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									 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
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
              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
  –   Difficulties with short term memory
  –   General medical examination normal
  –   Neurological examination normal except for
      mental status
  –   Progressive cognitive decline, death 4 years
                                           “I have lost myself.”

Alzheimer’s original patient: Auguste D.
Alzheimer‟s Disease
Memory loss
Language disturbances
Visuospatial deficits
   Impaired judgment,
   motivation, insight,
decreased social cognition
   depression, anxiety,
   sleep disturbance
   psychosis                  Alzheimer‟s original patient: Auguste D.

   The anatomical/circuitry correlates of
     these behaviors are now largely
   From Clinic to Community:
   characterizing the clinical picture of AD

       Alois Alzheimer             Martin Roth and
       Germany, 1907:
                                   Newcastle, 1964:

• single case report          • community survey
• rare, unusual disease of
                              • fairly common disease
  middle-aged                   of elderly
• “pre-senile dementia”       • “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
                          10               Mod/Severe
Number of Cases (in millions)





                                    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
•   “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)

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

• What are they? How should they be
  used? Research or general availability?
            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
Intervention                               Prevention/    Treatment
                                            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
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



                           S. Arnold, Cortex, 1991
                         Biochemical pathway of neurofibrillary
               A35          A28          A34           A38          A20            A21 A22, 10, 39          A44           A4       A18         A17
  S0         n=30                                                                                                                Brodmann areas
            trans-                          S3
  S1        entorhinal

             n=4         + entorhinal                                                                                Distribution of PHF-Tau
  S2                                                              S4

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

             n=12                                       + inferior temporal
             n=11                                                        + mid temporal
                                                        + anterior frontal, superior temporal, inferior
  S7         n=15

  S8         n=5                                                                                      + Broca area
  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
             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

• Biochemical: CSF Beta amyloid, 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
1990s   •   Co-registration of MRI
        •   Functional MRI
2000s   •   Amyloid Imaging

    Evolution of Volume Mapping
                                                  Enhancing ability to assess
                                                  variability of structural
                                                  change AND response to

               Helmuth L. Science.

Ethics Issues With Biomarkers

• Diagnostic information
• We can ascertain with high probability
  whether AD pathology is present in the
• How much to tell research participants
  about unvalidated research results?
Best markers across a broad
range are MRI and FDG-PET
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

      Concentration (pg/mL)


                                       Aβ                         Tau

Sunderland T, et al. JAMA. 2003;289:2094-2103.
CSF in MCI has
elevated tau,
decreased β-

                 Hansson et al.,2006
Imaging Amyloid in vivo in Humans
• Amyloid Cascade Hypothesis:
   – Amyloid deposition begins years before clinical sympto

• 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
follow-up ADRC evaluations
      Mean f/u: 24.0 months    40%
       (6-57 months)           20%                                  stable
                                0%                                  converters
     13 PiB positive           -20%
     (Mean f/u: 23.6 months)   -40%
                                      PiB Positive   PiB Negative
     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
                 60.00           Amyloid Plaques (Braak & Braak)

Proportion (%)

                                 DAT - Average of Three Studies
                         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)
                                                                  Controls                                                                    AD






               20 22 23 49 49 51 56 57 58 58 59 59 59 60 60 60 61 61 62 64 64 66 71 72 72 74 75 75 75 76 77 77 77 79 80 81 83 83 84 85 86 86 72 73 73 79 79 81 84 85 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
• 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 pore)
   – 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 pore)
   – Tau Rx (methylene blue, anti tau aggregant)
    Phase II Bapineuzemab Study

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

   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.

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