1. Webinar: Preventing Alzheimer's 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/NHGRI
Indiana University School of Medicine,
Indianapolis, IN USA 1
2. Webinar: Preventing Alzheimer's 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 2010
Indiana University School of Medicine,
Indianapolis, IN USA 2
3. Webinar: Preventing Alzheimer's 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 2010
Indiana University School of Medicine,
Indianapolis, IN USA 3
4. Webinar: Preventing Alzheimer's 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 4/22/12
Indiana University School of Medicine,
Indianapolis, IN USA 4
5. Webinar: Preventing Alzheimer's 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 AD
Indiana University School of Medicine,
Indianapolis, IN USA 5
6. Webinar: Preventing Alzheimer's 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
software
Indiana University School of Medicine,
Indianapolis, IN USA 6
7. Webinar: Preventing Alzheimer's 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, 2011
Indiana University School of Medicine,
Indianapolis, IN USA 7
8. Webinar: Preventing Alzheimer's 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 submitted
Indiana University School of Medicine,
Indianapolis, IN USA 8
9. Webinar: Preventing Alzheimer's 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, submitted
Indiana University School of Medicine,
Indianapolis, IN USA 9
10. Webinar: Preventing Alzheimer's 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, submitted
Indiana University School of Medicine,
Indianapolis, IN USA 10
11. Webinar: Preventing Alzheimer's 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 Alzheimer's disease are small,
from 5% to 15% for people at retirement age or younger, some
lifestyle choices and medical conditions can increase the risk.
Here's how various factors increase the chances, by percentage, of
developing Alzheimer's:
- 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 2011
Indiana University School of Medicine,
Indianapolis, IN USA 11
12. Webinar: Preventing Alzheimer's 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
