what role does genetics play in alzheimer’s disease? tricia a. thornton-wells, ph.d. center for...
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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 SymposiumKnoxville, TN14 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
© Jonathan L. Haines, 2011
Genes are instructions for building proteins
(e.g. digestive enzyme)
(e.g. saliva)
(e.g. neurotransmitter)
© Jonathan L. Haines, 2011
Differences in DNA sequence may change the way the protein works
Normal protein
Abnormal protein
ATGACCCGTTA
ATGCCCCGTTA
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.
Blennow K et al. The Lancet, 2006.
A plaquesNeurofibrillaryTangles with tau
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
© Jonathan L. Haines, 2011
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 1995
Early onset genes:Presenilin 1 (PS1) chr. 14
Presenilin 2 (PS2) on chr. 1
1. First AD gene mutation identified
Amyloid Precursor Protein (APP) gene identified on chr. 21 2. Genetic linkage for AD to chr. 193. Genetic linkage for AD to chr. 14
1993
• 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
Alzheimer Disease in Down Syndrome
© Jonathan L. Haines, 2011
Early Success in Identifying AD Genes
1991 1995
Early onset genes:Presenilin 1 (PS1) chr. 14
Presenilin 2 (PS2) on chr. 1
1. First AD gene mutation identified
Amyloid Precursor Protein (APP) gene identified on chr. 21 2. Genetic linkage for AD to chr. 193. Genetic linkage for AD to chr. 14
1993
First susceptibility gene identified Apolipoprotein E (APOE)
for late onset AD
© Jonathan L. Haines, 2011
APOE We all inherit 2 forms or copies of the APOE gene
22
33
44BAD COPY it increases risk, and decreases age of onset
NEUTRAL COPYit is the most common formneither increases nor decreases risk
GOOD COPY it appears to decrease risk, and increases age of onset
WWW. ALZGENE.ORG
A compendium of published association
results
1348 papers
662 genes
© Jonathan L. Haines, 2011
Alzheimer Disease Genetics2012
PS1 & PS2: <1%
APOE: ~40%APP: < 1%
Unknown: ~48%
10 “small effect” genes ~10%
© Jonathan L. Haines, 2011
© Jonathan L. Haines, 2011
Recent “Small Effect” Genetic Findings
Gene Odds Ratio
Gene Odds Ratio
APOE 3.20 MS4A4A 1.14
PICALM 1.19 CD2AP 1.12
EPHA1 1.19 CLU 1.12
BIN1 1.17 CD33 1.12
CR1 1.16 ARID58 1.08
ABCA7 1.15
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
© Jonathan L. Haines, 2011
• Tests for Gene X Gene Interactions
• Tests for Gene X Environment Interactions
• Tests for Pathway or Network Effects
New Approaches to Research
© Jonathan L. Haines, 2011
• Effect of mitochondrial genome
• Epigenetic changes
• RNA processing
New Approaches to Research
Mapping Genotype to Endophenotype
Gene Behavior
Levels of Variation
Cell
Statistical Modeling ofMolecularImagingData
Brain Connectivity
- Diffusion Tensor Imaging
- FunctionalConnectivity Analysis
In Vivo Assays of Variation
Protein
- MolecularImaging
- Expression Microarrays
Brain Structure and Function
- Diffusion Tensor Imaging
- Structural MRI- Functional MRI
- Observation- Surveys- ClinicalAssessment
- Genotyping- Copy number
quantification- Methylation
detection
Tricia A. Thornton-Wells
New Approaches to Research
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
Ongoing Research on Alzheimer Disease
Tricia Thornton-Wells, Ph.D.
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
Research on Dementia in Down Syndrome
Tricia Thornton-Wells, Ph.D.
© Jonathan L. Haines, 2011
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
Acknowledgements
Elisabeth Dykens
Sasha Key
Tracy McGregor
Lynette Henderson
John Gore
Adam Anderson
Bennett Landman
Manus DonahueJonathan Haines
Marylyn Ritchie
William Bush
Lana Olson
Lan Jiang
Kristin Brown-Gentry
Scott Dudek
Eric Torstenson
Thornton-Wells LabGenea Crockett Jennifer
Pryweller
Mary Ellen Koran Jennifer Vega
Laura Slosky Timothy Hohman
Funding: NIH P30-HD15052
Vanderbilt CTSA 1-UL1-RR024975T32 MH075883
VU Discovery Grant
Questions?
© Jonathan L. Haines, 2011