yoshida, Yuri Koide, Eriko Samura & Kurumi Fujii

  134. Clinical Research Center, The University of Tokyo Hospital, Tokyo, Japan

    Kaori Watanabe & Nagae Orihara

  135. Department of Nuclear Medicine, The University of Tokyo Hospital, Tokyo, Japan

    Toshimitsu Momose, Miwako Takahashi, Takuya Arai & Yoshiki Kojima

  136. Department of Diagnostic Radiology, The University of Tokyo Hospital, Tokyo, Japan

    Akira Kunimatsu & Harushi Mori

  137. Radiological Center, The University of Tokyo Hospital, Tokyo, Japan

    Masami Goto, Takeo Sarashina, Syuichi Uzuki, Seiji Katou, Yoshiharu Sekine & Yukihiro Takauchi

  138. Neuroscience, Faculty of Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Chiine Kagami

  139. Department of Neurology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan

    Kazutomi Kanemaru, Yasushi Nishina, Maria Sakaibara, Yumiko Okazaki, Rieko Okada & Maki Obata

  140. Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

    Shigeo Murayama, Kenji Ishii & Masaki Takao

  141. Clinical Support Corporation, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan

    Yuko Iwata, Mizuho Minami, Yasuko Hanabusa, Hanae Shingyouji & Kyoko Tottori

  142. Department of Radiology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan

    Aya Tokumaru, Makoto Ichinose, Kazuya Kume & Syunsuke Kahashi

  143. Department of Psychiatry, National Center Hospital National Center of Neurology and Psychiatry, Kodaira, Japan

    Kunimasa Arima, Shin Tanaka, Yuko Nagahusa, Masuhiro Sakata, Mitsutoshi Okazaki, Yuko Saito & Maki Yamada

  144. Department of Neurology, National Center Hospital National Center of Neurology and Psychiatry, Kodaira, Japan

    Tadashi Tukamoto

  145. Administration Office of J-ADNI, National Center Hospital National Center of Neurology and Psychiatry, Kodaira, Japan

    Tiine Kodama, Maki Obata, Tomoko Takeuchi & Keiichiro Ozawa

  146. Clinical Support Corporation, National Center Hospital National Center of Neurology and Psychiatry, Kodaira, Japan

    Yuko Iwata, Hanae Shingyouji, Yasuko Hanabusa, Yoshiko Kawaji & Kyouko Tottori

  147. Department of Radiology, National Center Hospital National Center of Neurology and Psychiatry, Tokyo, Japan

    Noriko Sato, Yasuhiro Nakata, Satoshi Sawada, Makoto Mimatsu, Daisuke Nakkamura, Takeshi Tamaru & Shunichirou Horiuchi

  148. Juntendo University Hospital, Mental Clinic, Tokyo, Japan

    Heii Arai, Tsuneyoshi Ota, Aiko Kodaka, Yuko Tagata & Tomoko Nakada

  149. PET/CT Dementia Research Center, Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan

    Eizo Iseki & Kiyoshi Sato

  150. PET/CT Dementia Research Center, Department of Neuro-Psychiatry, Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan

    Hiroshige Fujishiro

  151. Department of Neuro-Psychiatry, Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan

    Norio Murayama

  152. Radiology, Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan

    Masaru Suzuki, Satoshi Kimura & Masanobu Takahashi

  153. Department of Geriatric Medicine, Tokyo Medical University, Tokyo, Japan

    Haruo Hanyu, Hirofumi Sakurai, Takahiko Umahara, Hidekazu Kanetaka, Kaori Arashino, Mikako Murakami & Ai Kito

  154. Tokyo Medical University, Tokyo, Japan

    Seiko Miyagi, Kaori Doi & Kazuyoshi Sasaki

  155. Division of Neurology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan

    Mineo Yamazaki, Akiko Ishiwata, Yasushi Arai, Akane Nogami & Sumiko Fukuda

  156. Clinical Support Corporation, Nippon Medical School Hospital, Japan

    Kyouko Tottori, Mizuho Minami & Yuko Iwata

  157. Geriatric Medicine, Kyorin University, Mitaka, Japan

    Koichi Kozaki, Yukiko Yamada, Sayaka Kimura & Ayako Machida

  158. Radiation Medicine, Kyorin University, Mitaka, Japan

    Kuninori Kobayashi

  159. Tokyo Medical and Dental University Graduate school of Medicine and Dental Sciences, Tokyo, Japan

    Hidehiro Mizusawa, Nobuo Sanjo, Mutsufusa Watanabe, Takuya Ohkubo, Hiromi Utashiro, Yukiko Matsumoto, Kumiko Hagiya, Yoshiko Miyama, Hitoshi Shibuya, Isamu Ohashi & Akira Toriihara

  160. Clinical Research Center, Tokyo Medical and Dental University Hospital Faculty of Medicine, Tokyo, Japan

    Takako Shinozaki & Haruko Hiraki

  161. Department of Radiology, Tokyo Medical and Dental University Hospital Faculty of Medicine, Tokyo, Japan

    Shinichi Ohtani

  162. Clinical Center for Neurodegenerative, National Hospital Organization Kurihama Medical & Addiction Center, Yokosuka, Japan

    Toshifumi Matsui, Tomomi Toyama, Hideki Sakurai & Kumiko Sugiura

  163. Department of Psychiatry, Kitasato University School of Medicine, Sagamihara, Japan

    Yu Hayasaka

  164. Department of Radiology, National Hospital Organization Kurihama Medical & Addiction Center, Yokosuka, Japan

    Hirofumi Taguchi

  165. Neurosurgery, Shonan-atsugi Hospital, Atsugi, Japan

    Shizuo Hatashita

  166. Clinical Research Center, Shonan-atsugi Hospital, Atsugi, Japan

    Akari Imuta & Akiko Matsudo

  167. Radiology, Shonan-atsugi Hospital, Atsugi, Japan

    Daichi Wakebe, Hideki Hayakawa, Mitsuhiro Ono & Takayoshi Ohara

  168. Department of Cognitive Disorders, National Center of Geriatrics and Gerontology, Obu, Japan

    Yukihiko Washimi, Yutaka Arahata, Akinori Takeda, Akiko Yamaoka, Masashi Tsujimoto, Takiko Kawai & Ai Honda

  169. Dementia Care Research and Training Center, National Center of Geriatrics and Gerontology, Obu, Japan

    Yoko Konagaya

  170. Department of Psychiatry, National Center of Geriatrics and Gerontology, Obu, Japan

    Hideyuki Hattori, Kenji Yoshiyama & Rina Miura

  171. Center for Comprehensive Care and Research on Memory Disorders, National Center of Geriatrics and Gerontology, Obu, Japan

    Takashi Sakurai

  172. Department of Home Medical Care Support, National Center of Geriatrics and Gerontology, Obu, Japan

    Miura Hisayuki

  173. Department of Comprehensive Geriatric Medicine, National Center of Geriatrics and Gerontology, Obu, Japan

    Hidetoshi Endou

  174. Department of Geriatrics, National Center of Geriatrics and Gerontology, Obu, Japan

    Syousuke Satake & Young Jae Hong

  175. Department of Neurology, National Center of Geriatrics and Gerontology, Obu, Japan

    Katsunari Iwai, Masaki Suenaga & Sumiko Morita

  176. Department of Clinical and Experimental Neuroimaging, National Center of Geriatrics and Gerontology, Obu, Japan

    Kengo Itou, Takashi Kato & Ken Fujiwara

  177. Department of Radiology, National Center of Geriatrics and Gerontology, Obu, Japan

    Rikio Katou, Mariko Koyama, Naohiko Fukaya, Akira Tsuji, Hitomi Shimizu, Hiroyuki Fujisawa, Tomoko Nakazawa, Satoshi Koyama & Takanori Sakata

  178. Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan

    Masahito Yamada, Mitsuhiro Yoshita, Miharu Samuraki, Kenjiro Ono, Moeko Shinohara, Yuki Soshi, Kozue Niwa & Chiaki Doumoto

  179. Center for Clinical Research Management, Kanazawa University Hospital, Kanazawa, Japan

    Mariko Hata, Miyuki Matsushita & Mai Tsukiyama

  180. The Medical and Pharmacological Research Center Foundation, Kanazawa, Japan

    Nozomi Takeda, Sachiko Yonezawa & Ichiro Matsunari

  181. Department of Radiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan

    Osamu Matsui, Fumiaki Ueda & Yasuji Ryu

  182. Department of Neurology, Hamamatsu Medical Center, Hamamatsu, Japan

    Masanobu Sakamoto, Yasuomi Ouchi & Yumiko Fujita

  183. Hamamatsu University School of Medicine, Hamamatsu, Japan

    Yasuomi Ouchi

  184. Hamamatsu Medical Center, Hamamatsu, Japan

    Madoka Chita

  185. Department of Psychiatry, Hamamatsu Medical Center, Hamamatsu, Japan

    Rika Majima

  186. Department of Clinical Research Management, Hamamatsu Medical Center, Hamamatsu, Japan

    Hiromi Tsubota

  187. Department of Radiological Technology, Hamamatsu Medical Center, Hamamatsu, Japan

    Umeo Shirasawa, Masashi Sugimori, Wataru Ariya, Yuuzou Hagiwara & Yasuo Tanizaki

  188. Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Hidenao Fukuyama, Shizuko Tanaka-Urayama & Shin-Ichi Urayama

  189. Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Ryosuke Takahashi & Kengo Uemura

  190. Department of Geriatric Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Hajime Takechi

  191. Eli Lilly Japan K.K Medical Science, Kobe, Japan

    Chihiro Namiki

  192. Rakuwakai Misasagi Hospital, Kyoto, Japan

    Takeshi Kihara

  193. Shiga Medical Center Research Institute, Moriyama, Japan

    Hiroshi Yamauchi

  194. Takemura Clinic, Kyoto, Japan

    Emiko Maeda

  195. Tonami General Hospital, Tonami, Japan

    Natsu Saito

  196. University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Shiho Satomi

  197. Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan

    Konomi Kabata

  198. Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Tomohisa Okada

  199. Department of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Koichi Ishizu

  200. Department of Radiology and Nuclear Medicine Service, Kyoto University Hospital, Kyoto, Japan

    Shigeto Kawase & Satoshi Fukumoto

  201. Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Masanori Nakagawa, Masaki Kondo, Fumitoshi Niwa, Toshiki Mizuno, Yoko Oishi, Mariko Yamazaki & Daisuke Yamaguchi

  202. Department of Molecular Pathobiology of Brain Diseases (Department of Neurology), Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Takahiko Tokuda

  203. Tokyo Yakuriken Co., Ltd, Tokyo, Japan

    Kyoko Ito, Yoku Asano & Chizuru Hamaguchi

  204. Department of Radiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Kei Yamada, Chio Okuyama, Kentaro Akazawa & Shigenori Matsushima

  205. Kyoto Prefectural University of Medicine Hospital, Kyoto, Japan

    Takamasa Matsuo, Toshiaki Nakagawa, Takeshi Nii & Takuji Nishida

  206. Department of Psychiatry, Nara Medical University, Kashihara, Japan

    Kuniaki Kiuchi

  207. Faculty of Psychology, Doshisha University, Kyotanabe, Japan

    Masami Fukusumi

  208. Heartland Shigisan Hospital, Sango, Japan

    Hideyuki Watanabe

  209. Department of Radiology, Nara Medical University, Kashihara, Japan

    Toshiaki Taoka

  210. Central Radiology, Nara Medical University, Kashihara, Japan

    Akihiro Nogi

  211. Psychiatry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Suita, Japan

    Masatoshi Takeda, Toshihisa Tanaka, Hiroaki Kazui, Kenji Yoshiyama, Takashi Kudo, Masayasu Okochi, Takashi Morihara, Shinji Tagami, Masahiko Takaya, Tamiki Wada, Mikiko Yokokoji, Hiromichi Sugiyama, Daisuke Yamamoto, Keiko Nomura & Mutsumi Tomioka

  212. Department of Clinical Gene Therapy, Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Japan

    Naoyuki Sato

  213. Department of Complementary and Alternative Medicine, Osaka University Graduate School of Medicine, Suita, Japan

    Noriyuki Hayashi

  214. Japan Society for the Promotion of Science, Tokyo, Japan

    Shuko Takeda

  215. Uchida Clinic/Department of radiology, Osaka University Graduate School of Medicine, Ibaraki/Suita, Japan

    Eiichi Uchida, Yoshiyuki Ikeda & Mineto Murakami

  216. Department of Geriatrics and Neurology, Osaka City University Graduate School of Medicine, Osaka, Japan

    Takami Miki, Hiroyuki Shimada, Suzuka Ataka, Akitoshi Takeda & Yuki Iwamoto

  217. Osaka Municipal Kohsaiin Hospital, Suita, Japan

    Motokatsu Kanemoto

  218. Kishiwada City Hospital, Kishiwada, Japan

    Jun Takeuchi

  219. Department of Psychiatry, Kosaka Hospital, Higashiosaka, Japan

    Rie Azuma

  220. Osaka City University Hospital Center for Drug and Food Clinical Evaluation, Osaka, Japan

    Naomi Tagawa, Junko Masao, Yuka Matsumoto, Yuko Kikukawa, Hisako Fujii & Junko Matsumura

  221. Department of Nuclear Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan

    Susumu Shiomi & Joji Kawabe

  222. Department of Radiology, Osaka City University Hospital, Osaka, Japan

    Yoshihiro Shimonishi, Mitsuji Higashida, Tomohiro Sahara & Takashi Yamanaga

  223. Department of Radiology, Osaka City University Graduate School of Medicine, Osaka, Japan

    Yukio Miki & Shinichi Sakamoto

  224. Department of Radiological Science, Ibaraki Prefectural University of Health Sciences, Ami, Japan

    Hiroyuki Tsushima

  225. Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan

    Kiyoshi Maeda, Yasuji Yamamoto, Kazuo Sakai, Haruhiko Oda & Yoshihiko Tahara

  226. Kobe University Graduate School of Health Sciences, Kobe, Japan

    Toshio Kawamata

  227. Department of General Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

    Takashi Sakurai & Taichi Akisaki

  228. Derartment of Psychiatry and Neurology, Kobe University Hospital, Kobe, Japan

    Mizuho Adachi, Masako Kuranaga & Sachi Takegawa

  229. Department of Psychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical, Okayama, Japan

    Seishi Terada, Yuki Kishimoto, Naoya Takeda, Nao Imai, Mayumi Yabe & Reiko Wada

  230. Department of Psychiatry, Kawasaki Hospital, Kurashiki, Japan

    Takeshi Ishihara

  231. Department of Psychiatry, Okayama University Hospital, Okayama, Japan

    Hajime Honda & Osamu Yokota

  232. Department of Imaging Diagnosis, Okayama Diagnostic Imaging Center, Okayama, Okayama, Japan

    Kentaro Ida

  233. Department of Imaging Technology, Okayama Diagnostic Imaging Center, Okayama, Okayama, Japan

    Daigo Anami, Seiji Inoue & Toshi Matsushita

  234. Department of Administration, Okayama Diagnostic Imaging Center, Okayama, Japan

    Shinsuke Hiramatsu

  235. Okayama University Hospital, Okayama, Japan

    Hiromi Tonbara & Reiko Yamamoto

  236. Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan

    Kenji Nakashima, Kenji Wada-Isoe & Saori Yamasaki

  237. Division of Clinical Radiology, Tottori University Hospital, Yonago, Japan

    Eijiro Yamashita

  238. Department of Neuropsychiatry Kagawa University School of Medicine, Kagawa, Japan

    Yu Nakamura, Ichiro Ishikawa, Sonoko Danjo, Tomomi Shinohara & Yuka Kashimoto

  239. Kagawa University Hospital Cancer center, Kagawa, Japan

    Miyuki Ueno

  240. Department of Radiology, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Yoshihiro Nishiyama, Yuka Yamamoto & Narihide Kimura

  241. Department of Clinical Radiology, Kagawa University Hospital, Kagawa, Japan

    Kazuo Ogawa, Yasuhiro Sasakawa, Takashi Ishimori & Yukito Maeda

  242. Department of Neurology, Fukuoka University, Fukuoka, Japan

    Tatsuo Yamada, Shinji Ouma & Aika Fukuhara-Kaneumi

  243. Neues Corporation, Tokyo, Japan

    Nami Sakamoto & Rie Nagao

  244. Department of Radiology, Fukuoka University, Fukuoka, Japan

    Kengo Yoshimitsu & Yasuo Kuwabara

  245. Radiology Center, Fukuoka University Hospital, Fukuoka, Japan

    Ryuji Nakamuta & Minoru Tanaka

  246. Department of Psychiatry and Neuropathobiology, Faculty of Life Science, Kumamoto University, Kumamoto, Japan

    Manabu Ikeda & Yuusuke Yatabe

  247. Department of Neuropsychiatry, Kumamoto University Hospital, Kumamoto, Japan

    Mamoru Hashimoto, Keiichirou Kaneda, Kazuki Honda, Naoko Ichimi, Mariko Morinaga & Miyako Noda

  248. A Center of Support for Child Development, Kumamoto University Hospital, Kumamoto, Japan

    Fumi Akatuka

  249. Department of Medical Imaging, Kumamoto University, Kumamoto, Japan

    Mika Kitajima

  250. Department of Diagnostic Imaging, Faculty of Life Science, Kumamoto University, Kumamoto, Japan

    Toshinori Hirai & Shinya Shiraishi

  251. Department of Psychiatry, Shinshu University School of Medicine, Matsumoto, Japan

    Naoji Amano, Shinsuke Washizuka, Tetsuya Hagiwara, Yatsuka Okada & Tomomi Ogihara

  252. Department of Psychiatry, Shinshu University Hospital, Matsumoto, Japan

    Toru Takahashi, Shin Inuzuka, Nobuhiro Sugiyama, Takehiko Yasaki, Minori Kitayama, Tomonori Owa & Akiko Ryokawa

  253. Clinical Trial Research Center, Shinshu University Hospital, Matsumoto, Japan

    Rie Takeuchi, Satoe Goto, Keiko Yamauchi & Mie Ito

  254. Department of Radiology, Shinshu University School of Medicine, Matsumoto, Japan

    Tomoki Kaneko

  255. Radiology Division, Shinshu University Hospital, Matsumoto, Japan

    Hitoshi Ueda

  256. Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan

    Shuichi Ikeda

  257. Mihara Memorial Hospital, Isesaki, Japan

    Masaki Takao, Ban Mihara, Hirofumi Kubo, Akiko Takano, Gou Yasui, Masami Akuzawa & Kaori Yamaguchi

  258. Psychiatric Center, Yokohama City University Medical Center, Yokohama, Japan

    Toshinari Odawara & Naomi Oota

  259. Neurology, Yokohama City University Medical Center, Yokohama, Japan

    Megumi Shimamura & Mikiko Sugiyama

  260. Yokohama City University Medical Center, Yokohama, Japan

    Atsushi Watanabe

  261. Radiology, Yokohama City University Medical Center, Yokohama, Japan

    Shigeo Takebayashi, Yoshigazu Hayakawa, Mitsuhiro Idegawa & Noriko Toya

  262. Kindai University, Sayama, Japan

    Kazunari Ishii

Authors
  1. Takayuki Kondo
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  2. Norikazu Hara
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  3. Satoshi Koyama
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  4. Yuichiro Yada
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  5. Kayoko Tsukita
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  6. Ayako Nagahashi
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  7. Takeshi Ikeuchi
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  8. Kenji Ishii
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  9. Takashi Asada
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  10. Tetsuaki Arai
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  11. Ryo Yamada
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  12. Haruhisa Inoue
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Consortia

Alzheimer’s Disease Neuroimaging Initiative (ADNI)

  • Michael W. Weiner
  • , Paul Aisen
  • , Ronald Petersen
  • , Clifford R. Jack
  • , William Jagust
  • , John Q. Trojanowki
  • , Arthur W. Toga
  • , Laurel Beckett
  • , Robert C. Green
  • , John Morris
  • , Leslie M. Shaw
  • , Jeffrey Kaye
  • , Joseph Quinn
  • , Lisa Silbert
  • , 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
  • , 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
  • , Mary L. Creech
  • , Erin Franklin
  • , Mark A. Mintun
  • , Stacy Schneider
  • , Angela Oliver
  • , Daniel Marson
  • , Randall Griffith
  • , David Clark
  • , David Geldmacher
  • , John Brockington
  • , Erik Roberson
  • , Marissa Natelson Love
  • , Hillel Grossman
  • , Effie Mitsis
  • , Raj C. Shah
  • , Leyla deToledo-Morrell
  • , Ranjan Duara
  • , Daniel Varon
  • , Maria T. Greig
  • , Peggy Roberts
  • , Marilyn Albert
  • , Chiadi Onyike
  • , Daniel D’Agostino
  • , Stephanie Kielb
  • , James E. Galvin
  • , Brittany Cerbone
  • , Christina A. Michel
  • , Dana M. Pogorelec
  • , Henry Rusinek
  • , Mony J. de Leon
  • , Lidia Glodzik
  • , Susan De Santi
  • , P. Murali Doraiswamy
  • , Jeffrey R. Petrella
  • , Salvador Borges-Neto
  • , Terence Z. Wong
  • , Edward Coleman
  • , Charles D. Smith
  • , Greg Jicha
  • , Peter Hardy
  • , Partha Sinha
  • , Elizabeth Oates
  • , Gary Conrad
  • , 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
  • , Allan I. Levey
  • , James J. Lah
  • , Janet S. Cellar
  • , Jeffrey M. Burns
  • , Russell H. Swerdlow
  • , William M. Brooks
  • , 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
  • , Jared R. Brosch
  • , Scott Herring
  • , Cynthia Hunt
  • , Christopher H. van Dyck
  • , Richard E. Carson
  • , Martha G. MacAvoy
  • , Pradeep Varma
  • , Howard Chertkow
  • , Howard Bergman
  • , Chris Hosein
  • , Sandra Black
  • , Bojana Stefanovic
  • , Curtis Caldwell
  • , Ging-Yuek Robin Hsiung
  • , Howard Feldman
  • , Benita Mudge
  • , Michele Assaly
  • , Elizabeth Finger
  • , Stephen Pasternack
  • , Irina Rachisky
  • , Dick Trost
  • , Andrew Kertesz
  • , Charles Bernick
  • , Donna Munic
  • , Marek Marsel Mesulam
  • , Kristine Lipowski
  • , Sandra Weintraub
  • , Borna Bonakdarpour
  • , Diana Kerwin
  • , Chuang-Kuo Wu
  • , Nancy Johnson
  • , Carl Sadowsky
  • , Teresa Villena
  • , Raymond Scott Turner
  • , Kathleen Johnson
  • , Brigid Reynolds
  • , Reisa A. Sperling
  • , Keith A. Johnson
  • , Gad Marshall
  • , 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
  • , Curtis Tatsuoka
  • , Parianne Fatica
  • , Evan Fletcher
  • , Pauline Maillard
  • , John Olichney
  • , Charles DeCarli
  • , Owen Carmichael
  • , 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
  • , Anna Burke
  • , Nadira Trncic
  • , 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
  • , Laura A. Flashman
  • , Marc Seltzer
  • , Mary L. Hynes
  • , Robert B. Santulli
  • , Kaycee M. Sink
  • , Leslie Gordineer
  • , 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
  • , David Perry
  • , Jacobo Mintzer
  • , Kenneth Spicer
  • , David Bachman
  • , Nunzio Pomara
  • , Raymundo Hernando
  • , Antero Sarrael
  • , Norman Relkin
  • , Gloria Chaing
  • , Michael Lin
  • , Lisa Ravdin
  • , Amanda Smith
  • , Balebail Ashok Raj
  •  & Kristin Fargher

Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI)

  • Takeshi Iwatsubo
  • , Takashi Asada
  • , Hiroyuki Arai
  • , Morihiro Sugishita
  • , Hiroshi Matsuda
  • , Kengo Ito
  • , Michio Senda
  • , Kenji Ishii
  • , Ryozo Kuwano
  • , Takeshi Ikeuchi
  • , Noriko Sato
  • , Hajime Sato
  • , Shun Shimohama
  • , Masaki Saitoh
  • , Rika Yamauchi
  • , Takashi Hayashi
  • , Seiju Kobayashi
  • , Norihito Nakano
  • , Junichiro Kanazawa
  • , Takeshi Ando
  • , Chiyoko Takanami
  • , Masato Hareyama
  • , Masamitsu Hatakenaka
  • , Eriko Tsukamoto
  • , Shinji Ochi
  • , Mikio Shoji
  • , Etsuro Matsubara
  • , Takeshi Kawarabayashi
  • , Yasuhito Wakasaya
  • , Takashi Nakata
  • , Naoko Nakahata
  • , Shuichi Ono
  • , Yoshihiro Takai
  • , Satoshi Takahashi
  • , Hisashi Yonezawa
  • , Junko Takahashi
  • , Masako Kudoh
  • , Makoto Sasaki
  • , Yutaka Matsumura
  • , Yohsuke Hirata
  • , Tsuyoshi Metoki
  • , Susumu Hayakawa
  • , Yuichi Sato
  • , Masayuki Takeda
  • , Toshiaki Sasaki
  • , Koichiro Sera
  • , Kazunori Terasaki
  • , Yoshihiro Saitoh
  • , Shoko Goto
  • , Kuniko Ueno
  • , Hiromi Sakashita
  • , Kuniko Watanabe
  • , Ken Nagata
  • , Yuichi Sato
  • , Tetsuya Maeda
  • , Yasushi Kondoh
  • , Takashi Yamazaki
  • , Daiki Takano
  • , Mio Miyata
  • , Hiromi Komatsu
  • , Mayumi Watanabe
  • , Tomomi Sinoda
  • , Rena Muraoka
  • , Kayoko Kikuchi
  • , Hitomi Ito
  • , Aki Sato
  • , Toshibumi Kinoshita
  • , Hideyo Toyoshima
  • , Kaoru Sato
  • , Shigeki Sugawara
  • , Isao Ito
  • , Fumiko Kumagai
  • , Hiroyuki Arai
  • , Katsutoshi Furukawa
  • , Masaaki Waragai
  • , Naoki Tomita
  • , Nobuyuki Okamura
  • , Mari Ootsuki
  • , Katsumi Sugawara
  • , Satomi Sugawara
  • , Shunji Mugikura
  • , Atsushi Umetsu
  • , Takanori Murata
  • , Tatsuo Nagasaka
  • , Yukitsuka Kudo
  • , Manabu Tashiro
  • , Shoichi Watanuki
  • , Masatoyo Nishizawa
  • , Takeshi Ikeuchi
  • , Takayoshi Tokutake
  • , Saeri Ishikawa
  • , Emiko Kishida
  • , Nozomi Sato
  • , Mieko Hagiwara
  • , Kumi Yamanaka
  • , Takeyuki Watanabe
  • , Taeko Takasugi
  • , Shoichi Inagawa
  • , Kenichi Naito
  • , Masanori Awaji
  • , Tsutomu Kanazawa
  • , Kouiti Okamoto
  • , Masaki Ikeda
  • , Tsuneo Yamazaki
  • , Yuiti Tasiro
  • , Syunn Nagamine
  • , Shiori Katsuyama
  • , Sathiko Kurose
  • , Sayuri Fukushima
  • , Etsuko Koya
  • , Makoto Amanuma
  • , Noboru Oriuti
  • , Kouiti Ujita
  • , Kazuhiro Kishi
  • , Kazuhisa Tuda
  • , Takashi Asada
  • , Katsuyoshi Mizukami
  • , Tetsuaki Arai
  • , Etsuko Nakajima
  • , Katsumi Miyamoto
  • , Kousaku Saotome
  • , Tomoya Kobayashi
  • , Saori Itoya
  • , Jun Ookubo
  • , Toshiya Akatsu
  • , Yoshiko Anzai
  • , Junya Ikegaki
  • , Yuuichi Katou
  • , Kaori Kimura
  • , Ryou Kuchii
  • , Hajime Saitou
  • , Kazuya Shinoda
  • , Satoka Someya
  • , Hiroko Taguchi
  • , Kazuya Tashiro
  • , Masaya Tanaka
  • , Tatsuya Nemoto
  • , Ryou Wakabayashi
  • , Daisuke Watanabe
  • , Harumasa Takano
  • , Tetsuya Suhara
  • , Hitoshi Shinoto
  • , Hitoshi Shimada
  • , Makoto Higuchi
  • , Takaaki Mori
  • , Hiroshi Ito
  • , Takayuki Obata
  • , Yoshiko Fukushima
  • , Kazuko Suzuki
  • , Izumi Izumida
  • , Katsuyuki Tanimoto
  • , Takahiro Shiraishi
  • , Hitoshi Shinotoh
  • , Hitoshi Shimada
  • , Junko Shiba
  • , Hiroaki Yano
  • , Miki Satake
  • , Aimi Nakui
  • , Yae Ebihara
  • , Tomomi Hasegawa
  • , Yasumasa Yoshiyama
  • , Mami Kato
  • , Yuki Ogata
  • , Hiroyuki Fujikawa
  • , Nobuo Araki
  • , Yoshihiko Nakazato
  • , Takahiro Sasaki
  • , Tomokazu Shimadu
  • , Kimiko Yoshimaru
  • , Hiroshi Matsuda
  • , Etsuko Imabayashi
  • , Asako Yasuda
  • , Etuko Yamamoto
  • , Natsumi Nakamata
  • , Noriko Miyauchi
  • , Keiko Ozawa
  • , Rieko Hashimoto
  • , Taishi Unezawa
  • , Takafumi Ichikawa
  • , Hiroki Hayashi
  • , Masakazu Yamagishi
  • , Tunemichi Mihara
  • , Masaya Hirano
  • , Shinichi Watanabe
  • , Junichiro Fukuhara
  • , Hajime Matsudo
  • , Nobuyuki Saito
  • , Atsushi Iwata
  • , Hisatomo Kowa
  • , Toshihiro Hayashi
  • , Ryoko Ihara
  • , Toji Miyagawa
  • , Mizuho Yoshida
  • , Yuri Koide
  • , Eriko Samura
  • , Kurumi Fujii
  • , Kaori Watanabe
  • , Nagae Orihara
  • , Toshimitsu Momose
  • , Akira Kunimatsu
  • , Harushi Mori
  • , Miwako Takahashi
  • , Takuya Arai
  • , Yoshiki Kojima
  • , Masami Goto
  • , Takeo Sarashina
  • , Syuichi Uzuki
  • , Seiji Katou
  • , Yoshiharu Sekine
  • , Yukihiro Takauchi
  • , Chiine Kagami
  • , Kazutomi Kanemaru
  • , Shigeo Murayama
  • , Yasushi Nishina
  • , Kenji Ishii
  • , Maria Sakaibara
  • , Yumiko Okazaki
  • , Rieko Okada
  • , Maki Obata
  • , Yuko Iwata
  • , Mizuho Minami
  • , Yasuko Hanabusa
  • , Hanae Shingyouji
  • , Kyoko Tottori
  • , Aya Tokumaru
  • , Makoto Ichinose
  • , Kazuya Kume
  • , Syunsuke Kahashi
  • , Kunimasa Arima
  • , Tadashi Tukamoto
  • , Shin Tanaka
  • , Yuko Nagahusa
  • , Masuhiro Sakata
  • , Mitsutoshi Okazaki
  • , Yuko Saito
  • , Maki Yamada
  • , Tiine Kodama
  • , Maki Obata
  • , Tomoko Takeuchi
  • , Keiichiro Ozawa
  • , Yuko Iwata
  • , Hanae Shingyouji
  • , Yasuko Hanabusa
  • , Yoshiko Kawaji
  • , Kyouko Tottori
  • , Noriko Sato
  • , Yasuhiro Nakata
  • , Satoshi Sawada
  • , Makoto Mimatsu
  • , Daisuke Nakkamura
  • , Takeshi Tamaru
  • , Shunichirou Horiuchi
  • , Heii Arai
  • , Tsuneyoshi Ota
  • , Aiko Kodaka
  • , Yuko Tagata
  • , Tomoko Nakada
  • , Eizo Iseki
  • , Kiyoshi Sato
  • , Hiroshige Fujishiro
  • , Norio Murayama
  • , Masaru Suzuki
  • , Satoshi Kimura
  • , Masanobu Takahashi
  • , Haruo Hanyu
  • , Hirofumi Sakurai
  • , Takahiko Umahara
  • , Hidekazu Kanetaka
  • , Kaori Arashino
  • , Mikako Murakami
  • , Ai Kito
  • , Seiko Miyagi
  • , Kaori Doi
  • , Kazuyoshi Sasaki
  • , Mineo Yamazaki
  • , Akiko Ishiwata
  • , Yasushi Arai
  • , Akane Nogami
  • , Sumiko Fukuda
  • , Kyouko Tottori
  • , Mizuho Minami
  • , Yuko Iwata
  • , Koichi Kozaki
  • , Yukiko Yamada
  • , Sayaka Kimura
  • , Ayako Machida
  • , Kuninori Kobayashi
  • , Hidehiro Mizusawa
  • , Nobuo Sanjo
  • , Mutsufusa Watanabe
  • , Takuya Ohkubo
  • , Hiromi Utashiro
  • , Yukiko Matsumoto
  • , Kumiko Hagiya
  • , Yoshiko Miyama
  • , Takako Shinozaki
  • , Haruko Hiraki
  • , Hitoshi Shibuya
  • , Isamu Ohashi
  • , Akira Toriihara
  • , Shinichi Ohtani
  • , Toshifumi Matsui
  • , Yu Hayasaka
  • , Tomomi Toyama
  • , Hideki Sakurai
  • , Kumiko Sugiura
  • , Hirofumi Taguchi
  • , Shizuo Hatashita
  • , Akari Imuta
  • , Akiko Matsudo
  • , Daichi Wakebe
  • , Hideki Hayakawa
  • , Mitsuhiro Ono
  • , Takayoshi Ohara
  • , Yukihiko Washimi
  • , Yutaka Arahata
  • , Akinori Takeda
  • , Yoko Konagaya
  • , Akiko Yamaoka
  • , Masashi Tsujimoto
  • , Hideyuki Hattori
  • , Takashi Sakurai
  • , Miura Hisayuki
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  • , Takehiko Yasaki
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  • , Shuichi Ikeda
  • , Masaki Takao
  • , Ban Mihara
  • , Hirofumi Kubo
  • , Akiko Takano
  • , Gou Yasui
  • , Masami Akuzawa
  • , Kaori Yamaguchi
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  • , Atsushi Watanabe
  • , Naomi Oota
  • , Shigeo Takebayashi
  • , Yoshigazu Hayakawa
  • , Mitsuhiro Idegawa
  • , Noriko Toya
  •  & Kazunari Ishii

Contributions

H.I. conceived the project. T.K. and H.I. designed the experiment. T.K., K.T. and A.N. established iPSCs and iN-iPSCs. T.K. and K.T conducted SNP array analysis. T.K., S.K., Y.Y. and R.Y. conducted CDiP. N.H. and T.I. analyzed the exome database. K.I. analyzed the amyloid PET data. Y.Y. established a prediction algorithm. T. Asada and T. Arai recruited patients.

Corresponding author

Correspondence to Haruhisa Inoue.

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Competing interests

The authors declare no competing interests.

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Nature Aging thanks the anonymous reviewers for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Establishment of cortical neurons from iPSCs of patients with sporadic AD.

(a) Clinical information of patients who provided somatic cells as resource for iPSC establishment. (b) Generated iPSC lines expressed pluripotency markers TRA1-60 (green) and NANOG (red). Representative images from three independent experiments were shown. Nuclei were stained with 4’,6-diamidino-2-phenylindole: DAPI (blue). Scale bars = 200 μm. (c) Schema of differentiation method and assay (d) iPSC-derived neurons expressed excitatory cortical neuron markers, including MAP2 (green) and TBR2 (red) on day 8 of differentiation. Representative images from three independent experiments were shown. Scale bars = 50 μm. Purity of day 8 cortical neurons was shown as positivity for MAP2 (e) and SATB2 (f) with no significant variation among different patients (p = 0.7727 for MAP2, p = 0.3675 for SATB2, one way ANOVA). Data represent mean ± SD (n = 3 for each patient clone).

Extended data Fig. 2 Correlation between total protein concentration and cell density or Aβ species.

(a) Correlation plot between total protein concentration (μg/μL), Y-axis and disseminated cell density (104 cells per well of 96-well-plate). Linear fit (grey lines) is shown for three different clones from three different patients (n = 3 per clone). (b) Correlation plot between Aβ40 (pg/mL), Y-axis and total protein concentration (μg/μL), X-axis. Linear fit (blue lines) is shown for three different clones from three different patients (n = 3 per clone). (c) Correlation plot between Aβ42 (pg/mL), Y-axis and total protein concentration (μg/μL), X-axis. Linear fit (blue lines) is shown for three different clones from three different patients (n = 3 per clone). (d) Correlation plot between Aβ42/40 ratio, Y-axis and total protein concentration (μg/μL), X-axis. Linear fit (blue lines) is shown for three different clones from three different patients (n = 3 per clone).

Extended Data Fig. 3 Comparison of APOE genotype and Aβ phenotypes in induced cortical neurons from AD iPSCs.

Plots show the distribution of (a) Aβ40, (b) Aβ42, (c) Aβ42/40 ratio and (d) protein concentration among different genotypes. X-axes correspond to APOE ε4 genotypes (patients, N = 44 for APOE3/3, N = 44 for APOE3/4, N = 14 for APOE4/4) and Y-axes represent (a) Aβ40 amounts, (b) Aβ42 amounts, (c) Aβ42/40 ratio, and (d) protein concentration of iPSC-derived cortical neurons. Horizontal lines are the median weights within a genotypic group, and error bars indicate standard deviation (S.D.). p > 0.05: not significant (N.S.) (one-way ANOVA with (two-way ANOVA with Tukey’s multiple comparisons test). Abbreviation: APOE, Apolipoprotein E.

Extended Data Fig. 4 There was no significant correlation between Aβ phenotypes in AD iPSC-derived cortical neurons and clinical status.

Scatter plots (N = 102) show Aβ phenotypes, including (a) Aβ40 (left panel, blue), (b) Aβ42 (right panel, red), and (c) Aβ42/40 ratio (Y-axis). X-axis shows the onset age of cognitive dysfunction. The scatter plot does not show statistically significant correlation between Aβ phenotypes and age at onset (R-squared = 0.03, p-value = 0.074 for Aβ40; R-squared = 0.000030, p-value = 0.87 for Aβ42; R-squared = 0.000023, p-value = 0.96 for Aβ42/40 ratio). The plots show the distribution of Aβ phenotypes between genders. X-axes correspond to gender, male or female (patients, n = 36 for male, n = 66 for female), and y-axes represent (d) Aβ40 dose, (e) Aβ42 dose, and (f) Aβ42/40 ratio in the culture supernatant of iPSC-derived cortical neurons. Horizontal lines are the median weights within a genotypic group, and error bars indicate standard deviation (S.D.).

Extended Data Fig. 5 Cellular dissection of polygenicity identified the genetic loci and molecular pathway related with Aβ42/40 ratio in AD cortical neurons.

(a) Flowchart for genome-wide analysis. (b) Quantile-quantile (Q-Q) plot of observed – log10 (p-value) from genome-wide association analysis of Aβ42/40 ratio level versus those expected under null hypothesis. Genomic inflation factor (λ) was 0.9659, suggesting that there was no population stratification effect. (c) Genome-wide association study for CDiP was conducted to identify the genetic loci related to the Aβ42/40 ratio without adjustment for the APOE status. Linear association between SNPs and the Aβ42/40 ratio was analyzed. Manhattan plot showing observed –log10 (p-value) of all tested SNPs with Aβ42/40 ratio (y-axis). Chromosomes are shown on the x-axis. The red line corresponds to genome-wide Bonferroni-corrected significance threshold p < 5 × 10−8. (d) Pathway analysis for 24 genes, identified in CDiP with Aβ42/40 ratio A selection of top canonical pathways found using Ingenuity Pathway Analysis (IPA) package to identify the enriched canonical pathways which were significantly enriched by using gene sets, identified in CDiP with Aβ42/40 ratio. Pathway analysis identified 14 pathways (p < 0.01), including 5 neuron-related pathways (red) and 2 pathways known to alter Aβ production (blue). Horizontal axis = p-value by Fisher’s exact test of pathway analysis.

Extended Data Fig. 6 CDiP for p231-phosphorylated tau / total tau ratio of AD cortical neurons.

(a) Plots show the distribution of the p231-tau / total tau ratio (p231-tau ratio) among different APOE genotypes. X-axes correspond to APOE ε4 genotypes (patients, n = 44 for APOE3/3, n = 44 for APOE3/4, n = 14 for APOE4/4), and Y-axes represent p231-tau ratio of iPSC-derived cortical neurons. Horizontal lines are the median weights within a genotypic group, and error bars indicate S.D. (b) The plots show the distribution of p231-tau ratio between genders. X-axes correspond to gender, male or female (patients, n = 36 for male, n = 66 for female), and y-axes represent p231-tau ratio of iPSC-derived cortical neurons. Horizontal lines are the median weights within a genotypic group, and error bars indicate S.D. (c) Scatter plots (N = 102) of p231-tau ratio (Y-axis) and onset ages of cognitive dysfunction (X-axis). The scatter plot does not show statistically significant correlation between p231-tau ratio and age at onset. (d) Genome-wide association study for CDiP was conducted to identify the genetic loci related to the p231-tau ratio with adjustment for the APOE status. Linear association between SNPs and the p231-tau ratio was analyzed. Manhattan plot showing observed –log10 (p-value) of all tested SNPs with p231-tau ratio (Y-axis). The red line corresponds to genome-wide Bonferroni-corrected significant threshold p < 5 × 10−8. (e) Genome-wide association study for CDiP was conducted to identify the genetic loci related to the p231-tau ratio without adjustment for the APOE status. Linear association between SNPs and the p231-tau ratio was analyzed. Manhattan plot showing observed –log10 (p-value) of all tested SNPs with p231-tau ratio (Y-axis). The red line corresponds to genome-wide Bonferroni-corrected significant threshold p < 5 × 10−8.

Extended Data Fig. 7 Alteration of gene expression by siRNA treatment.

(a) Relative expression of target gene for siRNA treatment was quantified. Y-axis shows fold change VS. non-targeted control siRNA. Data represent mean ± S.D. (n = 2 for each target gene).

Extended Data Fig. 8 Genes identified by CDiP can be potential therapeutic targets for Aβ phenotypes.

(a) Aβ40, (b) Aβ42, and (c) total protein concentration was analyzed after siRNA treatment, which targeted identified genes in cellular dissection of polygenicity (CDiP), Aβ-related genes, including APP, and BACE1. Non-target siRNA was used as negative control. JNJ-40418677 1 μM, second generation of γ-secretase modulator (GSM) to suppress Aβ production, was used as positive control for altered Aβ phenotypes. X-axis shows alteration level in Aβ40 compared with non-treatment control (n = 2 biological replicates). Shown is mean ± S.D. p < 0.05: *; p < 0.01: **; p < 0.001: ***.; p < 0.0001: **** (one way ANOVA with Uncorrected Fisher’s LSD) (d) Comparing neuronal expression of genes, whose siRNA altered the Aβ42/40 ratio, between the brains of Alzheimer’s disease and non-demented control. Transcriptome data from Single-cell atlas of the Entorhinal Cortex in Human Alzheimer’s Disease was analyzed. (e) Comparison of neuronal expression of genes whose siRNA reduced Aβ42, between the brains of Alzheimer’s disease and non-demented control. (f) The single-cell-based transcriptome data of six AD brains and six control brains, which provide the transcriptome data for individual cell types, was utilized to investigate the expression status of focused genes. Genes with higher expression in AD brains were selected as the potential therapeutic target.

Extended Data Fig. 9 Clinical status of Aβ deposition in brain did not correlate with Aβ phenotypes in induced cortical neurons from AD iPSCs.

(a) Schema of small cohort (N = 19), including the clinical status of Aβ deposition, measured by PiB-PET. (b) There was no difference in age at onset between Aβ-negative and Aβ-positive patients. The box and whiskers plot showed the range (whiskers) from minimum to maximum, the median (horizontal line) and the 25% and 75% (box) percentiles. Clinical status of Aβ deposition in the brain did not affect Aβ phenotypes in induced cortical neurons, from human iPSCs including (c) Aβ40, (d) Aβ42, and (e) Aβ42/40 ratio (patients, n = 4 for Aβ negative, n = 15 for Aβ positive). Horizontal lines are the median weights within groups, and error bars indicate standard deviation (S.D.). (f) J-ANDI and ADNI population for investigating rare variants of Alzheimer’s disease. Abbreviation: PiB PET: Pittsburgh Compound-B positron emission tomography, ANDI: Alzheimer’s Disease Neuroimaging Initiative, J-ANDI: Japanese ADNI.

Extended Data Fig. 10 Dissecting Alzheimer’s pathology into cellular polygenic architecture of the pathological traits to reveal the polygenicity of AD.

(a) CDiP can provide the information of genetic background, linked to each cell-type and trait in Alzheimer’s pathology.

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Kondo, T., Hara, N., Koyama, S. et al. Dissection of the polygenic architecture of neuronal Aβ production using a large sample of individual iPSC lines derived from Alzheimer’s disease patients. Nat Aging 2, 125–139 (2022). https://doi.org/10.1038/s43587-021-00158-9

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