saykin webinar imaging_genetics_biomarkers_mt_sinai_113012

Webinar: Preventing Alzheimer's Disease (Genetics, Biomarkers & Neuroimaging, A. Saykin)

11/30/12

Indiana University School of Medicine, Indianapolis, IN USA 1

Genetics, Biomarkers & ImagingToward 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 WebinarPreventive 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 Bioengineeringg 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


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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 Progin Neurobiol 2011; and Jack et al Lancet Neurology 2010; 9:119–28.

Major Genes:EOAD & LOAD

Chromosome 19PS1

PS2APOE

LOAD: genetic factors account for ~60-80% of risk (Gatz et al 2006);

APOE accounts for up to 50%(Ashford & Mortimer 2002); soup to 30% remains to be found.

Chromosome 14

Chromosome 19

Chromosome 21Chromosome 1

APP21q21.3

APP MutationsChr. 21

21q21.3

Bekris et al 2010


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PS1 MutationsChr. 14

Bekris et al 2010

Colombian kindred

PS2 Mutations

Chr. 1

Bekris et al 2010

APOE VariantsChr.19

ApoE protein

Bekris et al 2010


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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)

http://www.alzgene.org/TopResults.asp * Current as of:4/22/12


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Biological Roles of New Candidate Genes

Gene Lipid Processing

Immune Function

Endocytosis

APOE X X X

ABCA7 X X

BIN1 X

CD33 X XCD33 X X

CD2AP X

CLU X X

CR1 X

EPHA1 X

MS4A family X

PICALM X

Saykin, 2011

M. Weiner, P. Aisen, R Peterson, C. Jack, W. Jagust,

FUNDED BY THE NATIONAL INSTITUTE ON AGING

Imaging & Biomarkers as Phenotypes

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


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J-ADNI

World Wide ADNI

C-ADNI K-ADNI

NA-ADNI

E-ADNI

A-ADNI

T-ADNI

Arg-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


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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

Risacher et al 2010

Sloan et al 2010

Potkin et al 2009; Saykin et al 2010

ROI

Circuit

Candidate Gene/SNP

Biological Pathway

Genome-wide Analysis

Egan et al 2001 COMTSwaminathan et al 2010 PiB

ROIs & amyloid pathwayPotkin et al 2009 Mol Psych

schizophrenia study

Reiman et al PNAS 2009;Also Ho et al 2010 FTO

Reiman et al 2008 cholesterol pathway genes

Shen et al 2010 ROIs; Stein et al 2010 voxels

Circuit

Whole Brain

40 1

2 AD

Saykin, 2011


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Role of APOE in Early MCI: Florbetapir PET

Risacher et al AAIC 2012 and submitted

Role of APOE in Early MCI: CSF


Role of APOE in Early MCI: Structure



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Rate of Change: Role of APOEMain 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

(n=179)

EMCI

(n=190)

LMCI

(n=115)

AD

(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 %) 41 (23%) 77 (41%) 49 (43%) 45 (64%)

Data are number (%) or mean (SD). CDR-SOB = Clinical Dementia Rating-Sum of Boxes. WMS-R = Wechsler Memory Scale-Revised. PET = positron emission tomography.

APOE ε4 allele (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

Recall (WMS-R)

14·94 (3·36) 10·93 (2·81) 8·74 (4·35) 4·20 (3·10)

Logical Memory Delayed

Recall (WMS-R)

14·08 (3·64) 8·87 (1·73) 6·13 (4·38) 1·67 (2·50)

Ramanan et al, submitted


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Influence of APOE


Topography of BCHE Influence on Florbetapir Uptake

R L


p <.05, FWE corrected

Covariates: age, sex, diagnosis and APOE ԑ4 status

ADNI, N=555

Additive Effects of APOE and BCHE



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BuChE in Aβ plaque deposition


Lifestyle & Environmental FactorsWhile the chances of developing Alzheimer's disease are small,from 5% to 15% for people at retirement age or younger, somelifestyle choices and medical conditions can increase the risk.Here's how various factors increase the chances, by percentage, ofdeveloping 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


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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 Progin Neurobiol 2011; and Jack et al Lancet Neurology 2010; 9:119–28.

saykin webinar imaging_genetics_biomarkers_mt_sinai_113012

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