What role does Genetics play in Alzheimer’s Disease? Tricia A. Thornton-Wells, Ph.D. Center for Human Genetics Research Vanderbilt University 26 th Annual

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



Genes are instructions for building proteins

(e.g. digestive enzyme)

(e.g. saliva)

(e.g. neurotransmitter)


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


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


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


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


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


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


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


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


Alzheimer Disease Genetics2012

PS1 & PS2: <1%

APOE: ~40%APP: < 1%

Unknown: ~48%

10 “small effect” genes ~10%



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


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


• Tests for Gene X Gene Interactions

• Tests for Gene X Environment Interactions

• Tests for Pathway or Network Effects



• Effect of mitochondrial genome

• Epigenetic changes

• RNA processing


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


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.


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?


Documents

What role does Genetics play in Alzheimer’s Disease? Tricia A. Thornton-Wells, Ph.D. Center for Human Genetics Research Vanderbilt University 26 th Annual