1. 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 Alzheimer’s Disease Symposium Knoxville, TN 14 June 2012

2. Outline Is Alzheimer’s Disease genetic? Early vs. Late-Onset Alzheimer’s Disease What do we know? What are we doing to learn more?

3. 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

4. The building blocks of DNA are arranged into very long strands DNA is organized into genes; and genes into chromosomes © Jonathan L. Haines, 2011

5. Genes are instructions for building proteins ( e.g. digestive enzyme ) ( e.g. saliva) (e.g. neurotransmitter)

6. © Jonathan L. Haines, 2011 Differences in DNA sequence may change the way the protein works Normal protein Abnormal protein ATGACCCGTTA ATGCCCCGTTA

7. 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  plaques Neurofibrillary Tangles with tau

8. 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

9. 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

10. Can we detect it earlier? Shaw et al., 2007

11. © 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

12. © 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

13. © 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

14. © 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

15. © Jonathan L. Haines, 2011 Early Success in Identifying AD Genes 19911995 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. 19 3. Genetic linkage for AD to chr. 14 1993

16. 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

17. © Jonathan L. Haines, 2011 Early Success in Identifying AD Genes 19911995 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. 19 3. Genetic linkage for AD to chr. 14 1993 First susceptibility gene identified Apolipoprotein E (APOE) for late onset AD

18. © Jonathan L. Haines, 2011 APOE We all inherit 2 forms or copies of the APOE gene 2 3 4 BAD COPY it increases risk, and decreases age of onset NEUTRAL COPY it is the most common form neither increases nor decreases risk GOOD COPY it appears to decrease risk, and increases age of onset

19. WWW. ALZGENE.ORG A compendium of published association results 1348 papers 662 genes © Jonathan L. Haines, 2011

20. Alzheimer Disease Genetics 2012 PS1 & PS2: <1% APOE: ~40% APP: < 1% Unknown: ~48% 10 “small effect” genes ~10% © Jonathan L. Haines, 2011

21. Recent “Small Effect” Genetic Findings GeneOdds Ratio GeneOdds Ratio APOE3.20MS4A4A1.14 PICALM1.19CD2AP1.12 EPHA11.19CLU1.12 BIN11.17CD331.12 CR11.16ARID581.08 ABCA71.15

22. 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

23. 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

24. © 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

25. © Jonathan L. Haines, 2011 Effect of mitochondrial genome Epigenetic changes RNA processing New Approaches to Research

26. Tricia A. Thornton-Wells New Approaches to Research

27. 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.

28. 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.

29. © 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

30. Acknowledgements Elisabeth Dykens Sasha Key Tracy McGregor Lynette Henderson John Gore Adam Anderson Bennett Landman Manus Donahue Jonathan Haines Marylyn Ritchie William Bush Lana Olson Lan Jiang Kristin Brown-Gentry Scott Dudek Eric Torstenson Thornton-Wells Lab Genea CrockettJennifer Pryweller Mary Ellen KoranJennifer Vega Laura SloskyTimothy Hohman Funding: NIH P30-HD15052 Vanderbilt CTSA 1-UL1-RR024975 T32 MH075883 VU Discovery Grant

31. Questions?

32. © Jonathan L. Haines, 2011