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  • While experienced Alzheimer's disease centers have can produce accurate clinical diagnoses ~90% of the time, AD is still a diagnosis of exclusion to a certain extent – no completely definitive blood tests, neuroimaging, or nueropsychology work-ups are available
  • Well established gene markers: 3 deteministic mutations (rare) APOE as a susceptibility polymorphism
  • NO significant differences between groups at any time point Mild to moderate clinical depression = 16-26 Severe clinical depression = 27+
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    1. 1. <ul><li>Supported by grants from: </li></ul><ul><li>National Human Genome Research Institute (ELSI) HG/AG-02213 (The REVEAL Study); </li></ul><ul><li>National Institute on Aging AG-09029 (The MIRAGE Study) </li></ul><ul><li>and AG-13846 (BU Alzheimer’s Disease Center) </li></ul>Genetic Research in Dementia: Risk Evaluation & Education for Alzheimer’s Disease Scott Roberts, PhD 1 Robert C. Green, MD, MPH 1,2 Departments of Neurology 1 and Medicine 2 (Genetics Program) Alzheimer’s Disease Center Boston University School of Medicine
    2. 2. Alzheimer’s Disease & Public Health <ul><li>AD is the most common cause of dementia among people age 65 and older. </li></ul><ul><li>An estimated 4.5 million in the US currently have AD. </li></ul><ul><li>Annual costs estimated at $100 billion </li></ul><ul><li>By 2050, 13.2 million older Americans are expected to have AD if current demographic trends continue and no preventive treatments become available. </li></ul>Source: NIA’s “Alzheimer's Disease: Unraveling the Mystery .” <ul><li>High caregiver burden (“death by a thousand subtractions”) </li></ul>
    3. 3. Established Gene Markers for AD Deterministic Mutations: Amyloid Precursor Protein (APP) Presenilin-1 (PS-1) Presenilin-2 (PS-2) Susceptibility Polymorphism: Apolipoprotein E (APOE) Lendon CL, et al. JAMA 1997;277(10):825-831
    4. 4. APOE Genotypes in the General Population
    5. 5. APOE Genotyping for Risk Assessment Why should we NOT do risk assessment for Alzheimer’s disease (at least with APOE)? <ul><li>APOE genotype is not a highly accurate marker </li></ul><ul><li>No progression/prevention intervention available </li></ul><ul><li>Five negative consensus recommendations </li></ul><ul><li>Discrimination or psychological harm may occur </li></ul>
    6. 6. APOE Genotyping for Risk Assessment Why SHOULD we do risk assessment for Alzheimer’s disease (using APOE)? <ul><li>Define at-risk populations for prevention trials </li></ul><ul><li>Identify responsive subgroups </li></ul><ul><li>Respond to clinical requests </li></ul><ul><li>Develop new “clinical technologies” for </li></ul><ul><li>susceptibility markers in common disorders </li></ul>
    7. 7. “ I don’t skate where the puck is. I skate to where it’s going.” - Hockey superstar Wayne Gretzky
    8. 8. Risk Evaluation & Education for AD (The REVEAL Study) <ul><li>An Intervention Trial where </li></ul><ul><li>Information is the Intervention: </li></ul><ul><li>What is the impact of </li></ul><ul><li>genetic risk assessment for </li></ul><ul><li>adult children of people with AD? </li></ul>
    9. 9. <ul><li>Who wants to know? </li></ul><ul><li>What happens to them? </li></ul><ul><li>What do they do? </li></ul>Key Questions
    10. 10. Study Protocol Enrollment Education Blood Draw and Randomization Risk Disclosure and Counseling using family hx, gender, APOE Follow up (6 weeks, 6 months, 12 months) Risk Disclosure and Counseling using family hx, gender alone
    11. 11. Baseline Demographics by Randomization Group Demographic Characteristic 55.3 (9.0); 37-78 Mean Age, yrs. (SD); Range Sex, % female Race/ethnicity, % White Mean yrs of education (SD); Range Marital status, % married No. of affected relatives, % 1 2+ Median income bracket 78.4% 90.2% 16.8 (2.5); 10-22 60.8% 45.1% 54.9% $70K-$99,999 52.0 (10.0); 30-76 69.4% 95.5% 16.7 (2.2); 12-22 66.7% 40.5% 59.5% $70K-$99,999 Control (N = 51) Intervention (N = 111)
    12. 12. Who Wants Genetic Risk Assessment? <ul><li>24% of systematically contacted research registry participants enrolled in the RCT </li></ul><ul><li>80% of Education Session attendees subsequently proceeded to randomization </li></ul><ul><li>Age (younger), education (higher), and gender (female) predicted RCT enrollment </li></ul>Roberts et al., Genetics in Medicine , 2004
    13. 13. Test Uptake Across Diseases Roberts et al., Genetics in Medicine , 2004 10% No Predictive Adulthood Huntington’s disease 4-23% No Carrier screening Childhood Cystic fibrosis 24% No Susceptibility Late adulthood Alzheimer’s disease 30% Yes Susceptibility Adulthood Hereditary nonpolyposis colorectal cancer 43% Yes Susceptibility Adulthood Breast-ovarian cancer 85% Yes Predictive Adulthood Familial adenomatous polyposis Estimated uptake rate Effective prevention/ treatment options? Type of testing Usual age of onset Disorder
    14. 14. Reasons Associated with Test Uptake Women strongly endorsed more reasons for seeking testing than men, p = .01 Roberts et al., ADAD , 2003 2.25 To learn information for family planning 2.52 To arrange long-term care 2.62 To arrange personal affairs 3.33 To prepare family for AD Odds ratio Strongly endorsed reason for seeking testing as predictor of study enrollment
    15. 15. Mean Depression Scores Clinically significant depression
    16. 16. Mean Anxiety Scale Scores Clinically significant anxiety
    17. 17. Mean Impact of Event Scale Scores Clinically significant impact
    18. 18. Changes in Health Behaviors  4+ group >  4- group, p < .05 Most common changes: Adding vitamins (48%) Changing diet (13%) Exercise (6%) 31% 24% 53% Respondents endorsing change to prevent AD Control  4-  4+
    19. 19. Insurance Changes Reported at 12 Month Follow-Up * Zick, Mathews, Roberts et al., Health Affairs , 2005
    20. 20. Conclusions <ul><li>Genetic risk assessment will become increasingly important part of medical care </li></ul><ul><li>Alzheimer’s disease and APOE represent an instructive paradigm </li></ul><ul><li>Need to develop empirically validated methods of disclosing genetic risk information </li></ul>
    21. 21. Acknowledgments/Investigators <ul><li>Boston University </li></ul><ul><li>Robert C. Green, MD, MPH </li></ul><ul><li>Tamsen Brown, MS, CGC </li></ul><ul><li>Dapo Akinleye, MPH </li></ul><ul><li>Lindsay A. Farrer, PhD </li></ul><ul><li>L. Adrienne Cupples, PhD </li></ul><ul><li>George Annas, JD, MPH </li></ul><ul><li>Weill Medical College/Cornell Univ. </li></ul><ul><li>Norman R. Relkin, MD, PhD </li></ul><ul><li>Lisa Ravdin, PhD </li></ul><ul><li>Susan LaRusse, MS, CGC </li></ul><ul><li>Beth Chisholm, MS </li></ul><ul><li>Elana Cox, MS, CGC </li></ul><ul><li>Howard University </li></ul><ul><li>Charmaine Royal, PhD </li></ul><ul><li>Thomas Obesisan, MD </li></ul><ul><li>Grace-Ann Fasaye, ScM </li></ul><ul><li>Case University </li></ul><ul><li>Peter Whitehouse, MD, PhD </li></ul><ul><li>Eric Juengst, PhD </li></ul><ul><li>Melissa J. Barber, ScM </li></ul><ul><li>Stephen Post, PhD </li></ul><ul><li>Indiana University </li></ul><ul><li>Kimberly A. Quaid, PhD </li></ul><ul><li>University of British Columbia </li></ul><ul><li>A. Dessa Sadovnick, PhD </li></ul><ul><li>King’s College, London </li></ul><ul><li>Theresa Marteau, PhD </li></ul><ul><li>Nat’l Human Genome Research Inst. </li></ul><ul><li>Barbara Biesecker, MS </li></ul><ul><li>Elizabeth Thomson, MS, RN </li></ul><ul><li>Duke University </li></ul><ul><li>Robert Cook-Deegan, MD </li></ul>