Alzheimer

Supported bySupported byNational Human Genome Research Institute and National Institute on AgingNational Human Genome Research Institute and National Institute on Aging

RO1 HG/AG 02213 (The REVEAL Study)RO1 HG/AG 02213 (The REVEAL Study)National Institute on Aging RO1 AG09029 (The MIRAGE Study), National Institute on Aging RO1 AG09029 (The MIRAGE Study),

K24 AG027841 and P30 AG13846 (BU ADCC)K24 AG027841 and P30 AG13846 (BU ADCC)

Enrichment of Prevention Trials throughEnrichment of Prevention Trials throughGenetic Risk Assessment and APOE DisclosureGenetic Risk Assessment and APOE Disclosure

for Alzheimer’s Disease: Data from the REVEAL Studyfor Alzheimer’s Disease: Data from the REVEAL Study

Robert C. Green, MD, MPHRobert C. Green, MD, MPHFellow in Genetics, Harvard Medical SchoolFellow in Genetics, Harvard Medical School

Professor of Neurology, Genetics and EpidemiologyProfessor of Neurology, Genetics and EpidemiologyBoston University Schools of Medicine and Public HealthBoston University Schools of Medicine and Public Health

Financial Disclosures in the Past 5 YearsFinancial Disclosures in the Past 5 Years

Research Grants: Research Grants: NIH, Myriad, Elan, LillyNIH, Myriad, Elan, Lilly

Speaking (compensated*): Speaking (compensated*): Pfizer, ForestPfizer, Forest

Advisory (compensated*): Advisory (compensated*): Schering-Plough, GlaxoSmithKline Schering-Plough, GlaxoSmithKline

Advisory (uncompensated): Advisory (uncompensated): 23andMe, Navigenics, Myriad23andMe, Navigenics, Myriad

Equity: Equity: NoneNone

*less than $5,000/year*less than $5,000/year

Can prevention trials be enriched through selection of Can prevention trials be enriched through selection of individuals who are at increased genetic risk for AD?individuals who are at increased genetic risk for AD?

Can a large sample of APOE e4 heterozygotes or Can a large sample of APOE e4 heterozygotes or homozygotes be collected in order to enrich homozygotes be collected in order to enrich

prevention trials?prevention trials?

Cumulative Risk of Dementia in Cumulative Risk of Dementia in First-Degree Relatives of Patients with ADFirst-Degree Relatives of Patients with AD

40 50 60 70 80 90 100

0

.1

.2

.3

.4

.5

.6

.7

Age (years)

Cu

mu

lati

ve R

isk

Relatives of White Probands

Spouses of White Probands

Lautenschlager et al, Lautenschlager et al, Ann NeurolAnn Neurol, 1996, 1996Green et al., Green et al., JAMAJAMA, 2002, 2002

Farrer et al., JAMA, 1997

Odds of Alzheimer’s Disease by Odds of Alzheimer’s Disease by APOE and AgeAPOE and Age

Should APOE Genotyping be used for Risk Should APOE Genotyping be used for Risk Assessment in Assessment in Asymptomatic IndividualsAsymptomatic Individuals??

• Is it an authentic marker for risk?Is it an authentic marker for risk?

Yes, but it offers only susceptibility information…Yes, but it offers only susceptibility information…

• Do people want to know their risk of developing AD?Do people want to know their risk of developing AD?

WOULD YOU LIKE TO KNOW YOUR OWN WOULD YOU LIKE TO KNOW YOUR OWN RISK OF DEVELOPING AD????RISK OF DEVELOPING AD????

APOE Genotyping for Risk AssessmentAPOE Genotyping for Risk AssessmentConventional Wisdom in 2000Conventional Wisdom in 2000

Why we should Why we should NOTNOT do risk assessment do risk assessment for Alzheimer’s Disease with APOE…for Alzheimer’s Disease with APOE…

• Psychological harm or discrimination may occurPsychological harm or discrimination may occur

• No treatment available to prevent ADNo treatment available to prevent AD

• Five (!) consensus conference recommendationsFive (!) consensus conference recommendations

APOE Genotyping for Risk AssessmentAPOE Genotyping for Risk AssessmentThe REVEAL “Rationale” in 2000The REVEAL “Rationale” in 2000

Why we should Why we should EXPLOREEXPLORE risk assessment for Alzheimer’s risk assessment for Alzheimer’s Disease using APOE…Disease using APOE…

• Define at-risk persons to enrich prevention trialsDefine at-risk persons to enrich prevention trials

• Explore responsive or vulnerable sub-populationsExplore responsive or vulnerable sub-populations

• Respond to self-interested family membersRespond to self-interested family members

• Develop clinical paradigms for the use of Develop clinical paradigms for the use of susceptibility markers in common disorderssusceptibility markers in common disorders

The REVEAL StudyThe REVEAL Study

Is risk information beneficial or toxic? Is risk information beneficial or toxic?

Empirically measure the benefits and risks of Empirically measure the benefits and risks of genetic susceptibility testing…genetic susceptibility testing…

REVEAL QuestionsREVEAL Questions

How can we clearly communicate risk How can we clearly communicate risk information based on genetics?information based on genetics?

Cupples et al. Genetics in Medicine, 2004

Gene

Risk

Risk of AD by APOE in Women

0102030405060708090

100

40 45 50 55 60 65 70 75 80 85

Age

Ris

k

APOE 34 General Population First Degree

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

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


Who wants to know?Who wants to know?

24%

64%

Systematically Ascertained Self Referred

Persons Agreeing to Participate in REVEAL

Roberts et al. Roberts et al. Genetics in MedicineGenetics in Medicine, 2004, 2004


What happens to them when they find out?What happens to them when they find out?

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 inEducation Session

183 Participated in Private Counseling and Blood

Draw

Follow Up at:Six WeeksSix Months

Twelve Months

162 Randomized

Green et al., NEJM, 2009

REVEAL I Study: Mean Anxiety Scale ScoreREVEAL I Study: Mean Anxiety Scale Score

0

1

2

3

4

5

6

7

8

6 week 6 month 12 month

BA

I Sco

re

GND GD GDε4- GDε4+Green et al., NEJM, 2009

REVEAL I Study: Adjusted Impact of Event Scores

0

2

4

6

8

10


IES

Sco

re

GND GD GDε4- GDε4+


Post-Disclosure Change to Depression Symptoms: Post-Disclosure Change to Depression Symptoms: 1 year1 year

0

5

10

15

20

25

30

35

-15 andbelow

-14 to -5 -4 to 4 5 to 14 15 andabove

Per

cen

tag

e o

f C

ases

Change in CES-D from baseline (points)

Controls

APOE ε4-

APOE ε4+

CES-D ScoreGreen et al., NEJM, 2009


Are they satisfied with the information?Are they satisfied with the information?

Would Do Risk Assessment Again…Would Do Risk Assessment Again…

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Yes No

Controls

Intervention Group

APOE ε4-

APOE ε4+



Can they recall the information?Can they recall the information?

0%

20%

40%

60%

80%

6 weeks 1 year

Accurate

Inaccurate

Don't Know

Recall of Disclosure InformationRecall of Disclosure InformationAPOE Status (positive or negative)APOE Status (positive or negative)

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

Recall of Risk Information:Recall of Risk Information:Lifetime Risk Figures within 5 PointsLifetime Risk Figures within 5 Points

Eckert et al., Genet Med, 2006


Does the information change their behavior Does the information change their behavior (insurance purchasing)?(insurance purchasing)?

Insurance Changes 1 YearAfter APOE Disclosure

0%

5%

10%

15%

20%

25%

30%

% e

nd

ors

ing

ch

an

ge

Health Life Disability LTC

Control E4 Negative E4 Positive

Zick et al., Health Affairs, 2005.


Does the information change their behavior Does the information change their behavior (health behavior)?(health behavior)?

Health Behavior Changes at 1 YearHealth Behavior Changes at 1 Year(Vitamins, Exercise, Medications)(Vitamins, Exercise, Medications)

0%

10%

20%

30%

40%

50%

60%

APOE ε4+ APOE ε4- Control

*

Chao, et al. Alz Dis Assoc Dis, 2008

0

5

10

15

20

25

30

35

40

Any Nutritional Change Supplements

ε4- ε4+

*

0

5

10

15

20

25

30

35

40


ε4- ε4+

*

0

5

10

15

20

25

30

35

40


ε4- ε4+

*

Health Behavior Changes at 6 WeeksHealth Behavior Changes at 6 Weeks(Nutrition and Supplements)(Nutrition and Supplements)

Vernarelli et al., in pressVernarelli et al., in press


Can genetic information be disclosed safely Can genetic information be disclosed safely in an abbreviated manner?in an abbreviated manner?

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 Weeks6 Months

12 Months

REVEAL II

The REVEAL II Study: The REVEAL II Study: Condensed “Education”Condensed “Education”

REVEAL II: Mean Adjusted BAI ScoresREVEAL II: Mean Adjusted BAI Scores

1

1.5

2

2.5

3

3.5

4

4.5


Mea

n B

AI S

core

Extended ε4- Condensed ε4+ Extended ε4- Condensed ε4+

*Adjusted for age, gender, years of education, baseline CES-D, baseline score (no baseline score for IES)

REVEAL II: Mean Adjusted IES ScoresREVEAL II: Mean Adjusted IES Scores

0

1

2

3

4

5

6

7

8

9

10


Mea

n IE

S S

core

Extended ε4- Condensed ε4+ Extended ε4- Condensed ε4+

*Adjusted for age, gender, years of education, baseline CES-D, baseline score (no baseline score for IES)


Does genetic testing change Does genetic testing change

self-perceived risk?self-perceived risk?

Among those who accurately recall their risk disclosure (n = 158)Among those who accurately recall their risk disclosure (n = 158)47.5% continue to believe otherwise!47.5% continue to believe otherwise!

Linnenbringer et al., Linnenbringer et al., Genetics in MedicineGenetics in Medicine, in press, in press


Who do people tell about Who do people tell about

their genetic results?their genetic results?

Who did you tell about the results of your test?

64%

51%

35%

12%

0%

10%

20%

30%

40%

50%

60%

70%

Family Member Spouse orSignificant Other

Friends HealthProfessional

Ashida et al., Ashida et al., J Health CommunicationJ Health Communication, in press., in press.

REVEAL III: The Impact of Pleiotropic EffectsREVEAL III: The Impact of Pleiotropic Effects

AD-only Risk Assessment(n=138)

Randomization(n=291)

Ed, Counsel & Test (n=153)• Educational Brochure

• Informed Consent• Q&A • Blood Draw

AD Risk Assessment w. CVD Risk Disclosure (n=119)

Ed, Counsel & Test (n=138)• Educational Brochure

• Informed Consent• Q&A • Blood Draw

6 Week Follow-Up (n=252)12 Month Follow-Up (n=195. In progress)

REVEAL III: What Were People Told?REVEAL III: What Were People Told?

At ConsentAt Consent

• “…“…Your APOE genotype can also give us some general information Your APOE genotype can also give us some general information about the chance for you to develop cardiovascular (heart) disease in the about the chance for you to develop cardiovascular (heart) disease in the future…”future…”

During Disclosure (& Boosters)During Disclosure (& Boosters)

• ““In addition to Alzheimer’s disease, APOE has been found to be In addition to Alzheimer’s disease, APOE has been found to be connected to heart disease. Some studies have shown that people who connected to heart disease. Some studies have shown that people who carry e4 also have a higher risk of developing heart disease. Potential carry e4 also have a higher risk of developing heart disease. Potential strategies to reduce the risk of coronary artery disease associated with strategies to reduce the risk of coronary artery disease associated with e4 include smoking cessation, a healthy diet, weight loss, treatment of e4 include smoking cessation, a healthy diet, weight loss, treatment of elevated cholesterol, and exercise (with your doctor’s permission).”elevated cholesterol, and exercise (with your doctor’s permission).”

• Those in control arm learn about CVD if they askThose in control arm learn about CVD if they ask

Any Behavior ChangeAny Behavior Change

No ε4 ε4+

% r

epo

rtin

g c

han

ge

45%

57%

48%

77%

0%

100%

AD-Only Risk InfoAD & CVD Risk Info

Exercise ChangeExercise Change

No ε4 ε4+

% r

epo

rtin

g c

han

ge

27%34%

24%

63%

0%

100%


Diet ChangeDiet Change

No ε4 ε4+

% r

epo

rtin

g c

han

ge

27%33%

28%

53%

0%

100%


Mental Exercise ChangeMental Exercise Change

No ε4 ε4+

% r

epo

rtin

g c

han

ge

16%

25%34% 37%

0%

100%


REVEAL IV (2010-2013)REVEAL IV (2010-2013)

Can we combine risk elements of Can we combine risk elements of GENOTYPE GENOTYPE and and PHENOTYPEPHENOTYPE? ?

What is the impact of APOE on risk of developing What is the impact of APOE on risk of developing AD in persons with MCI?AD in persons with MCI?

Data for Risk Estimates in REVEAL IVData for Risk Estimates in REVEAL IV

Petersen et al., Petersen et al., NEJM, 2005NEJM, 2005..

Data for Risk Estimates in REVEAL IVData for Risk Estimates in REVEAL IV

Estimated from primary data provided by Petersen et al.Estimated from primary data provided by Petersen et al.

Can prevention trials be enriched through selection of Can prevention trials be enriched through selection of individuals who are at increased genetic risk for AD?individuals who are at increased genetic risk for AD?

Can a large sample of APOE e4 heterozygotes or Can a large sample of APOE e4 heterozygotes or homozygotes be collected in order to enrich homozygotes be collected in order to enrich

prevention trials?prevention trials?

PARADEMagazine!

August 23, 2008

Direct toConsumerMarketing

(DTC)

Moleculargenetictesting

Personal Genome Testing and Disclosure

REVEAL

My Navigenics ResultsMy Navigenics Results

APOE-4 Genotypes in the US Caucasian Population

3/3 (67%)3/3 (67%)

2/3 (8%)2/3 (8%)

2/2 (1%)2/2 (1%)

3/4 (20%)3/4 (20%)

4/4 (2%)4/4 (2%)

2/4 (3%)

Enriched Research Registry

11,500 (23%) e4/ex11,500 (23%) e4/ex

50,000 volunteers50,000 volunteers

1000 (2%) e4/e41000 (2%) e4/e4

REVEAL Study Collaborators

ConsultantsGeorge Annas, JD, MPHBarbara Biesecker, MSDeepak Bhatt, MDDeborah Blacker, MD, ScDGail Geller, PhDEric Juengst, PhDJason Karlawish, MDTheresa Marteau, PhDRonald Petersen, PhD, MDKimberly Quaid, PhD Deborah Roter, DrPHEric Topel, MD

Boston UniversityRobert C. Green, MD, MPH (PI)Susan Hiraki, MS, CGCLindsay A. Farrer, PhDRobert Stern, PhDL. Adrienne Cupples, PhDTamsen Brown, CGCClara Chen, MHSWinston ChungMichael CassidyHolly Gooding

University of MichiganScott Roberts, PhD (Co-PI)Erin Linnenbringer, MS, CGCKurt Christensen, MPHWendy Uhlmann, MD, CGC

Howard UniversityThomas Obisesan, MD, MPH Grace-Ann Fasaye, ScM, CGC Charmaine Royal, PhDTiffiney Greer, CGC

Case Western

Melissa Barber, ScM

Peter Whitehouse, MD

Cornell

Normal Relkin, MD, PhD

Elana Cox, MS

Lisa Ravdin, PhD

External Advisory BoardRobert Cook-Deegan, PhD

Documents

Alzheimer