National Press Foundation

Washington, DC
December 7, 2010

Ethics in Alzheimer's Disease: New diagnostic

criteria, new biomarkers, new challenges

Steven T. DeKosky, MD
James Carroll Flippin Professor of Medical Science
Vice President and Dean
University of Virginia School of Medicine
Charlottesville, VA USA
 Disclosures
Consultant/Advisory Boards :
Bristol Myers Squibb, Eisai, Lilly, Merck, Novartis, Pfizer, PsychoGenics

Off-Label Discussion:
– None

Special acknowledgements:
Stephen Post, Stony Brook University
Robert Green, Boston University
 Categories of Ethics Questions in
AD (and other late life dementias)
• Moral, cultural and socio-political issues
• Respect and autonomy
– balance of responsibility to individual vs. society, e.g., driving
privileges

• End of Life Care

– Comfort, feeding, withholding nutrition or water

• Diagnosis and Truthtelling

• The Role of Biomarkers
– Confirmation of Diagnosis, Earlier Diagnosis, Risk Assessment in
Normals
Increasing Global Burden of AD:
Cultures differ in their dealing with dementia
 Moral, Cultural, and Socio-Political Issues

• Affirmation of and respect for people with AD and other disorders

involving loss of self (e.g., “deeply forgetful”)
– Example, South Korea efforts to honor people with dementia
– Justice and protection
• Whose responsibility are the Deeply Forgetful? Family? Society?
Government?
– South Korea’s view… all of them
• Respite for family caregivers
– Increased morbidity and mortality
• Ethicists: Cultivate a ‘culture of acceptance’
– The glass is half full (celebrate what is still available to others, not continue to
mourn for what is lost)
 Biomarkers

• Diagnostic Confirmation
• Increased Accuracy in MCI
• Risk Assessment in Asymptomatic People

• What are they? How should they be used?

Research or general availability?
 Natural History of
Neurodegenerative Disorders
Preclinical Symptomatic

Diagnosis
Neuronal Function

Clinical Ratings
Time

Model for the progression of loss of neuronal function in neurodegenerative

disorders. There is a prolonged period during which loss of neuronal function has
occurred but symptoms have not yet appeared.

DeKosky ST, Marek K. Science. 2003;302:830-834.

 Alzheimer’s Disease: Course,
Prevention, Treatment Strategies

Pre- Mild
Clinical Normal symptomatic Cognitive AD
State AD Impairment

Disease Progression
 Linking Clinical Symptoms With
Degree of Pathology
Secondary
Primary
Intervention Prevention/ Treatment
Prevention
Early Tx
Pre- Mild
Clinical Normal symptomatic Cognitive AD
State AD Impairment

Brain No Disease Early Brain AD Brain Mild,

Pathologic No Symptoms Changes Changes Moderate, or
State No Mild Severe
Symptoms Symptoms Impairment

Disease Progression
 Types of Biomarkers

• Genetic
– "Risk alleles" e.g. ApoLiprotein E; APOE
• Biochemical
– CSF Beta amyloid, tau, phosph-tau
• Neuroimaging
– MRI, FDG-PET, amyloid imaging
APOE and Alzheimer’s Disease
ALLELE FREQUENCY:
normal population: in AD:

E2 7% 7%
E3 79% 40-50%
E4 14% 40-50%

Potential mechanisms:
Impaired removal of beta amyloid
Diminished neural regeneration
Allele frequency twice as high in Africans
& African Americans as in Caucasians
 Genetic Biomarkers
• APOE is the major risk gene in AD
• REVEAL study, now 10 years on, has
tracked individuals views and reactions
to have genetic status “revealed.”
• Results benign thus far
• No other genes of near-equal power
are likely to be discovered
 REVEAL Conclusions
• Disclosure of APOE does not seem harmful
– may actually reduce anxiety for some who find they are e4-
• Persons alter their LTC insurance purchasing learning their
APOE genotype
– If widespread would have insurance industry implications
• APOE4+ carriers
– more likely to make changes (vitamins, exercise) even knowing such changes are
not proven
– Also more likely to purchase unregulated neutraceuticals
• The impact is less than expected
– people come into the study with a baseline perception of their own risk
– seem to have a psychological inertia
 Structural and Biochemical
Biomarkers
• Biochemical: CSF Beta amyloid, tau,
phosph-tau
– Diagnostic as well as predictive value

• Neuroimaging: MRI, FDG-PET, amyloid

imaging
– Used for diagnostic confirmation in a symptomatic
person, for earlier definitive diagnosis in mild or
uncertain symptoms (e.g., MCI), and for detection of AD
pathology in asymptomatic individuals.
 39

Evolution of Neuroimaging in AD
• Computed Tomography
• MRI
• Volumetric MRI
• Co-registration of MRI
• Functional MRI
• FDG Glucose PET
• Amyloid Imaging
Helmuth L. Science.
2002;297:1260-1262.

www.loni.ucla.edu/~thompson/AD_4D/dynamic.html.
Ethics Issues With Biomarkers
• Diagnostic information
• We can ascertain with high probability
whether AD pathology is present in the
brain
• How much to tell research participants
about unvalidated research results?
Best markers across a broad
range are MRI and FDG-PET

β42
F A g ing
CS id im a
m y lo pp u
A I hi
F t a
E T MR CS
G -P
FD
Cog

n
Fx
Biomarkers for Earlier Diagnosis

“They stipulate that there must also be at least one or more

abnormal biomarkers among structural neuroimaging with
MRI, molecular neuroimaging with PET, and cerebrospinal fluid
analysis of amyloid β or tau proteins. “

Lancet Neurol 2007; 6: 734–46

 CSF in Alzheimer’s Disease:
Low Aβ and High Tau
AD Patients Control Patients
700
Concentration (pg/mL)

600

500

400

300

200

100

Aβ Tau

underland T, et al. JAMA. 2003;289:2094-2103.

CSF in MCI has
elevated tau,
decreased β-
amyloid
A combination of CSF T-tau and A42
at baseline yielded a sensitivity of 95%
and a specificity of 83% for detection
of incipient AD inpatients with MCI.
The relative risk of progression to AD
substantially increased in patients with
MCI who had pathological
concentrations of T-tau and A42 at
baseline (hazard ratio 17·7, p0·0001).
The association between pathological
CSF and progression to Alzheimer’s
disease was much stronger than, and
independent of, established risk
factors including age, sex, education,
APOE genotype, and plasma
homocysteine.
Hansson et al.,2006
 Imaging Amyloid in vivo in Humans
• Amyloid Cascade Hypothesis:
– Amyloid deposition begins years before clinical symptoms

• Ability to image brain amyloid will impact:

– Diagnosis (sensitivity and specificity TBD)
– Prognosis (different patterns of progression?)
– Monitoring anti-amyloid therapeutic interventions
– Efficiency of drug development
• Current ligands, more in development:
– PiB, AV-45, BF227, FDDNP. Bay compound

• PiB: Now in use in over 40 centers around the world

• F18-PiB in development at both GE and Pittsburgh
– Just as accurate as C11-PiB
PIB PET in AD and Control
 PIB Retention Distribution Volume Ratio (DVR)

C-8 C-2 MCI-2 MCI-10 MCI-4 AD-2

1.06 1.64 1.04 1.62 2.59 2.48

Frontal DVR
 Prediction of Outcome Utilizing PiB
Imaging in MCI:
PiB+ Cases Develop AD; PiB- Cases Do Not

23/26 patients have had

follow-up ADRC evaluations 80%
60%
Mean f/u: 24.0 months 40%
reverters
(6-57 months) 20% stable
0% converters
-20%
13 PiB positive -40%
PiB Positive PiB Negative
(Mean f/u: 23.6 months)
10 PiB negative
(Mean f/u: 24.5 months)

Wolk, et al., 2009

 Prevalence of Plaques Precede DAT
Figure 4. Appearance of plaques and DAT
70.00
60.00 Amyloid Plaques (Braak & Braak)

50.00
Proportion (%)

DAT - Average of Three Studies

40.00
30.00
20.00
10.00
0.00
46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85 86-90
Age (years)
 Mean Cortical PIB Binding in Nondemented
Controls and AD (N=41)
1.200
Controls AD
1.000

0.800

0.600
scBP

0.400

0.200

0.000

-
0.200 2022
2022234949
4949515657585859
5859595960
59606060616162
61626464
64646671
6671727274
72747575
75757576
75767777
77777779
777980
8081838384
83848586
85868672
8672737379
73797981
79818485
848586

Subject AGE

Mintun et al, 2006, Neurology

 Longitudinal Change in PiB Retention in a
Questionably Positive Control over Two Years

2 yrs
 PiB Binding (amyloid plaque density)
in Cognitively Normal Elderly and AD

Aizenstein et al., Arch. Neurol. 2008; 65: 1509-1517

Heterogeneity of Amyloid Binding in
Asymptomatic Normal Elderly

Courtesy of Reisa Sperling, Harvard Univ.

How will disease-modifying
medications affect the field?
• Immediate pressure to identify subjects as
early as possible
• Amyloid scans beginning at age 50,
repeated every 5 years, as for colon
cancer
• Public Health Message: “At 50, get
evaluated head to tail! Have your
colonoscopy and your PiB Scan.”
 Operational Research Criteria
for Preclinical AD
• Not intended as clinical diagnostic criteria

• Prognostic utility of these biomarkers in

individual subjects remains unclear
• Not all individuals with neuroimaging
evidence of AD changes will develop clinical
symptoms during life
– 30% of non-demented 80+ year olds have evidence
of AD in the brain at autopsy