Alzheimer Disclosure by jnr89047

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									        Enrichment of Prevention Trials through
    Genetic Risk Assessment and APOE Disclosure
for Alzheimer’s Disease: Data from the REVEAL Study


                  Robert C. Green, MD, MPH
          Fellow in Genetics, Harvard Medical School
      Professor of Neurology, Genetics and Epidemiology
    Boston University Schools of Medicine and Public Health


                                   Supported by
    National Human Genome Research Institute and National Institute on Aging
                     RO1 HG/AG 02213 (The REVEAL Study)
         National Institute on Aging RO1 AG09029 (The MIRAGE Study),
                  K24 AG027841 and P30 AG13846 (BU ADCC)
     Financial Disclosures in the Past 5 Years


Research Grants:            NIH, Myriad, Elan, Lilly

Speaking (compensated*):    Pfizer, Forest

Advisory (compensated*):    Schering-Plough, GlaxoSmithKline

Advisory (uncompensated):   23andMe, Navigenics, Myriad

Equity:                     None



                                             *less than $5,000/year
 Can prevention trials be enriched through
selection of individuals who are at increased
             genetic risk for AD?

     Can a large sample of APOE e4
heterozygotes or homozygotes be collected
    in order to enrich prevention trials?
         Cumulative Risk of Dementia in
   First-Degree Relatives of Patients with AD

                  .7
                            Relatives of White Probands
                  .6
Cumulative Risk




                  .5        Spouses of White Probands


                  .4

                  .3

                  .2

                  .1

                  0

                       40         50         60           70     80           90         100
                                              Age (years)      Lautenschlager et al, Ann Neurol, 1996
                                                                     Green et al., JAMA, 2002
Odds of Alzheimer’s Disease by
        APOE and Age




                         Farrer et al., JAMA, 1997
Should APOE Genotyping be used for Risk
Assessment in Asymptomatic Individuals?


    • Is it an authentic marker for risk?

          Yes, but it offers only susceptibility information…


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



WOULD YOU LIKE TO KNOW YOUR OWN
   RISK OF DEVELOPING AD????
 APOE Genotyping for Risk Assessment
    Conventional Wisdom in 2000


Why we should NOT do risk assessment
for Alzheimer’s Disease with APOE…


• Psychological harm or discrimination may occur

• No treatment available to prevent AD

• Five (!) consensus conference recommendations
     APOE Genotyping for Risk Assessment
       The REVEAL “Rationale” in 2000

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

     • Define at-risk persons to enrich prevention trials

     • Explore responsive or vulnerable sub-populations

     • Respond to self-interested family members

     • Develop clinical paradigms for the use of
     susceptibility markers in common disorders
              The REVEAL Study



Is risk information beneficial or toxic?

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




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


Risk




       Cupples et al. Genetics in Medicine, 2004
                  Risk of AD by APOE in Women

       100
        90
        80
        70
        60
Risk




        50
        40
        30
        20
        10
         0
             40   45   50   55   60      65     70      75      80      85
                                   Age

                  APOE 34    General Population           First Degree

                                      Cupples et al., Genetics in Medicine, 2004
 Cupples et al., Genetics in Medicine, 2004
Christensen et al., Genetics in Medicine, 2008
REVEAL Questions




Who wants to know?
Persons Agreeing to Participate in REVEAL

 Systematically Ascertained              Self Referred




  24%
                                      64%




                              Roberts et al. Genetics in Medicine, 2004
         REVEAL Questions




What happens to them when they find out?
 REVEAL I: Randomized Clinical Trial
                        301 Participated in
                       Informational Phone
                            Interview



                        218 Participated in
                        Education Session


                    183 Participated in Private
                      Counseling and Blood
                               Draw


                             162
                          Randomized


 51 Assigned to Receive Risk          111 Assigned to Receive Risk
Assessment Without Genotype            Assessment With Genotype
         Disclosure                            Disclosure


                           Follow Up at:
                            Six Weeks
                            Six Months
                          Twelve Months
                                                                Green et al., NEJM, 2009
                REVEAL I Study: Mean Anxiety Scale Score

            8

            7

            6

            5
BAI Score




            4

            3

            2

            1

            0
                     6 week          6 month          12 month
                              GND   GD     GDε4-   GDε4+    Green et al., NEJM, 2009
  REVEAL I Study: Adjusted Impact of Event Scores


            10

             8
IES Score




             6


             4

             2

             0
                 6 week          6 month              12 month

                          GND   GD    GDε4-   GDε4+

                                                           Green et al., NEJM, 2010
                      Post-Disclosure Change to Depression Symptoms:
                                           1 year

                       35

                       30
Percentage of Cases




                                                                               Controls
                       25
                                                                               APOE ε4-
                       20                                                      APOE ε4+

                       15

                       10

                        5

                        0
                            -15 and       -14 to -5      -4 to 4     5 to 14      15 and
                              below                                                above
                                                  CES-D Score
                                      Change in CES-D from baseline (points)
                                                                                Green et al., NEJM, 2009
        REVEAL Questions




Are they satisfied with the information?
       Would Do Risk Assessment Again…


100%
 90%
 80%                          Controls
 70%                          Intervention Group
 60%                          APOE ε4-
 50%                          APOE ε4+
 40%
 30%
 20%
 10%
  0%
            Yes                 No
                                         Green et al., NEJM, 2009
     REVEAL Questions




Can they recall the information?
       Recall of Disclosure Information
      APOE Status (positive or negative)

80%
                                              Accurate
                                              Inaccurate
60%                                           Don't Know



40%



20%



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

40%

30%


20%

10%


 0%
      6 weeks    1 year   6 weeks         1 year


                                    Eckert et al., Genet Med, 2006
          REVEAL Questions




Does the information change their behavior
          (insurance purchasing)?
                              Insurance Changes 1 Year
                                After APOE Disclosure
                             Control     E4 Negative     E4 Positive
                     30%

                     25%
% endorsing change




                     20%

                     15%

                     10%

                     5%

                     0%
                           Health      Life     Disability      LTC
                                                        Zick et al., Health Affairs, 2005.
          REVEAL Questions




Does the information change their behavior
             (health behavior)?
      Health Behavior Changes at 1 Year
      (Vitamins, Exercise, Medications)

60%


50%
            *
40%


30%


20%


10%


 0%
      APOE ε4+     APOE ε4-              Control
                              Chao, et al. Alz Dis Assoc Dis, 2008
     Health Behavior Changes at 6 Weeks
         (Nutrition and Supplements)


40

35
                                                       *
30

25

20

15

10

5

0
       Any Nutritional Change               Supplements

                                ε4-   ε4+
                                               Vernarelli et al., in press
          REVEAL Questions



Can genetic information be disclosed safely
       in an abbreviated manner?
                                    357 Participated in
                                     Phone Interview
REVEAL II
                                    352 Randomized



      120 Assigned to Extended Protocol          232 Assigned to Condensed Protocol


        112 Completed Pre-education                   217 Completed Pre-education
              Questionnaire                          Questionnaire & Medical History


        106 Participated in in-person           210 Completed Education Brochure
             Education Session                            Sent by Mail


101 Participated in Individual Counseling        198 Participated in Question and Answer
 Session, Medical History & Blood Draw                     Session, Blood Draw


    93 Received Risk Assessment/APOE                       187 Received Risk
                disclosure                            Assessment/APOE disclosure


                                        Follow-up:
                                         6 Weeks
                                         6 Months
                                        12 Months
 The REVEAL II Study:
Condensed “Education”
                       REVEAL II: Mean Adjusted BAI Scores

                 4.5
                  4
Mean BAI Score




                 3.5
                  3
                 2.5
                  2
                 1.5
                  1
                                   6 week                               6 month                              12 month

                   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 Scores

                 10
                 9
                 8
Mean IES Score




                 7
                 6
                 5
                 4
                 3
                 2
                 1
                 0
                                  6 week                              6 month                            12 month

                 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 Questions




Does genetic testing change
   self-perceived risk?
Among those who accurately recall their risk disclosure (n = 158)
            47.5% continue to believe otherwise!




                                  Linnenbringer et al., Genetics in Medicine, in press
 REVEAL Questions




Who do people tell about
 their genetic results?
  Who did you tell about the results of your test?


70%

60%          64%

50%                            51%
40%

30%                                          35%

20%

10%                                                                12%

0%
      Family Member      Spouse or        Friends             Health
                      Significant Other                    Professional

                                             Ashida et al., J Health Communication, in press.
REVEAL III: The Impact of Pleiotropic Effects


                          Randomization
                             (n=291)


   Ed, Counsel & Test (n=153)          Ed, Counsel & Test (n=138)
      • Educational Brochure              • Educational Brochure
        • Informed Consent                  • Informed Consent
       • Q&A • Blood Draw                  • Q&A • Blood Draw


   AD-only Risk Assessment          AD Risk Assessment w. CVD Risk
           (n=138)                         Disclosure (n=119)


                    6 Week Follow-Up (n=252)
              12 Month Follow-Up (n=195. In progress)
           REVEAL III: What Were People Told?

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

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

• Those in control arm learn about CVD if they ask
                              Any Behavior Change


100%

                            AD-Only Risk Info
                            AD & CVD Risk Info               77%
       % reporting change




                                          57%
                            45%                  48%




 0%
                                  No ε4                ε4+
                                   Exercise Change


100%

                            AD-Only Risk Info
                            AD & CVD Risk Info
       % reporting change




                                                             63%



                                           34%
                             27%                 24%



 0%
                                   No ε4               ε4+
                                      Diet Change

100%

                            AD-Only Risk Info
                            AD & CVD Risk Info
       % reporting change




                                                                53%


                                           33%
                             27%                    28%




 0%
                                   No ε4                  ε4+
                             Mental Exercise Change


100%

                            AD-Only Risk Info
                            AD & CVD Risk Info
       % reporting change




                                                 34%         37%
                                          25%
                            16%


 0%
                                  No ε4                ε4+
         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?
Data for Risk Estimates in REVEAL IV




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




                Estimated from primary data provided by Petersen et al.
 Can prevention trials be enriched through
selection of individuals who are at increased
             genetic risk for AD?

     Can a large sample of APOE e4
heterozygotes or homozygotes be collected
    in order to enrich prevention trials?
PARADE
  Magazine!

August 23, 2008

   Direct to
  Consumer
  Marketing
    (DTC)

   Molecular
    genetic
    testing
Personal Genome Testing and Disclosure




                                  REVEAL
My Navigenics Results
   APOE-4 Genotypes in the
   US Caucasian Population



               3/3 (67%)




               3/4 (20%)
2/4 (3%)                      2/3 (8%)


    4/4 (2%)               2/2 (1%)
Enriched Research Registry

     50,000 volunteers




    11,500 (23%) e4/ex




     1000 (2%) e4/e4
                       REVEAL Study Collaborators

Boston University               Howard University            Consultants
Robert C. Green, MD, MPH (PI)   Thomas Obisesan, MD, MPH     George Annas, JD, MPH
Susan Hiraki, MS, CGC           Grace-Ann Fasaye, ScM, CGC   Barbara Biesecker, MS
Lindsay A. Farrer, PhD          Charmaine Royal, PhD         Deepak Bhatt, MD
Robert Stern, PhD               Tiffiney Greer, CGC          Deborah Blacker, MD, ScD
L. Adrienne Cupples, PhD                                     Gail Geller, PhD
Tamsen Brown, CGC               Case Western                 Eric Juengst, PhD
Clara Chen, MHS                 Melissa Barber, ScM          Jason Karlawish, MD
Winston Chung                                                Theresa Marteau, PhD
Michael Cassidy                 Peter Whitehouse, MD         Ronald Petersen, PhD, MD
Holly Gooding                                                Kimberly Quaid, PhD
                                Cornell                      Deborah Roter, DrPH
University of Michigan          Normal Relkin, MD, PhD       Eric Topel, MD
Scott Roberts, PhD (Co-PI)      Elana Cox, MS
Erin Linnenbringer, MS, CGC
Kurt Christensen, MPH           Lisa Ravdin, PhD
Wendy Uhlmann, MD, CGC
                                External Advisory Board
                                Robert Cook-Deegan, PhD

								
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