Saykin webinar imaging_genetics_biomarkers_mt_sinai_113012
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Presentation delivered by Dr. Andrew Saykin on the 30th of November 2012 - additional information at www.mcisymposium.org/webinar

Presentation delivered by Dr. Andrew Saykin on the 30th of November 2012 - additional information at www.mcisymposium.org/webinar

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Saykin webinar imaging_genetics_biomarkers_mt_sinai_113012 Saykin webinar imaging_genetics_biomarkers_mt_sinai_113012 Document Transcript

  • Webinar: Preventing Alzheimers Disease 11/30/12(Genetics, Biomarkers & Neuroimaging, A.Saykin) Genetics, Biomarkers & Imaging Toward a Future Personalized Medicine of Alzheimer’s Disease Andrew J. Saykin, PsyD, ABCN Depts. of Radiology & Imaging Sciences, Medical & Molecular Genetics, Neurology & Psychiatry; Indiana University School of Medicine, and the Indiana Alzheimer Disease Center Mt. Sinai Webinar Preventive Treatment for AD 11-30-2012 Disclosures & Acknowledgements • National Institute on Aging – ADNI U01 AG024904 & RC2 AG036535 – R01 AG19771 & P30 AG10133 (IADC) – U01 AG032984, U24 AG21886, P30 AG010129, K01 AG030514 • Institute of Biomedical Imaging and Bioengineering g g g g • Foundation for the NIH – Anonymous Foundation (Challenge Grant) – Gene Network Sciences, Merck, Pfizer (DNA ext.) • Alzheimer’s Association & Brin Wojcicki Foundation – Sequencing of ADNI-GO/2 • Saykin disclosures for related work: – Siemens Healthcare, Welch-Allyn, Eli Lilly, Pfizer Overview – Genetics of Alzheimer’s disease - Current status • Early onset or familial AD – genes & mutations • Late Onset AD (LOAD) – APOE and Genome-wide association studies (GWAS) – Alzheimer’s Disease Neuroimaging Initiative (ADNI) • Neuroimaging & other biomarkers as an endophenotypes – Methodological issues in mapping between quantitative biomarker phenotypes and genetic data – Emerging findings, challenges & future directions: • Genome-wide whole brain analysis • Selected genes of interest emerging from imaging genetics • APOE, other candidate genes & pathways-based analyses • Next Generation Sequencing in ADNI and NIA/NHGRIIndiana University School of Medicine,Indianapolis, IN USA 1
  • Webinar: Preventing Alzheimers Disease 11/30/12(Genetics, Biomarkers & Neuroimaging, A.Saykin) Toward personalized diagnostics and therapeutics of AD: Role of gene variation in onset, progression & Rx How do genes modify these curves? Modified from Shaw et al Nat Rev Drug Dis 2007; Trojanowski & Hampel Prog in Neurobiol 2011; and Jack et al Lancet Neurology 2010; 9:119–28. Major Genes: PS2 EOAD & LOAD APOE LOAD: genetic factors account for ~60-80% of risk (Gatz et al 2006); APOE accounts for up to 50% (Ashford & Mortimer 2002); so up to 30% remains to be found. PS1 Chromosome 19 APP 21q21.3 Chromosome 1 Chromosome 14 Chromosome 21 APP Mutations Chr. 21 21q21.3 Bekris et al 2010Indiana University School of Medicine,Indianapolis, IN USA 2
  • Webinar: Preventing Alzheimers Disease 11/30/12(Genetics, Biomarkers & Neuroimaging, A.Saykin) Chr. 14 PS1 Mutations Colombian kindred Bekris et al 2010 PS2 Mutations Chr. 1 Bekris et al 2010 Chr.19 APOE Variants ApoE protein Bekris et al 2010Indiana University School of Medicine,Indianapolis, IN USA 3 View slide
  • Webinar: Preventing Alzheimers Disease 11/30/12(Genetics, Biomarkers & Neuroimaging, A.Saykin) Naj et al ADGC GWAS Meta-analysis (~23K: ADNI AD cases & controls included) published online 3 April 2011; doi:10.1038/ng.801 Hollingworth et al GWAS Meta-analysis (~ 26K: ADNI AD cases & controls included) published online 3 April 2011; doi:10.1038/ng.803 Case/control GWAS: Top Ten (2011) * Current as of: http://www.alzgene.org/TopResults.asp 4/22/12Indiana University School of Medicine,Indianapolis, IN USA 4 View slide
  • Webinar: Preventing Alzheimers Disease 11/30/12(Genetics, Biomarkers & Neuroimaging, A.Saykin) Biological Roles of New Candidate Genes Gene Lipid Immune Endocytosis Processing Function APOE X X X ABCA7 X X BIN1 X CD33 X X CD2AP X CLU X X CR1 X EPHA1 X MS4A family X PICALM X Saykin, 2011 Imaging & Biomarkers as Phenotypes FUNDED BY THE NATIONAL INSTITUTE ON AGING M. Weiner, P. Aisen, R Peterson, C. Jack, W. Jagust, J. Trojanowski, L. Shaw, A. Toga, L. Beckett, D. Harvey, C. Mathis, A. Gamst. R. Green. A. Saykin, S. Potkin, J. Morris, L Thal (D), Neil Buckholz, David Lee, Holly Soares Industry Scientific Advisory Board (ISAB) and Site PIs, Study Coordinators, and 821 subjects enrolled in 58 sites in US and Canada For more information & data access: http://adni.loni.ucla.edu/ ADNI-1: Naturalistic Study of ADIndiana University School of Medicine,Indianapolis, IN USA 5
  • Webinar: Preventing Alzheimers Disease 11/30/12(Genetics, Biomarkers & Neuroimaging, A.Saykin) World Wide ADNI C-ADNI K-ADNI J-ADNI E-ADNI NA-ADNI T-ADNI Arg-ADNI A-ADNI Future ADNI sites Courtesy of Maria Carillo of the Alzheimer’s Association Weiner et al Alzheimer’s & Dementia 6:202-211 (2010) Imaging Biomarkers and Phenotypes: I. Automated Cortical Parcellation and High Throughput Computation FreeSurfer (MGH) II. Voxel-Based Morphometry (VBM) SPM 8 softwareIndiana University School of Medicine,Indianapolis, IN USA 6
  • Webinar: Preventing Alzheimers Disease 11/30/12(Genetics, Biomarkers & Neuroimaging, A.Saykin) III. Amyloid Imaging: Neuropathological Validation JAMA Jan 19, 2011 Amyvid FDA Approval 2012 Imaging, Biomarkers & Clinical Endophenotypes Gene “Chip” Other QT phenotypes: clinical, cognitive, fluid biomarker data Brain-Genome Association Strategies Candidate Biological Genome-wide Gene/SNP Pathway Analysis ROI Sloan et al Potkin et al 2009; Risacher et al 2010 2010 Saykin et al 2010 Circuit Swaminathan et al 2010 PiB Potkin et al 2009 Mol Psych Egan et al 2001 COMT ROIs & amyloid pathway schizophrenia study 0 4 1 Whole Brain 2 AD Reiman et al PNAS 2009; Reiman et al 2008 Shen et al 2010 ROIs; Also Ho et al 2010 FTO cholesterol pathway genes Stein et al 2010 voxels Saykin, 2011Indiana University School of Medicine,Indianapolis, IN USA 7
  • Webinar: Preventing Alzheimers Disease 11/30/12(Genetics, Biomarkers & Neuroimaging, A.Saykin) Role of APOE in Early MCI: Florbetapir PET Risacher et al AAIC 2012 and submitted Role of APOE in Early MCI: CSF Risacher et al AAIC 2012 and submitted Role of APOE in Early MCI: Structure Risacher et al AAIC 2012 and submittedIndiana University School of Medicine,Indianapolis, IN USA 8
  • Webinar: Preventing Alzheimers Disease 11/30/12(Genetics, Biomarkers & Neuroimaging, A.Saykin) Rate of Change: Role of APOE Main effect versus Interaction Risacher et al Neurobiology of Aging (2010); 31:1401-1418 Amyloid Gene Pathway PET Study: [11C]PiB DHCR24 (seladin - selective AD indicator – cholesterol synthesis pathway) Swaminathan et al, Brain Imaging & Behavior (2012) DOI 10.1007/s11682-011-9136-1 [18F]Florbetapir GWAS Sample (ADNI-GO/2, N=555) HC EMCI LMCI AD (n=179) (n=190) (n=115) (n=71) Age (years) 76·68 (6·25) 71·04 (7·41) 75·61 (8·14) 75·87 (8·15) Gender (women, %) 87 (49%) 83 (44%) 41 (36%) 27 (38%) Education (years) 16·27 (2·72) 15·89 (2·65) 16·11 (2·90) 16·04 (2·87) APOE ε4 allele (present %) (present, 41 (23%) 77 (41%) 49 (43%) 45 (64%) CDR-SOB 0·07 (0·29) 1·22 (0·73) 1·73 (1·18) 5·63 (2·70) Mini Mental Status Examination 29·07 (1·25) 28·39 (1·52) 27·74 (1·84) 21·68 (4·24) Logical Memory Immediate 14·94 (3·36) 10·93 (2·81) 8·74 (4·35) 4·20 (3·10) Recall (WMS-R) Logical Memory Delayed 14·08 (3·64) 8·87 (1·73) 6·13 (4·38) 1·67 (2·50) Recall (WMS-R) Data are number (%) or mean (SD). CDR-SOB = Clinical Dementia Rating-Sum of Boxes. WMS-R = Wechsler Memory Scale-Revised. PET = positron emission tomography. Ramanan et al, submittedIndiana University School of Medicine,Indianapolis, IN USA 9
  • Webinar: Preventing Alzheimers Disease 11/30/12(Genetics, Biomarkers & Neuroimaging, A.Saykin) Influence of APOE Ramanan et al, submitted Topography of BCHE Influence on Florbetapir Uptake R L Covariates: p <.05, FWE age, sex, corrected diagnosis and ADNI, N=555 APOE ԑ4 status Ramanan et al, submitted Additive Effects of APOE and BCHE Ramanan et al, submittedIndiana University School of Medicine,Indianapolis, IN USA 10
  • Webinar: Preventing Alzheimers Disease 11/30/12(Genetics, Biomarkers & Neuroimaging, A.Saykin) BuChE in Aβ plaque deposition Ramanan et al, submitted Lifestyle & Environmental Factors While the chances of developing Alzheimers disease are small, from 5% to 15% for people at retirement age or younger, some lifestyle choices and medical conditions can increase the risk. Heres how various factors increase the chances, by percentage, of developing Alzheimers: - Physical inactivity 21% - Depression 15% - Smoking 11% - Midlife hypertension 8% - Midlife obesity 7% - Low education 7% - Diabetes 3% Source: Deborah Barnes and Kristine Yaffe, University of California, San Francisco Presented at AAIC 2011Indiana University School of Medicine,Indianapolis, IN USA 11
  • Webinar: Preventing Alzheimers Disease 11/30/12(Genetics, Biomarkers & Neuroimaging, A.Saykin) Exercise, Diet, Mental Stimulation: Personalized diagnostics and therapeutics of AD: Current status and next steps How do genes modify these curves? Modified from Shaw et al Nat Rev Drug Dis 2007; Trojanowski & Hampel Prog in Neurobiol 2011; and Jack et al Lancet Neurology 2010; 9:119–28.Indiana University School of Medicine,Indianapolis, IN USA 12