1. Neuroethics of Dementia Issues at the beginning & the end of living with Alzheimer’s disease
Jason Karlawish, MD
University of Pennsylvania
Penn Memory Center

2. Disclosures
The research reported in this talk was made possible by grants from the Alzheimers Association and NIA
I am the site PI for a clinical trial supported by NIA and Lilly and NIA and Novartis
I have no paid consulting, no IP or equity

3. Diagnosed,
August 2000
MMSE 27.
This story was published in 2010
MMSE 6.
Died,
March 2015.

4. From a category of disease… … To a continuum of decline
Kim SYH, Karlawish J, & Berkman BE. Ethics of
Genetic and Biomarker Test Disclosures in
Neurodegenerative Disease Prevention Trials.
Neurology 2015.
Karlawish J. How Are We Going To Live With
Alzheimer's Disease? Health Affairs 2014.
Sperling RA, Karlawish J, Johnson KA.
Preclinical Alzheimer disease-the challenges
ahead. Nature Reviews Neurology 2013.
Karlawish J. Addressing the ethical, policy, and
social challenges of pre-clinical Alzheimer's
disease. Neurology 2011.

5. What Are the Cognitive Consequences of Preclinical AD?
Lim et al., Alz Dementia, 2014

6. Surveys of general population about willingness to learn AD gene or biomarker results
79% of 314 telephone survey respondents (random US sample) would take a hypothetical genetic test to predict whether they would eventually develop AD 
45% would take the test if only partially predictive
In the Health and Retirement Study, 60% of 1461 older adults indicated interest in testing that would help them learn about their AD risk 
67% of 2678 adults across US and four European countries were “somewhat” or “very likely” to get a medical test to detect early AD if available 
P.J. Neumann, J.K. Hammitt, C. Mueller, H.M. Fillit, J. Hill, N.A. Tetteh, et al.
Public attitudes about genetic testing for Alzheimer's disease
Health Aff (Millwood), 20 (2001), pp. 252–264
J.S. Roberts, S.J. McLaughlin, C.M. Connell
Public beliefs and knowledge about risk and protective factors for Alzheimer's disease
Alzheimers Dement, 10 (5 Suppl) (2014), pp. S381–S389
E.M. Wikler, R.J. Blendon, J.M. Benson
Would you want to know? Public attitudes on early diagnostic testing for Alzheimer's disease
Alzheimers Res Ther, 5 (2013), p. 43
Neumann. Public attitudes about genetic testing for Alzheimer's disease. Health Aff
Roberts. Public beliefs and knowledge about risk and protective factors for Alzheimer's disease.
Alz Dement
Wikler. Would you want to know? Public attitudes on early diagnostic testing for
Alzheimer's disease. Alzheimers Res Ther

8. March 6, 2015

9. The Anti-Amyloid in Asymptomatic Alzheimer’s Study
Harkins et al. Development of a process to disclose amyloid imaging results to cognitively normal
older adult research participants. Alz Rez Ther. 2015

10. Safety of disclosing amyloid status
Cognitively normal older adults (n=97) in trial testing effects of aerobic exercise on AD biomarkers and cognitive decline
27 elevated amyloid
70 not elevated amyloid
Well-educated, predominately Caucasian
No differences in age, education, sex, race, or family history of dementia by amyloid status
Burns JM, Johnson DK, Liebmann EP, Bothwell RJ, Morris JK, Vidoni ED. Safety of disclosing amyloid status in cognitively normal older adults. Alzheimers Dement doi: /j.jalz PubMed PMID:
Burns JM, Johnson DK, Liebmann EP, Bothwell RJ, Morris JK, Vidoni ED. Safety of disclosing amyloid status in cognitively normal older adults. Alzheimers Dement doi: /j.jalz PubMed PMID:

11. Outcomes Depression (CES-D) & Anxiety (BAI)
both measured at baseline, disclosure, 6 weeks & 6 months post-disclosure
Impact of testing (modified IGT-AD)
measured at 6 weeks & 6 months post-disclosure
Burns JM, Johnson DK, Liebmann EP, Bothwell RJ, Morris JK, Vidoni ED. Safety of disclosing amyloid status in cognitively normal older adults. Alzheimers Dement doi: /j.jalz PubMed PMID:

12. Anxiety and depression symptoms before and after disclosure
Anxiety and depression symptoms before and after disclosure. Data at baseline, immediately postdisclosure (day of disclosure), and 6 weeks and 6 months postdisclosure on the Center for Epidemiologic Studies—Depression Scale (Panel A) and the Beck Anxiety Inventory (Panel B). There was no difference in depressive symptoms across groups over time. A minimal increase in anxiety symptoms was apparent immediately postdisclosure in the amyloid-elevated group but was not sustained over time.

13. Anxiety and depression symptoms before and after disclosure
Anxiety and depression symptoms before and after disclosure. Data at baseline, immediately postdisclosure (day of disclosure), and 6 weeks and 6 months postdisclosure on the Center for Epidemiologic Studies—Depression Scale (Panel A) and the Beck Anxiety Inventory (Panel B). There was no difference in depressive symptoms across groups over time. A minimal increase in anxiety symptoms was apparent immediately postdisclosure in the amyloid-elevated group but was not sustained over time.

14. Test-Related Distress
6 weeks (7.2 vs. 1.8) and 6 months (5.3 vs. 1.9) after disclosure “elevated amyloid” group had higher total IGT-AD scores compared with the “not elevated amyloid”
At 6 months, 84.6% reported “never” regretting obtaining their test result and no one reported “sometimes” or more often regretting obtaining their test result after disclosure
Two amyloid-elevated participants reported “frequent” concerns on IGT-AD items: n = 1 for “worry about risk of AD” and n = 1 for “frustration about lack of AD prevention guidelines”
Burns JM, Johnson DK, Liebmann EP, Bothwell RJ, Morris JK, Vidoni ED. Safety of disclosing amyloid status in cognitively normal older adults. Alzheimers Dement doi: /j.jalz PubMed PMID:

15. Sources of Stigma: Discrimination & Aesthetics
The disease label “AD” was generally not associated with stronger stigmatizing reactions.
Expecting symptoms to get worse, regardless of disease label, stronger endorsement of:
Structural discrimination
Pity
Social distance
Johnson, R., Harkins, K., Cary, M., Sankar, P., & Karlawish, J. (2015). The relative contributions of disease label and disease prognosis to Alzheimer’s stigma: A vignette-based experiment. Social Science & Medicine, 143, 117–127.

16. Sources of Stigma: Pity & Social Distance
Johnson, R., Harkins, K., Cary, M., Sankar, P., & Karlawish, J. (2015). The relative contributions of disease label and disease prognosis to Alzheimer’s stigma: A vignette-based experiment. Social Science & Medicine, 143, 117–127.

17. Correlates of AD stigma: Results
Characteristics and beliefs in the general public related to stigmatizing attributions toward a person with Alzheimer’s disease.
- Females reported more pity but reacted less negatively to poor aesthetic characteristics.
- Adults who believed AD was a mental illness rated symptoms more severely.
Stites,S.D., Johnson, R., Harkins, K., Sankar, P., Xie, D., & Karlawish, J. (2016). Identifiable Characteristics and Potentially Malleable Beliefs Predict Stigmatizing Attributions toward Persons with Alzheimer’s Disease Dementia: Results of a Survey of the U.S. General Public. Health Communication, 1–10.

18. Correlates of AD stigma: Results
Older respondents expected that persons with AD would receive less support, have social interactions limited by others, and face institutional discrimination.
Stites,S.D., Johnson, R., Harkins, K., Sankar, P., Xie, D., & Karlawish, J. (2016). Identifiable Characteristics and Potentially Malleable Beliefs Predict Stigmatizing Attributions toward Persons with Alzheimer’s Disease Dementia: Results of a Survey of the U.S. General Public. Health Communication, 1–10.

19. Correlates of AD stigma: Results
Stites,S.D., Johnson, R., Harkins, K., Sankar, P., Xie, D., & Karlawish, J. (2016). Unpublished.

20. Study Of Knowledge and Reactions to Amyloid Testing
Aim #1: How do cognitively normal adults make
sense of/understand their amyloid PET result?
Aim #2: What is the impact of this knowledge on
social relationships, perceptions of stigma and
discrimination, and perceptions of time, the future?

21. Demographics Characteristic Elevated Amyloid (n=50)
Not Elevated Amyloid
(n=30)
N (%)
Sex
Male
25 (50%)
13 (43%)
Female
17 (57%)
Age
35 (70%)
25 (83%)
≥ 75
15 (30%)
5 (17%)
Race/Ethnicity
Caucasian/non-Hispanic
49 (98%)
28 (93%)
Asian
1 (2%)
Caucasian/Hispanic
1 (3%)
Multiracial/Hispanic
Education
High School
Some College/College Degree
19 (38%)
11 (37%)
Post Graduate Education
30 (60%)
19 (63%)

22. Not Elevated Amyloid (n=30)
Demographics
Characteristic
Elevated Amyloid (n=50)
Not Elevated Amyloid (n=30)
N (%)
Family history of AD
Yes
40 (80%)
21 (70%) No
10 (20%)
8 (27%)
Unknown
1 (3%)
Marital Status
Married/Living with Partner
36 (72%)
26 (83%)
Divorced/Separated
8 (16%)
2 (7%)
Widowed
4 (8%)
Single
2 (4%)
Employment Status
Retired
31 (62%)
20 (67%)
Part-Time
14 (28%)
7 (23%)
Full-Time
5 (10%)
3 (10%)

23. The meaning of your result
Results of “What was the result of your amyloid PET scan?” and “Was that the result you expected?”
Most do not use the terms “elevated” or “not elevated” but variations on “amyloid” & whether it was “present” or “absent,” or some amount along a continuum
If result expected, it was because of a perceived family history or cognitive symptoms, particularly trouble with word finding and memory
Most understood result as placing them at either higher or lower risk of getting AD dementia

24. Ambiguity of amyloid PET scan result
Meaning of amyloid PET scan result Feelings of ambiguity, especially amongst “elevated”
Results
Elevated (n=50)
Not Elevated (n=30) #
Ambiguity of amyloid PET scan result
Difficult to interpret due to absence of scale or baseline
Desires clarification / more Information
Frustration at lack of Information 20 3

25. “How does sharing PET scan result compare to sharing other medical information?”
Results
Elevated
N=50
Not Elevated
N=30
The same 17 7
Different 33 23

26. Copyright © American Psychiatric Association. All rights reserved.
From: Effect of Knowledge of APOE Genotype on Subjective and Objective Memory Performance in Healthy Older Adults
Am J Psychiatry. 2014;171(2): doi: /appi.ajp
Figure Legend:
Scores on Immediate and Delayed Recall From the Logical Memory Subtest for Participants With (ε4+ ) or Without (ε4−) the APOE ε4 Allele Who Knew (Informed) or Did Not Know (Not Informed) Their APOE Genotypeaa Error bars represent standard deviation.
Date of download:
5/20/2014
Copyright © American Psychiatric Association. All rights reserved.

27. “How does your memory compare to others your age
“How does your memory compare to others your age?” “Did learning your PET scan result change how you feel about your memory?”
Elevated (n=50)
Not Elevated
(n=30)
CODE #
More aware of memory & memory issues 18
Previously felt fine – No change 14 13
Previously felt impaired/at risk – No change 10 1
Previously felt impaired/at risk – Confirmation/explanation 8
Previously felt impaired/at risk – Reinterpreted in light of result, relieved anxiety 16

29. Summary Points
The diagnosis of AD is transforming from one based on clinical pathological correlation to one based on clinical actuarial correlation. 
From a diagnosis that explains a problem, to a diagnosis that explains the future (think hypertension).
The field will likely divide about what to call AD: described by the pathology (amyloidosis, tauopathy), the severity of cognitive impairment, and whether a state of the disease is a stage of disease or a risk factor (preclinical AD versus asymptomatic at risk for AD).
A biomarker based diagnosis will undermine who is “normal”

30. Summary Points
People who have symptoms of cognitive problems or a family history have an expectation of an elevated amyloid result
People who have an elevated result want more specificity – less ambiguity – than the category. How much amyloid is a trope for how much risk of getting Alzheimer’s disease dementia.
If we educate people about the testing and assess well-being and readiness, they generally tolerate the information. It does not cause a catastrophic reaction.

31. Summary Points
The information does cause people to decide who to tell (family, friends, co-workers) and what to tell them. They may experience stigma and a change in their sense of the future,
As therapies carve out the disease in a pre-clinical stage, we may change our sense of when a person is dying of the disease, shifting the experience “leftward.”

32. Practicing Palliative Care
Karlawish et al. A consensus-based approach to providing palliative care to
Patients who lack decision-making capacity. Annals Int Med. 1999; 130:

33. Steps to providing palliative care to patients who lack decision-making capacity

34. Steps to providing palliative care to patients who lack decision-making capacity

35. “Soon she developed
a rapid loss of memory...”
“…only a tangle of fibrils indicates the place
where a neuron was previously located.”

36. Diagnosed
August 2000
MMSE 27
This story ran 2010
MMSE 6
Died
March 2015

39. Coming Soon: The New www.makingsenseofalzheimers.org