Washington, DC
December 7, 2010
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
• Diagnostic Confirmation
• Increased Accuracy in MCI
• Risk Assessment in Asymptomatic People
Diagnosis
Neuronal Function
Clinical Ratings
Time
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
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
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
600
500
400
300
200
100
Aβ Tau
50.00
Proportion (%)
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
2 yrs
PiB Binding (amyloid plaque density)
in Cognitively Normal Elderly and AD