Alzheimer’s Disease Past, Present, and Future - PowerPoint by eve17457


									   Alzheimer’s Disease:
 Past, Present, and Future

     John C. Morris, MD
Harvey A. and Dorismae Hacker Friedman
  Distinguished Professor of Neurology
     Disclosure Statement (07-08)
        Sources of Research Support        Fees > $10,000
    1.     National Institute on Aging
    2.     Anonymous Foundation                   None
    3.     Dana Foundation
    4.     Eli Lilly
                                            Stock Equity
    5.     Elan                                   None
    6.     Avid Pharmaceuticals
                                            Speaker‟s Bureaus
      Consulting Relationships                   None
    1.   Bristol-Myers Squibb
    2.   C2N                                Editorial Boards
    3.   CoMentis                                 Alzheimer’s Disease &
    4.   Janssen-Cilag                            Associated Disorders
    5.   Lilly
    6.   Merck
    7.   Myriad
    8.   Neurochem
    9.   Neuroptix
    10. Novartis
    11. Schering Plough
    12. Wyeth/Elan
     WU ADRC Collaborators
David Balota       David Holtzman   Eugene Rubin
Randall Bateman    Terri Hosto      Robert Schmidt
Angie Berry        Pamela Jackson   Stacy Schneider
Virginia Buckles   Eugene Johnson   Yvette Sheline
Nigel Cairns       Raphael Kopan    Joy Snider
David Carr         Dan Marcus       Avi Snyder
Mary Coats         Marie Meisel     Martha Storandt
John Csernansky    Philip Miller    Christy Tomlinson
Jan Duchek         Pam Millsap      Lei Wang
Anne Fagan         Mark Mintun      Vicki Weir
Becky Fierberg     Sue Neidenbach   Consuelo Wilkins
James Galvin       Angela Oliver    James Williams
Alison Goate       Arie Perry       Monique Williams
Betsy Grant        Joseph Price     Chengjie Xiong
Denise Head        Cathy Roe        Allyson Zazulia
    History of Alzheimer’s Disease:
   Lucretius, Roman poet/philosopher (99 BC-55 BC) De Rerum Natura
     – “dementia” = being out of one‟s mind (from “demens” = without mind)
   William Shakespeare‟s King Lear (1603-1606)
       “I fear I am not in my perfect mind,
       Methinks I should know you, and know this man;
       Yet I am doubtful; for I am mainly ignorant
       What place this is; and all the skill I have
       Remembers not these garments; nor I know not
       Where I did lodge last night” IV, vii63.

   Thomas Willis, physician/scientist; Cerebri anatomi, first use of
    “neurology” (1664)
     – “Stupidity” could be genetic in origin (“fools beget fools”) or acquired with
       aging (“become by degrees dull and at length foolish by the mere declining
       of age, without any great errors of living”)
 PreAlzheimer: Causes of Dementia

Physical                     Moral
Progress of age              Domestic trials
Abuse of wine                Disappointed affections
Apoplexy (stroke)            Frights
Falls upon the head          Political shocks
Menstrual disorders          Masturbation

  Esquirol E, “Mental Maladies, A Treatise on
  Insanity; Paris: Balliére, 1838
    Alois Alzheimer (1864-1915)
   Born in Markbreit, Franconia, Germany
   Following medical school graduation in 1888 (thesis: “On the
    Earwax Glands”), became medical officer at the Frankfurt Asylum
    for the Insane and Epileptic
   Harmonious collaboration with Franz Nissl, who had developed
    tissue staining methods that permitted histological examination of
    nerve cells
     – Study “psychiatric symptoms under the microscope”
     – Published on general paresis (neurosyphilis), arteriosclerotic dementia
       and Binswanger‟s disease, epilepsy, and other disorders
   Joined Emil Kraepelin at the Royal Psychiatric Clinic in Munich in
    1903, establishing a neuropathology laboratory that attracted
    students from around the world (F Lewy, H Creutzfeldt, A Jacob, S
    Fuller, etc.)
   Became Chair of Psychiatry at the University of Breslau in 1912;
    died of cardiac and renal failure in 1915 at age 51
    Auguste D.
The Original Alzheimer Patient

Admitted to Frankfurt Asylum Nov 26, 1901 at age 51y
   Mistrust of husband and female neighbor
   Mistakes in food preparation; neglected housework;
    could not find way around apartment; hid objects, then
    could not find them
   Delusions of harm
   Memory deficits, perseverative, aphasic
   Agitated, screaming, strikes other patients
Died at age 55y in April 1906; bedridden, decubitus, 74 lbs
    Alzheimer’s Case Presentation of
    Auguste D, November 3, 1906
   37th Assembly of Southwest German Psychiatrists in
    Tübingen, Germany
    – “atrophied brain; numerous ganglia cells have disappeared”
    – “remarkable changes in neurofibrils”
    – “millet-seed lesions, characterized by the deposits of a peculiar
      substance spread over entire cerebral cortex”
    – “we clearly have a distinct disease process”
   No questions; report considered inappropriate for
    inclusion in the Conference Proceedings
   “No mental illness can be explained from anatomic
    findings”, R. Gaupp, 1906; Freudian psychoanalytic
    theory held that mental illness resulted from conflicts
    between the conscious and subconcious mind, often
    related to childhood trauma
History of Alzheimer’s Disease:
Emil Kraepelin
   Coined the term, “Alzheimer‟s disease” (Psychiatrie:
    Ein Lehrbuch fur Studierende und Ärzte, Leipzig,
   “The clinical pattern of Alzheimer‟s disease …differs
    decisively from presbyophrenia, which accompanies
    the simple age-related neuronal alterations…The
    imperceptible transition… of senile dementia to the
    common psychological alterations of old age make
    any precise…definition of the illness arbitrary.”
   Hence, the concept of AD was fixed as “presenile
    dementia”, whereas “senile dementia” was
    considered as part of the spectrum of aging.
    History of Alzheimer’s Disease:
   Grünthal (1925): “a differential diagnosis between
    senile dementia and Alzheimer‟s disease cannot be
    made on the basis of histopathological images.”
   Electron microscopic studies in the 1960s by M Kidd
    and R Terry (with H Wisniewski, M Shelanski, B Ghetti,
    K Iqbal, D Dickson, etc.) revealed the ultrastructural
    features of AD
    – Plaques: amyloid fibrillar core
    – Tangles: paired helical filaments
   Tomlinson, Blessed and Roth (1968, 1970) showed
    that the brains of healthy and demented older adults
    differ and that most demented persons have AD
    History of Alzheimer’s Disease:
   Dementia largely results from AD
    – Hachinski (1974): “the concept that „hardening of the arteries‟
      describes mental decline in the aged probably is the most
      common misdiagnosis in medicine.”
    – Normal pressure hydrocephalus (NPH)
        » Adams, Fisher, Hakim et al., NEJM 1965:273:117-126
        » By the 1970s, it was recognized that most cases of presumed NPH
          instead were AD (Sohn et al., Neurology, 1973;23:1058-1065

   AD potentially is treatable with neurotransmitter-based
    – GC Cotzias (1968): therapeutic benefit of L-DOPA in PD
    – Cholinergic studies in AD
        » Drachman and Leavitt (1974): scopolamine replicates AD
          symptoms in normal people
        » Cholinergic deficit (ChAT) in AD brains (Davies and Maloney,
          1976; Bowen et al., 1976; Perry et al., 1997)
History of Alzheimer’s Disease
1970-1980 (cont)
   Appreciation that AD is the same neuropathological
    disorder regardless of the age at which dementia
    appears; AD is distinct from healthy brain aging; and
    it is not simply atherosclerotic dementia
   R Katzman: brought AD into the spotlight
    1977: 1st US conference on AD (organized by R
     Katzman, R Terry, and K Bick), helped develop AD
    Robert Katzman, MD
     programs at NIMH, NINCDS, and NIA
    Bronx, NY

                              Arch Neurol 1976;33:217-218
National Population: Notice the
increase in the elderly as baby-boomers age

     1950              1980     2000        2020

                 Elderly      Non-Elderly

Source: U.S. Census Bureau
History of Alzheimer’s Disease
   Alzheimer‟s Association founded in Chicago
    in 1980; Jerome Stone, President
   1984: A watershed year
    – Aβ sequenced (Glenner and Wong)
    – NINCDS-ADRDA criteria for the clinical diagnosis
      of AD (McKhann et al)
    – Standardized cognitive measures and global
      scales (Alzheimer‟s Disease Assessment Scale;
      Clinical Dementia Rating; etc.)
    – Alzheimer‟s Disease Research Centers
      established at NIA; Zaven Khachaturian
    Alzheimer’s Disease Research Centers
   1984                                        Center Director
    –   Harvard-Mass General                      John Growdon
    –   Johns Hopkins University                   Donald Price
    –   University of California, San Diego      Robert Katzman
    –   Mount Sinai School of Medicine                Ken Davis
    –   University of Southern California           Caleb Finch
   1985
    –   University of Kentucky                William Markesbery
    –   Duke University                               Allen Roses
    –   University of Washington                    George Martin
    –   University of Pittsburgh                   Francois Boller
    –   Washington University                       Leonard Berg
   1988-89
    –   Case Western Reserve University        Peter Whitehouse
    –   University of Michigan                      Anne Young
    –   Columbia University                    Michael Shelanski
    –   Baylor College of Medicine                 Stanley Appel
    –   University of Texas, Southwestern      Roger Rosenberg
    Alzheimer’s Disease Research Centers
   1984                                       Center Director
    –   Harvard-Mass General
    –   Johns Hopkins University                  Donald Price
    –   University of California, San Diego
    –   Mount Sinai School of Medicine
    –   University of Southern California
   1985

    – University of Washington
    – University of Pittsburgh
    – Washington University
   1988-89

    – University of Michigan
    – Columbia University                     Michael Shelanski
History of Alzheimer’s Disease:
1980-1990 (cont)
   Amyloid precursor protein (APP)
    gene cloned
   Multicenter collaborative studies
    – Consortium to Establish a Registry
      for Alzheimer‟s Disease (CERAD)
    – Tacrine trial
   Michigan ADRC established (1989)
    Contributions of the MADRC:
   Sid Gilman succeeded Anne Young as Director in 1992
   Michigan Dementia Program: A Statewide Consortium
    – Community education programs, state health policies for AD,
      referral network for patients with dementia, and
      neuropathological criteria for diagnosis of AD
   Studies of nonAlzheimer dementias including
    Parkinson‟s disease, dementia with Lewy bodies,
    progressive supranuclear palsy, and multiple system
   Foster NL et al., “Frontotemporal dementia and
    parkinsonism linked to chromosome 17: A consensus
    conference.” Annals of Neurology 1997;41:706-715
Contributions of the MADRC:
1989-present (cont)
   In vivo imaging studies of
    neurotransmitters and transporters,
    central cholinesterase activity, and
    cortical hypometabolism
   Gilman S et al., “Clinical effects of
    Abeta immunization (AN1792) in
    patients with AD in an interrupted trial”,
    Neurology 2005;64:1553-1562
   External Advisory Committee
History of Alzheimer’s Disease
   APP mutation causing dominantly inherited
    AD (Goate et al., 1991)
   Presenilin 1 (St George-Hyslop et al., 1992)
    and Presenilin 2 (Rogaev et al., 1995)
    mutations identified
   ApoE identified as the major susceptibility
    gene for AD (Strittmatter et al., 1993)
   Transgenic mice developed
History of Alzheimer’s Disease:
1990-2000 (cont)
   Concept of mild cognitive impairment, or
    MCI (Flicker et al., 1991; Petersen, 1995)
   Alzheimer‟s Disease Cooperative Study
    (ADCS) established in 1991
   Tacrine approved in 1993
   Donepezil approved in 1996, rivastigmine in
   National Alzheimer‟s Coordinating Center
    (NACC) established in 1999
History of Alzheimer’s Disease:
   Galantamine approved in 2001, memantine approved in
   Alzheimer‟s Disease Neuroimaging Initiative (ADNI)
    established in 2004; the Alzheimer‟s Disease Genetics
    Consortium (ADGC) and the Dominantly Inherited
    Alzheimer Network (DIAN) established in 2008
   Uniform Data Set (UDS) adopted by all 29 Alzheimer‟s
    Disease Centers in 2005 (Morris JC et al., The Uniform
    Data Set, Alzheimer‟s Disease and Associated
    Disorders 2006;20:210-216)
   Clinical trials of potentially “disease-modifying” therapies
    are conducted (e.g., AN1792)
Status of Selected “Disease-
modifying Agents for Alzheimer’s
Disease (2008)
   Amyloid
    –   Tarenflurbil (Flurizan®; Myriad) – Phase 3 Failed
    –   Bapineuzemab (Elan) – Phase 3 in progress
    –   ACC-001 (Wyeth) – Phase 2 in progress
    –   LY450139 (Lilly) – Phase 3 in progress
   Tau
    – Methylthioninium chloride (Rember®; TauRx) –
      Phase 3 to begin in 2009
   Other
    – Dimebon (Medivation/Pfizer) – Phase 3 in
From Hopeless to Hope
Then                           Now
 1983: NIH spends $22          NIH spends ~$640 million
  million on AD research         annually

 No AD research                29 NIA-funded Alzheimer‟s
  infrastructure                 Disease Centers

 269 indexed articles on AD    3365 articles on AD indexed
  in 1983                        in 2007
 Diagnosis uncertain           Diagnostic accuracy of 90%

 No prescription meds          Five FDA-approved drugs
                      Diagnostic Thresholds for Dementia
               Dementia results from progressive neuronal deterioration, from
               minimal to extensive. Conventional diagnosis draws a line in its
               course, labeling one side as demented and the other not.
                                                                        Very Mild or
                                            Threshold 1
Cognitive Abilities

                                            Threshold 2                 Mild

                                            Threshold 3


                           Course of Dementia
                     Appearance of Plaques and DAT

                 60.00           Amyloid Plaques (Braak & Braak)

Proportion (%)

                                 DAT – Average of 3 Studies




                         46-50   51-55   56-60   61-65   66-70   71-75   76-80   81-85   86-90

                                                   Age (years)
    DAT=dementia of Alzheimer type.
    Courtesy of Dr Mark Mintun.
   Chronic Disease Model of AD
  Preclinical phase                                    Clinical phase

Diffuse plaques

Neuritic plaques, NFTs,
neuron and synapse loss
                           Antecedent biomarkers

Cognitive impairment

Functional loss

 Genetic & environmental                    Onset of             Death
         factors                           symptoms
    Potential Indicators of Preclinical AD

   Cognitive – absence of learning effect; attentional profiles;
    response latency; intraindividual variability
   Personality – neuroticism; conscientiousness
   Genetics – apoE genotype; genomics
   Fluid biomarkers – assays for plasma and CSF Aβ40/42,
    tau, and p-tau; proteomics/metabolomics/lipidomics
   Neuroimaging – multiple modalities, including MRI
    (volume, shape, cortical thickness; whole brain and
    regional volumes) and PET imaging with amyloid tracers
    (e.g., PIB)
       In vivo Amyloid Imaging with Pittsburgh
       Compound B (PIB) (Klunk et al, Ann Neurol 2004)
                                      6       1
                               H 3C            S                  CH 3
                                                  N+              CH 3
                                      Histology - Thioflavin T

Amyloid Plaques

                                                      PET Imaging -
                                                  [11C]6-OH-BTA-1 (PIB)
                                                  HO         S
  Courtesy of William Jagust
Mean Cortical PIB Binding By Age
Morris JC, Mintun M, et al, in preparation

        0%    3.3%    20%     37.5%    20%
                          Analysis of CSF Ab42 levels may be useful as a screening
                          tool to identify the presence of PIB+ brain amyloid.

                                             93% Specificity
CSF Ab 42 (pg/ml)



                    500                                                      443 pg/ml

                    250                                                      100% Sensitivity
                      -0.25    0.00    0.25     0.50   0.75    1.00   1.25
                                 mean cortical PIB binding
                                    (amyloid binding potential)

                          Solid squares, CDR 1-2, mild-moderate DAT
                          Open triangle, CDR 0.5, very mild DAT                    Fagan et al, Arch Neurol
                          Solid triangles, CDR 0.5, non-AD dementia                2007;64:343-349
                          Open circles, CDR 0, cognitively normal
                       Structural Brain Change Correlates with CSF Aβ
                       Levels in Nondemented Aging Fagan AM et al, Ann
                       Neurol, in press

n Non-Demented                   B.                            CSF Ab 42 in Non-Demented
                                                                                                               B.                             A.CSF Ab 42 CSF Ab 4242 in Mild DAT
                                                                                                                                               A.          CSF Ab in Mild DAT
                                                                                                                                                          in Non-Demented                                              B.
                                                                                                                                                                                                                        B.                             Plasm
                                A. 1250                       CSF Ab 40 in Non-Demented
                                                                                                                                                1250           1250                                                       200                200
                                              25000            r=0.30

                                                                                                                                                                                                                       Plasma Ab42 (pg/mL)
                                                               p=0.01                                                                                                                                 n.s.

                                                                                                                                                                                                                      Plasma Ab42 (pg/mL)
                                                                                                                                                                                                        n.s.                                       n.s.
                               CSF Ab42 (pg/mL)

                                                                                                                                            CSF Ab42 (pg/mL)
                                                1000               n.s.                                                                               p=0.01
                                                                                                                                                       1000                                                                                          n.s.

                                                                                                                                            CSF Ab42 (pg/mL)
                                                                                                               CSF Ab42 (pg/mL)
                                                                                                                                     1000                      1000
                              CSF Ab40 (pg/mL)

                                                 750                                                                                                           750
                                              15000                                                                                  750
                                                 500                                                                                                           500
                                              10000                                                                                  500

                                                      250                                                                                                      250
                                                    5000                                                                             250
                                                           0                                                                                                     00                                                                          00
                                                          00.65            0.70    0.75      0.80       0.85                            0
   0.75     0.80       0.85                                                                                                                                      0.65
                                                                                                                                                                   0.65    0.70
                                                                                                                                                                             0.70     0.75
                                                                                                                                                                                        0.75     0.80
                                                                                                                                                                                                   0.80      0.85
                                                                                                                                                                                                               0.85                          0.65
                                                                                                                                                                                                                                               0.65       0.7
                                                          0.65            0.70    0.75     0.80       0.85                              0.65                       0.70      0.75       0.80       0.85
 whole brain volume                                                normalized whole brain volume                                                                        normalized whole brain volume                                                 normal
                                                                  normalized whole brain volume                                                                           normalized whole brain
                                                                                                                                                               normalized whole brain volume volume                                                     norm
intracranial volume)                                               (fractional intracranial volume)                                                                     (fractional intracranial volume)                                              (fractio
                                                                  (fractional intracranial volume)                                                             (fractional(fractional intracranial volume)
                                                                                                                                                                           intracranial volume)                                                         (frac

n Non-Demented                 D.                            Plasma Ab 42Non-Demented                                                                                                                                 D.
                              C.1250                         CSF Tau in in Non-Demented                         D.                          C. 1500 Ab 42 CSF Tau in Mild DAT
                                                                                                                                             C. 1500
                                                                                                                                             Plasma     CSF Tau in Mild DAT
                                                                                                                                                          in Non-Demented                                              D.300
                                  1000                                                                                                                                                                                                       300
                              Plasma Ab42 (pg/mL)

                                                                                                                                                                                                                      CSF ptau 181 (pg/mL)
                                                                    n.s.                                                                                                                         r=-0.46

                                                                                                                                                                                                                      CSF ptau 181 (pg/mL)
                                                                                                               Plasma Ab42 (pg/mL)

                                                                                                                                            CSF tau (pg/mL)
                                            1000                  n.s.                                                                                         n.s.                              p=0.01
                               CSF tau (pg/mL)

                                                                                                                                            CSF tau (pg/mL)
                                                                                                                                     750                 1000
                                                                                                                                                           1000                                                                        200
                                                    500                                                                                                        500
                                                                                                                                                                 500                                                                   100
                                                    250                                                                              250

                                                       0                                                                                                         00                                                                          00
  0.75      0.80       0.85                          0                                                                                 0
                                                        0.65            0.70        0.75     0.80      0.85                                                      0.65      0.70      0.75        0.80        0.85                            0.65         0.7
                                                     0.65             0.70        0.75     0.80       0.85                             0.65                        0.65
                                                                                                                                                                   0.70      0.70
                                                                                                                                                                             0.75      0.75
                                                                                                                                                                                       0.80        0.80
                                                                                                                                                                                                   0.85        0.85                            0.65         0
whole brain volume                                              normalized whole brain volume
                                                              normalized whole brain volume                                                                            normalized whole brain volume
                                                                                                                                                               normalized whole brain volume volume
                                                                                                                                                                          normalized whole brain                                                      normal
ntracranial volume)                                              (fractional intracranial volume)
                                                              (fractional intracranial volume)                                                                          (fractional intracranial volume)
                                                                                                                                                               (fractional intracranial volume) volume)
                                                                                                                                                                          (fractional intracranial                                                    (fractio
    Relationships Between CSF
    Biomarkers and Imaging Markers
   In nondemented elderly, reduced levels of CSF Aβ42 correlate
    with increased [11C] PIB mean cortical binding potential
   In nondemented elderly, reduced levels of CSF Aβ42 correlate
    with whole brain volume loss
   In clinically diagnosed AD, higher levels of CSF tau/ptau
    correlate with whole brain volume loss
   CSF Aβ42 is a useful marker for the presence of amyloid
    plaques in preclinical AD
   Preclinical AD is not benign as it is associated with brain

Fagan AM et al, Arch Neurol 2007; 64:343-349
Fagan AM et al, Ann Neurol, in press
       Longitudinal Cognitive Performance in
       Nondemented People with [11C] PIB Imaging
   Mean cortical [11C] PIB binding potential (MCBP) values in
    94 nondemented persons, age 65-88 years, were
    correlated with cognitive performance (longitudinal
    cognitive performance in 68)
   Elevated MCBP values in 17 nondemented individuals
        » No correlation with global cognitive composite score at time of
        » Slopes for global composite (and for visuospatial and working
          memory factors) showed significant declines
   Preclinical AD has a cognitive signature: declining
    cognitive test performance prior to clinical diagnosis of
Storandt M et al, Submitted
The Cognitive Signature of Preclinical AD
Storandt M, et al., Submitted

                           MCBP=0.07, apoE 3/4, 80 yo woman (11 yrs educ), MMSE = 30
                           MCBP=0.37, apoE 3/4, 84 yo man (16 yrs educ), MMSE = 30
                           MCBP=0.59, apoE 3/3, 77 yo man (18 yrs educ), MMSE = 27
                 Hypothetical Progression of Alzheimer Changes
                              Mechanism                                         Biomarker
Preclinical AD

                       Upstream events (e.g.,
                       Aβ dimers, oligomers)                                        ?

                    Aβ aggregation; deposition                               ↓ CSF Aβ42 levels
                    as cerebral diffuse plaques

                           Amyloid plaques
                           become fibrillar
                                                                            ↓ CSF Aβ42 levels;
                                                                             amyloid imaging
Symptomatic AD

                       Amyloid plaques exert                                Brain volume loss;
                       pathobiological signature                             cognitive decline

                        Substantial neuronal/                               Dementia is manifested;
                         synaptic damage                                  dementia severity marked by
                                                                         increasing volume loss, ↑ CSF
                 Note: Other processes (e.g., inflammation; oxidative            tau/ptau levels
                     stress; vascular insufficiency) likely contribute
Key Points
   As the population ages, AD soon will
    reach epidemic proportions

   Improvements in diagnosis focus on
    early detection

   AD is a treatable disorder now, but
    newer, potentially disease-modifying
    therapies may have their greatest
    impact in preventing AD
               In Memorium

Leonard Berg      Leon Thal   Robert Katzman
 1927-2007        1944-2007    1925 - 2008

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