This document discusses genetics research on Alzheimer's disease. It covers several key points: - Three genes - PSEN1, PSEN2, and APP - are responsible for early-onset Alzheimer's disease in rare familial cases. PSEN1 mutations account for the most cases. - ApoE4 is the strongest genetic risk factor for the more common late-onset Alzheimer's disease. Carriage of one or two ApoE4 alleles increases risk and decreases amyloid clearance. - Genome-wide association studies have identified new genetic loci associated with Alzheimer's risk, including Clusterin and PICALM, though Alzheimer's has a complex genetic architecture. - Ongoing research aims to discover biomarkers, through

1. Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
S
ALZHEIMER’S DISEASE:
GENETIC ASPECTS
SIMON LAWS, PHD.
5TH/6TH OCTOBER 2010

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. 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. 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. 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. 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

8. Proteomics: Data-mining
McCUSKER
RESEARCHFOUNDATION
INC
ALZHEIMER’S
AD: A COMPLEX NEURODEGENERATIVE DISEASE

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

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. 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. 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