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. 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
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. 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
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
Notas do Editor
Novel Genetic FactorsCandidate Gene ApproachLinkage StudiesGenome Wide Association Studies