National Press Foundation

Washington, DC
May 24, 2011

Advances in Alzheimer's Disease:

New Technologies and New Ethical Issues

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


 Research Grants:
– Elan, Forest, Janssen, Novartis


Special acknowledgements:
 Stephen Post, Stony Brook University
 Robert Green, Boston University
–

 Outline of Discussion
• From rare disease to coming epidemic
• Technology and research breakthroughs
– The value of basic research
– Examples in Alzheimer’s Disease
• Ethical issues arising
• Advances in technology and their
effects on AD research, therapies,
and caregiving

 Case Study
 46 year old married female
– General good health; on no medications
– No major medical problems
– Sub-acute onset of pathological jealousy
– Onset of dysnomia (calls a pitcher a ‘milk
pourer’)
– Difficulties with short term memory
– General medical examination normal
– Neurological examination normal except for
mental status
– Progressive cognitive decline, death 4 years
later
 “I have lost myself.”

Alzheimer’s original patient: Auguste D.

Alzheimer’s Disease
Memory loss
Language disturbances
Visuospatial deficits
“Frontal-Dysexecutive”:
Impaired judgment,
motivation, insight,
decreased social
cognition
Neuropsychiatric
symptoms:
depression, anxiety,
sleep disturbance
psychosis Alzheimer’s original patient: Auguste D.

The anatomical/circuitry correlates of

these behaviors are now largely
identified
 From Clinic to Community:
characterizing the clinical picture of AD

 Alois Alzheimer  Martin Roth and

 Germany, 1907: colleagues

 Newcastle, 1964:
• single case report • community survey
• rare, unusual disease of
middle-aged • fairly common disease
• “pre-senile dementia” of elderly
• “senile dementia”
Majority of cases of dementia in late life are AD,
with many cases showing additional co-morbidities
 1976 Katzman editorial:
an alarm is sounded
• Katzman, R. The prevalence and malignancy of Alzheimer
disease. A major killer.
Archives of Neurology, 1976

• Predicted a massive increase in the number of cases of

Alzheimer’s Disease in the 21st century

• No clear difference between presenile and senile onset with

respect to symptoms or pathology

• Stimulated research in aging and AD brain

•
 Prevalence of Mild, Moderate/Severe and
Total Cases of AD: 2000-2050
12
Mild
10 Mod/Severe
Number of Cases (in millions)

0
2000 2010 2020 2030 2040 2050

Assume no new therapy

Sloane, et al., Ann. Rev.
Public Health 2002. 23:213–31
Increasing Global Burden of AD:
Cultures differ in their dealing with dementia
 Technology & Alzheimer
Breakthroughs
• “Heavy metal” (silver) stains and Alzheimer
• Radioassay for ChAT (Fonnum) in 1975
• Protein purification techniques
• Gene sequencing
• Neuroimaging: CT, MRI, PET
• Computing power to calculate…and to share!
 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
 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?
•
 Alzheimer’s Disease: Course,
Prevention, Treatment Strategies

Pre- Mild
Clinical symptomatic
Normal Cognitive AD
State Impairment
AD

Disease Progression
 Linking Clinical Symptoms With
Degree of Pathology
Seconda
Primary ry
Treatme
Intervention Preventi Preventi
nt
on on/
Early Tx
Pre- Mild
Clinical symptomatic
Normal Cognitive AD
State Impairment
AD
Brain No Disease Early Brain AD Brain Mild,
Pathologic No Symptoms Changes Changes Moderate, or
State No Mild Severe
Symptoms Symptoms Impairment

Disease Progression
Major Pathological Changes in AD

• Brain shrinkage (atrophy)

• Neuritic Plaques
– altered metabolism of APP
– Deposition of beta amyloid
• Neurofibrillary Tangles
– Cytoskeletal pathology [girders and trusses]
– Altered metabolism of tau protein
• Neuronal death in specific brain regions (why some
regions and not others?)
• Specific Neurotransmitter deficits (especially ACh,
serotonin, norepinephrine, glutamate)
–
NeuroFibrillary Tangles & Neuritic Plaques

Neurofibrillary tangles

Inflammatory surround

Compacted amyloid core

The ‘inflammatory surround’ consists of distorted

and degenerating synaptic processes, activated
microglia, and astrocytic processes
Tau (Microtubule Associated Protein MAP2):
Axonal Dissolution and Dysfunction in AD
Tangle (NFT) & Plaque (NP) Distribution In AD at
Autopsy: The Static View of the 1980s-90s

NFT

NP

S. Arnold, Cortex, 1991

 Biochemical pathway of neurofibrillary
Stages
degeneration
A35 A28 A34 A38 A20 A21 A22, 10, 39 A44 A4 A18 A17
S0 n=30 Brodmann areas
n=3
trans- S3
S1 entorhinal

n=4 + entorhinal Distribution of PHF-Tau

S2 S4

n=16 + hippocampus
S3
n=10 + anterior temporal ctx
S4 S6

n=12 + inferior temporal

S5
n=11 + mid temporal
S6
S8
+ anterior frontal, superior temporal, inferior
S7 n=15
parietal

S8 n=5 + Broca area

S9c
S9a n=6 + motor cortex

S9b,c n=13 + occipital areas

S10 n=27 All cortical areas affected.

Delacourte A, et al. Neurology. 1999;52:1158-1165.

 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 (~40% v 22%)
 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.
 Evolution of Neuroimaging

1970s • Computed Tomography

• MRI
1980s • Volumetric MRI
• FDG Glucose PET
• Co-registration of MRI
1990s
• Functional MRI
2000s
• Amyloid Imaging
•
 39

Evolution of Volume Mapping

Enhancing ability to assess
variability of structural
change AND response to
medications.

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 ging
CS im a
y loi d p
Am hi p t au
I SF
ET MR C
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
Concentration (pg/mL)

Aβ Tau

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

CSF in MCI has
elevated tau,
decreased β-
amyloid

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 (GE), AV-45 (AVID/Lilly), Bayer

• PiB: Now in use in over 60 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
 Amyloid Imaging Agents

Florbetapir (Amyvid)

Florbetaben (Bayer)
AV45 (AVID/Lilly)
 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

80%
follow-up ADRC evaluations
60%
 Mean f/u: 24.0 months 40% reverters
20%
 (6-57 months) 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 Am yloid 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
202223
2349
4949
4951
5156
5657
5758
5858
5859
5959
5959
5960
6060
6060
6061
6161
6162
6264
6464
6466
6671
7172
7272
7274
7475
7575
7575
7576
7677
7777
7777
7779
7980
8081
8183
8383
8384
8485
8586
8686
8672
7273
7373
7379
7979
7981
8184
8485
8586
86

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
 Overview of Phase III AD Trials
• Negative Phase III:
– Xaliproden (5HT1A agonist with neurotrophic effects in vitro)
– Tramiprosate (GAG anti-aggregant)
– Tarenflurbil (R flurbiprofen, gamma secretase modulator)
– Rosiglitazone (Peroxisome proliferators activated receptor PPAR-ү)
– Leuprolide (LHRH endocrine)
– Dimebon (5HT6 antagonist, H1 antagonist + mitochondrial transition po
– Semagacestat (gamma secretase inhibitor)
• Phase III in progress
– Bapineuzumab (passive immunotherapy; monoclonal Ab N-terminal )
– Solanezumab (passive immunotherapy; monoclonal mid domain Ab)
– IVIG (passive immunotherapy; polyclonal pooled Abs)
– Dimebon (5HT6 antagonist, H1 antagonist + mitochondrial transition po
– Tau Rx (methylene blue, anti tau aggregant)
 Phase II Bapineuzemab Study

“Due to varying
doses and a lack of
statistical
precision, this
Class II ascending
dose trial provides
insufficient
evidence to
support or refute a
benefit of
bapineuzumab.”

Salloway et al., 2009

11C-PiB PET assessment of change in amyloid-β load
in patients with AD treated with bapineuzumab:
a phase 2, double-blind, placebo-controlled, ascending-dose study

Rinne et al., Lancet Neurology 2010

 Loss of amyloid on PET Scan—
how much is enough?

Rinne et al., Lancet Neurology 2010

 Revised Diagnostic Criteria
Preliminary recommendations from the
NIA/Alzheimer’s Association Workgroup

• Pre-Clinical AD
• Mild Cognitive Impairment
• Alzheimer’s Disease

DeKosky et al Revision of the criteria for Alzheimer’s

disease: A symposium
Alzheimers Dement 2011;7:e1-e12.