This document summarizes research from the REVEAL studies, which explored the risks and benefits of disclosing genetic risk information for Alzheimer's disease based on APOE genotype. Key findings include: - People generally did not experience long-term psychological harm from receiving risk information. Anxiety and depression scores returned to baseline. - Participants were generally able to recall their risk information accurately over time. - Disclosure did not negatively impact insurance purchasing or health behaviors, and sometimes increased preventative behaviors like exercise. - Condensed education protocols could safely disclose risk information. - Providing additional risk information for cardiovascular disease in addition to Alzheimer's disease further increased preventative behavior changes.

4. Cumulative Risk of Dementia in First-Degree Relatives of Patients with AD 40 50 60 70 80 90 100 0 .1 .2 .3 .4 .5 .6 .7 Age (years) Cumulative Risk Lautenschlager et al, Ann Neurol , 1996 Green et al., JAMA , 2002

5. Farrer et al., JAMA , 1997 Odds of Alzheimer’s Disease by APOE and Age

9. The REVEAL Study Is risk information beneficial or toxic? Empirically measure the benefits and risks of genetic susceptibility testing…

11. Cupples et al. Genetics in Medicine , 2004 Gene Risk

12. Cupples et al., Genetics in Medicine , 2004

13. Cupples et al., Genetics in Medicine , 2004 Christensen et al., Genetics in Medicine , 2008

15. Persons Agreeing to Participate in REVEAL 24% 64% Systematically Ascertained Self Referred Roberts et al. Genetics in Medicine , 2004

17. REVEAL I: Randomized Clinical Trial 301 Participated in Informational Phone Interview 51 Assigned to Receive Risk Assessment Without Genotype Disclosure 111 Assigned to Receive Risk Assessment With Genotype Disclosure 218 Participated in Education Session 183 Participated in Private Counseling and Blood Draw Follow Up at: Six Weeks Six Months Twelve Months 162 Randomized Green et al., NEJM , 2009

18. REVEAL I Study: Mean Anxiety Scale Score Green et al., NEJM , 2009

19. REVEAL I Study: Adjusted Impact of Event Scores Green et al., NEJM , 2010

20. Post-Disclosure Change to Depression Symptoms: 1 year CES-D Score Green et al., NEJM , 2009 0 5 10 15 20 25 30 35 -15 and below -14 to -5 -4 to 4 5 to 14 15 and above Percentage of Cases Change in CES-D from baseline (points) Controls APOE ε 4- APOE ε 4+

22. Would Do Risk Assessment Again… 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Yes No Controls Intervention Group APOE ε 4- APOE ε 4+ Green et al., NEJM , 2009

24. 0% 20% 40% 60% 80% 6 weeks 1 year Accurate Inaccurate Don't Know Recall of Disclosure Information APOE Status (positive or negative) Eckert et al., Genet Med , 2006

25. Recall of Risk Information: Lifetime Risk Figures within 5 Points Eckert et al., Genet Med , 2006 0% 10% 20% 30% 40% 50% 60% 6 weeks 1 year 6 weeks 1 year Accurate Inaccurate Don't Know

27. Insurance Changes 1 Year After APOE Disclosure Zick et al., Health Affairs , 2005 .

29. Health Behavior Changes at 1 Year (Vitamins, Exercise, Medications) * Chao, et al. Alz Dis Assoc Dis , 2008 0% 10% 20% 30% 40% 50% 60% APOE ε 4+ APOE ε 4- Control

30. Health Behavior Changes at 6 Weeks (Nutrition and Supplements) * * Vernarelli et al., in press *

32. 120 Assigned to Extended Protocol 232 Assigned to Condensed Protocol 112 Completed Pre-education Questionnaire 357 Participated in Phone Interview 106 Participated in in-person Education Session 198 Participated in Question and Answer Session, Blood Draw 210 Completed Education Brochure Sent by Mail 217 Completed Pre-education Questionnaire & Medical History 93 Received Risk Assessment/APOE disclosure 101 Participated in Individual Counseling Session, Medical History & Blood Draw 187 Received Risk Assessment/APOE disclosure 352 Randomized Follow-up: 6 Weeks 6 Months 12 Months REVEAL II

33. The REVEAL II Study: Condensed “Education”

34. REVEAL II: Mean Adjusted BAI Scores *Adjusted for age, gender, years of education, baseline CES-D, baseline score (no baseline score for IES)

35. REVEAL II: Mean Adjusted IES Scores *Adjusted for age, gender, years of education, baseline CES-D, baseline score (no baseline score for IES)

37. Among those who accurately recall their risk disclosure (n = 158) 47.5% continue to believe otherwise! Linnenbringer et al., Genetics in Medicine , in press

39. Who did you tell about the results of your test? Ashida et al., J Health Communication , in press.

42. Any Behavior Change No ε 4 ε 4+ % reporting change 45% 57% 48% 77% 0% 100% AD-Only Risk Info AD & CVD Risk Info

43. Exercise Change No ε 4 ε 4+ % reporting change 27% 34% 24% 63% 0% 100% AD-Only Risk Info AD & CVD Risk Info

44. Diet Change No ε 4 ε 4+ % reporting change 27% 33% 28% 53% 0% 100% AD-Only Risk Info AD & CVD Risk Info

45. Mental Exercise Change No ε 4 ε 4+ % reporting change 16% 25% 34% 37% 0% 100% AD-Only Risk Info AD & CVD Risk Info

46. REVEAL IV (2010-2013) Can we combine risk elements of GENOTYPE and PHENOTYPE ? What is the impact of APOE on risk of developing AD in persons with MCI?

47. Data for Risk Estimates in REVEAL IV Petersen et al., NEJM, 2005 .

48. Data for Risk Estimates in REVEAL IV Estimated from primary data provided by Petersen et al.

50. PARADE Magazine! August 23, 2008 Direct to Consumer Marketing (DTC) Molecular genetic testing

51. Personal Genome Testing and Disclosure REVEAL

52. My Navigenics Results

53. APOE-  4 Genotypes in the US Caucasian Population 3/3 (67%) 2/3 (8%) 2/2 (1%) 3/4 (20%) 4/4 (2%) 2/4 (3%)

54. Enriched Research Registry 11,500 (23%) e4/ex 50,000 volunteers 1000 (2%) e4/e4