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Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
S
ALZHEIMER’S DISEASE:
GENETIC ASPECTS
SIMON LAWS, PHD...
Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
ALZHEIMER DISEASE: GENETICS
PSEN1
PSEN2
APP
Other
EARL...
Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
Chromosome: 21q21
~10-15% of EOFAD cases
21 Pathogenic...
Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
Chromosome: 14q24.3
50-60% of EOFAD cases
164 Pathogen...
Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
IMMUNOHISTOCHEMISTRYANALYSIS:
CONTROL,EOADANDLOADSUBJE...
Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
DIAN is a 6 year multicentre study involving 10 sites ...
Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
ALZHEIMER DISEASE: GENETICS
PSEN1
PSEN2
APP
Other
EARL...
Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
AD: A COMPLEX NEURODEGENERATIVE DISEASE
Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
APOLIPOPROTEIN E: GENETIC RISK
*Martins et al., 1995, ...
Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
APOLIPOPROTEIN E: GENETIC RISK
Reiman et al., 2009
Pro...
Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
AD: A COMPLEX NEURODEGENERATIVE DISEASE
Functional Can...
Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
GENOME WIDE ASSOCIATION STUDIES (GWAS)
Harold et al., ...
Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
BIOMARKER DISCOVERY AND THE IDENTIFICATION OF A DIAGNO...
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Alzheimer's disease: Genetic Aspects

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Presentation by Simon Laws PhD on 5th & 6th October 2010

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  • Novel Genetic FactorsCandidate Gene ApproachLinkage StudiesGenome Wide Association Studies
  • Transcript of "Alzheimer's disease: Genetic Aspects"

    1. 1. Proteomics: Data-mining McCUSKER RESEARCHFOUNDATION INC ALZHEIMER’S S ALZHEIMER’S DISEASE: GENETIC ASPECTS SIMON LAWS, PHD. 5TH/6TH OCTOBER 2010
    2. 2. Proteomics: Data-mining McCUSKER RESEARCHFOUNDATION INC ALZHEIMER’S ALZHEIMER DISEASE: GENETICS PSEN1 PSEN2 APP Other EARLY ONSET AD (EOAD) Age at onset < 65 years ≤5% of AD cases Familial (EOFAD) 3 Gene Loci Autosomal Dominant Inheritance
    3. 3. Proteomics: Data-mining McCUSKER RESEARCHFOUNDATION INC ALZHEIMER’S Chromosome: 21q21 ~10-15% of EOFAD cases 21 Pathogenic Mutations (Ex 16/17) - 68 Families 7 21q Genomic Duplications - 8 Families 5 Mutations - Non-pathogenic or unclear AMYLOID PRECURSOR PROTEIN Alzheimer Disease & Frontotemporal Dementia Mutation Database http://www.molgen.ua.ac.be/ADMutations/default.cfm?MT=0&ML=0&Page=Home APP MUTATIONS
    4. 4. Proteomics: Data-mining McCUSKER RESEARCHFOUNDATION INC ALZHEIMER’S Chromosome: 14q24.3 50-60% of EOFAD cases 164 Pathogenic Mutations - 361 Families 5 Mutations - Non-pathogenic or unclear PRESENILIN 1 Alzheimer Disease & Frontotemporal Dementia Mutation Database http://www.molgen.ua.ac.be/ADMutations/default.cfm?MT=0&ML=0&Page=Home PRESENILIN 2 Chromosome: 1q31-q42 <5% of EOFAD cases 10 Pathogenic Mutations - 18 Families 3 Mutations - Non-pathogenic or unclear Presenilin Mutations
    5. 5. Proteomics: Data-mining McCUSKER RESEARCHFOUNDATION INC ALZHEIMER’S IMMUNOHISTOCHEMISTRYANALYSIS: CONTROL,EOADANDLOADSUBJECTS. Control EOAD (PSEN1 Mutation) LOAD Brain Region: Frontal Cortex PSEN1 Mutation – Y256S Age of Onset – 25 yrs A COMMON THEME?
    6. 6. Proteomics: Data-mining McCUSKER RESEARCHFOUNDATION INC ALZHEIMER’S DIAN is a 6 year multicentre study involving 10 sites worldwide. The major aim of the study is: AIM: To collecting and analysing clinical and neuropsychological sequence of changes that occurring in dominantly inherited AD by neuroimaging (MRI, FTD-PET and PIB-PET) and neuropathological testing. REQUIREMENT: The study is seeking to establish a cohort of 400 people who are at high risk of developing autosomal dominant AD. The cost of research is US$10,000 per person every 3 years. STUDY LAYOUT: The study will commence in the second half of 2010 and Each site (of which the Sir James McCusker ADRU is one) will aim to recruit 40 people. Participants will undergo periodic assessments over 6 years, including clinical and neuropsychological assessment, collection of blood and CSF, and neuroimaging. EARLY DIAGNOSIS & BIOMARKERS
    7. 7. Proteomics: Data-mining McCUSKER RESEARCHFOUNDATION INC ALZHEIMER’S ALZHEIMER DISEASE: GENETICS PSEN1 PSEN2 APP Other EARLY ONSET AD (EOAD) Age at onset < 65 years ≤5% of AD cases Familial (EOFAD) 3 Gene Loci Autosomal Dominant Inheritance LATE ONSET AD (LOAD) Age at onset > 65 years ~95% of AD cases Familial Predominantly Sporadic Multiple Gene Loci - Genetic Risk Factors
    8. 8. Proteomics: Data-mining McCUSKER RESEARCHFOUNDATION INC ALZHEIMER’S AD: A COMPLEX NEURODEGENERATIVE DISEASE
    9. 9. Proteomics: Data-mining McCUSKER RESEARCHFOUNDATION INC ALZHEIMER’S APOLIPOPROTEIN E: GENETIC RISK *Martins et al., 1995, NeuroReport; Laws et al., 1999, NeuroReport 0 5 10 15 1/2 2 Odds Ratio* vs. 0: 3.7 vs. 1: 6.2 vs. 0/1: 12.7 vs. 0: 18.8 #ofε4Alleles Zhong, Weisgraber, 2009, J. Biol. Chem. Estimated human genotype frequency of APOE Allele ε2 ε3 ε4 ε2 ~1% ~11% ~2% ε3 ~62% ~22% ε4 ~2% AD: ~43% ~15% All ethnicities http://www.alzgene.org
    10. 10. Proteomics: Data-mining McCUSKER RESEARCHFOUNDATION INC ALZHEIMER’S APOLIPOPROTEIN E: GENETIC RISK Reiman et al., 2009 Proc Natl Acad Sci U S A., 106(16): 6820–6825 Peripheral Clearance of Beta Amyloid following tail vein injection of 20 μg Aβ42 n=5 E3 n=5 E4 n=5 E2 5 min 10 min 15 min 30 min 60 min 90 min Aβ Clearance: ApoE knock-in Mice (8 Wks Old) non-E4E4
    11. 11. Proteomics: Data-mining McCUSKER RESEARCHFOUNDATION INC ALZHEIMER’S AD: A COMPLEX NEURODEGENERATIVE DISEASE Functional Candidate Gene Approach Genome Wide Linkage Studies (Functional & Positional Candidate Gene Approach) Genome Wide Association Studies UNCOVERING NOVEL GENETIC FACTORS
    12. 12. Proteomics: Data-mining McCUSKER RESEARCHFOUNDATION INC ALZHEIMER’S GENOME WIDE ASSOCIATION STUDIES (GWAS) Harold et al., Nature Genetics 41, (2009) Clusterin APOE Locus PICALM
    13. 13. Proteomics: Data-mining McCUSKER RESEARCHFOUNDATION INC ALZHEIMER’S BIOMARKER DISCOVERY AND THE IDENTIFICATION OF A DIAGNOSTIC SIGNATURE AIM: Identify the best biomarker (a substance used as an indicator of a biological state e.g. Alzheimer’s) signature for the diagnosis, prediction and monitoring of Alzheimer’s disease. SIGNIFICANCE: • Early diagnosis or accurate prediction  prevention/treatment strategies initiated when they are most effective • Monitoring response to medical/lifestyle interventions. FUTURE WORK: • Discovery of the optimal panel of biomarkers is likely to require a combined approach. Proteins, Lipids and Genes (‘multi-omic’) • Best chance of capturing the optimal panel of biomarkers. EARLY DIAGNOSIS & BIOMARKERS

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