Transcript 4 Thornton Wells

What role does Genetics play in
Alzheimer’s Disease?
Tricia A. Thornton-Wells, Ph.D.
Center for Human Genetics Research
Vanderbilt University
26th Annual Alzheimer’s Disease Symposium
Knoxville, TN
14 June 2012
Outline
• Is Alzheimer’s Disease genetic?
• Early vs. Late-Onset Alzheimer’s Disease
• What do we know?
• What are we doing to learn more?
What are genes?
• Our body’s blueprint and instructions
• Arranged like beads on a string
• Produce proteins that determine how we
grow and develop
• Come in pairs (one from each parent)
• Humans have ~30,000 genes
© Jonathan L. Haines, 2011
The building
blocks of DNA are
arranged into very
long strands
DNA is
organized into
genes; and
genes into
chromosomes
© Jonathan L. Haines, 2011
Genes are instructions for
building proteins
(e.g. saliva)
(e.g. digestive enzyme)
(e.g. neurotransmitter)
© Jonathan L. Haines, 2011
Differences in DNA sequence may
change the way the protein works
Normal protein
ATGACCCGTTA
Abnormal protein
ATGCCCCGTTA
© Jonathan L. Haines, 2011
Is it really Alzheimer Disease?
• Alzheimer disease can only
diagnosed with an autopsy or
brain biopsy
• Clinical diagnosis is correct
80-90% of the time when
made by an Alzheimer
disease expert.
A plaques
Neurofibrillary
Tangles with tau
Blennow K et al. The Lancet, 2006.
Alzheimer Disease
• Senile plaques are necessary
– But probably not sufficient
• Plaques might trigger brain
inflammation
– Not everyone responds the same way
• Genetic or lifestyle factors might alter
risk for AD
Alzheimer Disease
• Few treatments for Alzheimer disease
– All are most effective early on
• Brain changes begin > 10 years
before symptoms begin
• Early identification of brain changes is
key to providing treatment and
life planning
Can we detect it earlier?
Shaw et al., 2007
Impact of Alzheimer Disease
• Affects about 5 million people in the U.S.
• Prevalence doubles every 5 years after age 60
– Approaching 50% in those age 85 & older
• Most common cause of dementia in older adults
– Early onset (<60 years)
<10%
– Late onset (>60 years)
>90%
• Occurs worldwide, in multiple ethnic groups
• In the U.S., higher prevalence in African Americans and
Hispanic Americans than European Americans
© Jonathan L. Haines, 2011
The Genetic Epidemiology of
Alzheimer Disease
• Some rare large families, the high prevalence of AD
• Identification of the first rare genetic mutation in AD in 1991
• Family and twin studies support a strong genetic role
– Estimates are variable
– Heritability ~40-60%
• (Unknown) environmental factors may play a significant
role in AD
© Jonathan L. Haines, 2011
Strategies for Finding
Alzheimer Disease Genes
• Large multigenerational families
– Rare early onset families were the first to be studied
• Smaller families
– Usually only siblings
• Large case-control datasets
• Large population-based datasets
– Usually longitudinal studies of healthy older individuals
© Jonathan L. Haines, 2011
Strategies for Finding
Alzheimer Disease Genes
• Broad Search: Genome Screens (by Location)
– Find genes based on inheritance in families
– Look for chromosomal regions shared in common among affected
individuals within a family
• Targeted Search: Candidate Genes (by Function)
– Use what we know about the biology of the disease
– Find variations in a gene more often in affected individuals than in
healthy individuals
© Jonathan L. Haines, 2011
Early Success in Identifying AD Genes
1991
First AD gene mutation
identified
Amyloid Precursor Protein (APP)
gene identified on chr. 21
2. Genetic linkage for AD to chr. 19
3. Genetic linkage for AD to chr. 14
1993
1995
1.
Early onset genes:
Presenilin 1 (PS1) chr. 14
Presenilin 2 (PS2) on chr. 1
© Jonathan L. Haines, 2011
Alzheimer Disease
in Down Syndrome
• Early onset (3 copies of APP)
• By 40 years, Alzheimer-type senile
plaques in the brain
• 75% affected by age 65 years
• Depression & personality changes
precede dementia, perhaps more often
in Down syndrome
www.denverdsclinic.org
Early Success in Identifying AD Genes
First susceptibility gene identified
Apolipoprotein E (APOE)
for late onset AD
1991
First AD gene mutation
identified
Amyloid Precursor Protein (APP)
gene identified on chr. 21
2. Genetic linkage for AD to chr. 19
3. Genetic linkage for AD to chr. 14
1993
1995
1.
Early onset genes:
Presenilin 1 (PS1) chr. 14
Presenilin 2 (PS2) on chr. 1
© Jonathan L. Haines, 2011
APOE
We all inherit 2 forms or copies of the APOE gene
2
GOOD COPY
it appears to decrease risk, and
increases age of onset
3
NEUTRAL COPY
it is the most common form
neither increases nor decreases risk
4
BAD COPY
it increases risk, and
decreases age of onset
© Jonathan L. Haines, 2011
1348
papers
A compendium
of published
association
results
662
genes
WWW. ALZGENE.ORG
© Jonathan L. Haines, 2011
Alzheimer Disease Genetics
2012
PS1 & PS2: <1%
10 “small effect” genes ~10%
Unknown: ~48%
APOE: ~40%
APP: < 1%
© Jonathan L. Haines, 2011
Recent “Small Effect”
Genetic Findings
Gene
APOE
PICALM
EPHA1
BIN1
CR1
ABCA7
Odds
Ratio
3.20
1.19
1.19
1.17
1.16
1.15
Gene
MS4A4A
CD2AP
CLU
CD33
ARID58
Odds
Ratio
1.14
1.12
1.12
1.12
1.08
© Jonathan L. Haines, 2011
New Approaches to Research
Alzheimer Disease Genetics
Consortium (ADGC)
• Assembled 13 different datasets from many different
individual researchers across the U.S.
• 11,840 cases and 10, 931 controls
• Largest combined dataset to date
• Supported primarily by the National Institute on Aging
(NIA/NIH)
• Also support from the Alzheimer Association
New Approaches to Research
International Genetics of Alzheimer
Disease Project (IGAP)
• Bring together the expertise and resources of many
different Alzheimer disease research groups
– Consolidate and harmonize sample collections
– Integrate expertise in diagnosis, genetics, epidemiology,
analysis
– Generally working to combine data in phases
• Phase 1: Analysis of existing GWAS data
• Phase 2: Genotyping and analysis of additional datasets
New Approaches to Research
• Tests for Gene X Gene Interactions
• Tests for Gene X Environment
Interactions
• Tests for Pathway or Network Effects
© Jonathan L. Haines, 2011
New Approaches to Research
• Effect of mitochondrial genome
• Epigenetic changes
• RNA processing
© Jonathan L. Haines, 2011
New Approaches to Research
Mapping Genotype to Endophenotype
Levels of Variation
Gene
- Genotyping
- Copy number
quantification
- Methylation
detection
Protein
- Molecular
Imaging
- Expression
Microarrays
Cell
Statistical
Modeling of
Molecular
Imaging
Data
Brain Structure
and Function
- Diffusion Tensor
Imaging
- Structural MRI
- Functional MRI
Brain
Connectivity
- Diffusion Tensor
Imaging
- Functional
Connectivity
Analysis
Behavior
- Observation
- Surveys
- Clinical
Assessment
In Vivo Assays of Variation
Tricia A. Thornton-Wells
Ongoing Research
on Alzheimer Disease
MRI Study of brain structure and function
Participants needed:
• Adults 30-75 years of age with Down Syndrome
• Adults 50+ years with Family History or Symptoms
• Adults 65+ years with Normal Cognition
2 or 3 visits:
~ 5 hours total
*Longitudinal study over 3 years
van Rooden S et al., Radiology 2009
Haris et al. J Neuroimaging 2010
Tricia Thornton-Wells, Ph.D.
Research on Dementia
in Down Syndrome
MRI Study of brain structure and function
Participants needed: Adults 30-75 years of age with DS
2 or 3 visits:
~ 5 hours total
*Longitudinal study over 3 years
•
Also looking for genetic factors that protect from Alzheimer
disease
Tricia Thornton-Wells, Ph.D.
Reasons To Be
Optimistic
• We’ve already been
successful
• Collaborative efforts
and greatly increased
sample sizes
• New enabling
technologies
• New study designs
Bettens, K. et al. Hum. Mol. Genet. 2010
Thanks to my students, post-docs, lab members, collaborators, dedicated
researchers, and the individuals and families throughout the world who have made
this progress possible
© Jonathan L. Haines, 2011
Acknowledgements
Thornton-Wells Lab
Genea Crockett
Mary Ellen Koran
Laura Slosky
Jonathan Haines
Marylyn Ritchie
William Bush
Lana Olson
Lan Jiang
Kristin Brown-Gentry
Scott Dudek
Eric Torstenson
Jennifer Pryweller
Jennifer Vega
Timothy Hohman
John Gore
Adam Anderson
Bennett Landman
Manus Donahue
Funding:
NIH P30-HD15052
Vanderbilt CTSA 1-UL1-RR024975
T32 MH075883
VU Discovery Grant
Elisabeth Dykens
Sasha Key
Tracy McGregor
Lynette Henderson
Questions?
© Jonathan L. Haines, 2011