Experimental Therapies for
Alzheimer’s Disease
Pierre N. Tariot, MD
Director
Banner Alzheimer's Institute
Phoenix, Arizona
Research Professor of Psychiatry
University of Arizona College of Medicine
Disclosures
 Consulting fees: Acadia, AC Immune, Avid, Baxter Healthcare
Corp., Bristol Myers Squibb, Eisai, Inc., Epix Pharmaceuticals,
Forest Laboratories, Memory Pharmaceuticals, Inc., Myriad
Pharmaceuticals, Sanofi-Aventis, Schering-Plough, and Worldwide
Clinical Trials;
 Consulting fees and research support from Abbott Laboratories,
AstraZeneca, AVID, Elan, GlaxoSmithKline, Eli Lilly, Medivation,
Merck and Company, Pfizer Inc., Toyama, and Wyeth
Laboratories;
 Educational fees from Alzheimer’s Foundation of America;
 Research support only: NA.
 Other research support: NIA, NIMH, Alzheimer’s Association,
Arizona Department of Health Services, and the Institute for Mental
Health Research.
 Investments: none to disclose.
 Patents: I am listed as a contributor to a patent, “Biomarkers of
Alzheimer’s Disease.”
 Speakers’ bureaus: NA.
2
General Principles
for Managing Illness
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Optimize physical, social, intellectual stimulation
Importance of maintenance of medical and dental health
Medication oversight
Monitor for delirium
Healthy diet
Discuss possible changes in emotions and behavior that
can occur, and how to mitigate them
Review driving safety
Discuss legal, financial issues
Review relevant community resources
Discuss coping strategies
Discuss availability of clinical trials
Establish ongoing monitoring plan
3
Prevention, Risk Reduction, and/or
Optimizing Brain Health?
 Social, mental, and physical activity shown to be inversely
associated with risk for dementia and AD
 Exercise speculated to enhance brain neurotrophic factors
and modify apoptosis
 Longitudinal cohort studies show risk of AD increased
among people who have received shorter periods of
education
 Intellectually challenging activity has been associated with
reduced risk of dementia in longitudinal studies
 Reasonable to encourage patients to maintain or increase
physical activity, exercise, cognitive and leisure activities,
and social interaction, though it is not known whether these
interventions reduce dementia risk
Bassil N, Grossberg GT. Primary Psychiatry. 2009;16:33-38.
4
4
Goals for the Treatment of
Alzheimer’s
•Improve memory
•Improve functional status
•Improve behavioral symptoms
•Slow progression
•Delay or prevent onset
Pharmacologic Treatments for AD
MOA
NMDA-Receptor
Antagonist
Cholinesterase Inhibitors
Drug
Donepezil
Galantamine
Rivastigmine
Memantine
Mild-moderate AD;
severe AD
Mild-moderate AD
Mild-moderate AD
Moderate-severe AD
Initial
dose
Tablet:
5 mg qd
Tablet/oral solution:
4 mg bid
ER capsule: 8 mg qd
Capsule/oral
solution: 1.5 mg bid
Patch: 4.6 mg qd
Tablet/oral solution: 5
mg qd
Maximal
dose
Tablet:
10 mg qd
Tablet/oral solution:
12 mg bid
ER capsule: 24 mg qd
Capsule/oral
solution: 6 mg bid
Patch: 9.5 mg qd
Tablet/oral solution:
10 mg bid
Indication
ER = extended-release; MOA = mechanism of action; NMDA = N-methyl-D-aspartate.
National Institute on Aging. Alzheimer’s disease medications. November 2008. NIH Publication
No. 08-3431. Available at: http://www.nia.nih.gov/Alzheimers/Publications/medicationsfs.htm.
Accessed July 24, 2009.
6
Cholinesterase Inhibitor Therapy
in AD
Disease Severity
MCI
 Benefits
cognition?
Early-Stage Dementia
 Benefits
cognition
Moderate Dementia
 Benefits cognition
 Preserves global status
 Preserves ADLs
 Benefits behavior?
Class approved for mild-moderate AD
Donepezil also approved for severe AD
Severe Dementia
 Benefits cognition
 Preserves global status
 Preserves ADLs
 Benefits
behavior?
7
Memantine Therapy for AD*
Disease Severity
MCI

Role unknown
Mild-Moderate Dementia

Inconsistent effects
Moderate-Severe Dementia
Benefits cognition
Preserves global
function
 Preserves ADLs
 Benefits behavior


*Approved for moderate-severe AD in the U.S., alone or in combination with
cholinesterase inhibitors
8
Pharmacologic Treatments for AD:
Common Side Effects
Cholinesterase Inhibitors
•
•
•
•
•
•
Nausea
Vomiting
Diarrhea
Weight loss
Loss of appetite
Muscle weakness
•
•
•
•
NMDA-Receptor
Antagonist
Dizziness
Headache
Constipation
Confusion
National Institute on Aging. Alzheimer’s disease medications. November 2008. NIH
Publication
No. 08-3431. Available at:
http://www.nia.nih.gov/Alzheimers/Publications/medicationsfs.htm. Accessed July 24,
2009.
9
How Might Promising Advances in AD
Treatment Address Unmet Needs?
 Disease modification
– Increasing neuroprotection against existing Aβ plaques and
neurofibrillary tangles
– Reverse existing neuronal damage
 Improved efficacy





– Not just cognition, but also ADLs and behavior
Enduring response
Delay in disability
Fewer side effects
Simple to administer
Reduced number of treatment unresponsive patients
Husain MM, et al. Neuropsychiatr Dis Treat. 2008;4(4):765–777.
10
Amyloid Plaques and Neurofibrillary
Tangles in Alzheimer’s Disease and Normal
Aging
Plaques
Alzheimer’s
Tangles
Courtesy of Harry Vinters, MD.
Normal
A Proposed Temporal Progression Of Alzheimer’s Disease
Genetic Factors
Environmental factors
APP mutations
Presenilin 1,2 mutations
APOE4 alleles
APOE2 alleles
Family history
Head Injury
Toxins
Age
Endogenous Factors
Protective Factors
Diet
Cardiovascular risk factors
Diabetes
Smoking
Education
Menopause
Physical Activity
Intellectual Activity
Estrogen
Anti-inflammatory Drugs
Net effect = stress and vulnerability to stress
Molecular Phenotype
Neuropathology
Clinical Phenotype
INITIAL STRESSORS
Normal
Normal
Normal
Normal
Proximal Apoptosis
APP dysregulation
Impaired neurotrophic function
Oxidative stress
Excitotoxicity
FAILED STRESS RESPONSE
Cell cycle dysregulation
Kinase/phosphatase dysfunction
Protein misfolding
Altered DNA repair
Vascular/membrane dysfunction
CELL INJURY
Inflammation
Cytoskeletal dysfunction
Synaptic dysfunction
Mitochondrial damage
CELL DEATH
Distal apoptosis
Neurotransmitter failure
Tangles, Plaques
Tangles, Plaques
Neurodegeneration
The figure depicts apparently continuous processes, though they are likely to be asynchronous .
Mild Cognitive
Impairment
Dementia
Yaari and Tariot 2008
Interventions That Might
Prevent or Delay AD
 Antihypertensive therapy
 Hormonal agents (estrogen)
 NSAIDs (naproxen and celecoxib)
 High-dose vitamin B, folic acid
supplementation
 Statins
 PPAR-gamma agonists
 Fish oil, omega 3 fatty acids
 Weight control, healthy diet
13
13
The Search for New AD Therapies
 Drugs/nutraceuticals
(based on epidemiologic observations)
 Neurotransmitter-based therapies
 Glial modulating drugs
 Neuroprotective drugs
 Amyloid modulating drugs
 Tau modulating drugs
14
Overview of Supplements etc.
 Anti-oxidants: no pending treatment trials data; hope
for prevention trial at some point, or via dietary
study
 Anti-inflammatory agents: all AD studies (-); MCI trial
(-); ADAPT prevention trial results mixed: no
cognitive benefit, possible risk reduction with
naproxen only
 Hormonal therapies: largest AD treatment studies
were (-); discouraging WHIMS results; but none
started early enough, possibly wrong form used, so
question may still be open.
 Homocysteine-lowering: ADCS (B6+B12+folate) trial
in AD completed, no benefit seen
 Omega-3-fatty acid: anti-amyloid/neuroprotective
(ADCS), (-) results in AD; equivocal results in ageassociated memory impairment
15
Neurotransmitter Therapies
 Acetylcholine-releasing drugs
 Nicotinic agonists (alpha 7, alpha 4-beta 2)
 Serotonin: 5-HT4 partial agonists, 5-HT1A
agonists/antagonists, 5-HT6 antagonists
 Norepinephrine/dopamine: MAO-A and
MAO-B inhibitors
 GABA: GABA-B antagonists
 Glutamate: AMPA potentiators
 Glycine: partial agonists
MAO=monoamine oxidase; GABA=gamma-aminobutyric acid; AMPA=alpha-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid.
16
Glial Modulating Drugs
 Affect glial cells directly
(nitroflurbiprofen, ONO-2506,
tacrolimus)
 RAGE receptor antagonists (TTP 488)
 TNF alpha antagonists (etanercept)
17
Neuroprotective/Neurotrophic Strategies
 Mitochondrial stabilizers
(Dimebon/latrepirdine; also has
multineurotransmitter effects)
 Phosphodiesterase-4 (PDE4) inhibitors
 Neurotrophic drugs
18
Dimebon/latreperdine clinical
outcomes
 Dimebon patients improved compared with placebo
on 5 efficacy endpoints (n=183, MMSE 10-24; 6 mo
followed by 6 mo blinded extension)
–
–
–
–
Cognition: ADAS-cog, MMSE
Overall global function: CIBIC
Activities of daily living: ADCS-ADL
Behavior: NPI
 Results supported by HD study demonstrating effects
on MMSE (P=0.03) in Dimebon-treated patients
Doody RS, et al. Lancet. 2008;372:207215.
19
Dimebon Effects: ADAS-cog
P=0.0077
P<0.0001
P<0.0001
P<0.0001
2.0
4.0
5.9
6.9
Mean Change From Baseline Score
Dimebon-Placebo Difference
Clinical
Improvemen
t
–3.0
–2.0
–1.0
0.0
1.0
2.0
3.0
4.0
5.0
Dimebon (n = 89)
6.0
Placebo (n = 94)
Baseline
12
* Patients were moved to blinded extension.
Doody RS, et al. Lancet. 2008;372:207-215.
Clinical
Deterioration
26*
39
52
Week
20
Latrepirdine Study Results: Adverse Events
AEs >3% in placebo group and at least twice the rate of latrepirdine
Adverse Event
Latrepirdine (n=89)
Placebo (n=94)
Delusion
2 (2.2%)
5 (5.3%)
Hallucination
0 (0.0%)
4 (4.3%)
Alanine aminotransferase 
1 (1.1%)
3 (3.2%)
Aspartate aminotransferase 
1 (1.1%)
3 (3.2%)
Constipation
0 (0.0%)
3 (3.2%)
Adapted with permission from Doody RS, et al. Lancet.
2008;372:207-215.
21
21
Confirmatory Phase 3 dimebon
Trial: Negative
 Enrollment in confirmatory trial of dimebon in mild-tomoderate AD began Spring 2008
– Pla, 5 TID, 20 TID
– OLEX offered
 Enrollment completed in June with 598 patients (initial
goal was 525)
 @ 70 sites in the US, Europe, and South America
 Primary endpoints were ADAS-cog and CIBIC-plus
22
Other Phase 3 Dimebon studies:
• 12-month trial of Dimebon added to ongoing treatment with
donepezil HCl tablets in mild-moderate AD
• Pla, 5 TID, 20 TID
• Enrollment began April 2009, with target enrollment of 1050
patients
• 6-month trial of dimebon added to ongoing treatment with
donepezil in mod severe AD w behavioral symptoms
• Pla vs 20 TID
• 6-month trial of dimebon added to ongoing treatment with
memantine in mod severe AD
• Pla vs 20 TID
23
Case Example: Why Amyloid
Matters
 Plaques are a hallmark of the illness
 The major (rare) causes of familial
Alzheimer’s all involve abnormal processing
of the amyloid protein
 Leads to highly toxic intermediates
 Can we block this cascade?
24
APP
gene
Production
-Amyloid–related
disease-modifying strategies
APP
Cu++
Chelator
A
Monomer
?
Immunotherapy
Antisense
Secretase
modulators
A
Oligomer
Aggregation
A
Fibril
Deposition
Fibrillogenesis
modulators
Relkin, 2006.
Diffuse
Plaque
Senile
Plaque
Anti-amyloid Immunotherapy:
Amyloid “Vaccine” Reduces Plaque Burden and
Memory Loss in Transgenic Mouse Model of AD
Amyloid Stain (Mouse Brain)
Vaccinated
Unvaccinated
Morgan et al. Nature. 2000;408:982-985.
26
Active Immunization
 Elan Phase II clinical trial of active immunization
with an aggregated Aβ in adjuvant (AN1792) (Gilman
et al. Neurology. 2005)
– n=372
– terminated prematurely
– 18/300 receiving AN1792 developed a sterile
meningoencephalitis related to cerebral T
lymphocyte infiltration (0/72 on placebo)
– 59 (19.7%) developed adequate Aβ response
• This is seen with other active vaccines
– No clinical benefit seen in Aβ responders or nonresponders on most clinical measures
—continued
27
Vaccination with AN-1792:
First demonstration of reversal of AD neuropathology ?
Parietal neocortex, non-immunized
patient at comparable stage of AD
Nicoll et al. Nat Med. 2003;9:448-452.
Parietal neocortex, immunized AD
patient in Elan AN-1792 Trial
Active Immunization: Followup
 Ongoing follow-up offered after active treatment
stopped
 288 had paired volumetric MRIs (Fox et al. 2005)
 Those with higher anti-AN1792 Aβs had greater:
– decreases in WBV
– ventricular enlargement
 Not correlated with impaired cognition
 1-year follow-up of those who at least 1 dose of
AN1792 showed that patients with an anti-Aβ
antibody response exhibited slower rates of
cognitive and functional decline and reduced
cerebral spinal fluid (CSF) concentrations of tau
protein compared with nonresponders
29
Holmes et al followup (2008)
30
Holmes et al, cont’d
31
Active Vaccination, cont’d
 2nd-generation vaccines use small pieces of Aß to avoid
activating T-cells responsible for meningoencephalitis
 Since T cell epitopes exist mainly in the C-terminal portion of
Aβ, vaccines using shorter N-terminal peptides are in
development.
 Since T helper 1 (Th1) immune responses activate
encephalitogenic T cells and induce continuous inflammation in
the CNS, vaccines inducing Th2 immune responses may hold
promise.
– N-terminal short Aβ peptides with Th2 adjuvant or Th2stimulating molecules,
– DNA vaccines,
– recombinant viral vector vaccines,
– recombinant vegetables
– others.
32
Active Vaccination, cont’d
 ACC-001 is in phase II testing in patients with
mild-moderate AD.
 CAD106 consists of the first 6 N-terminal
amino acids of Aβ attached to a virus-like
particle, which is believed to stimulate B cells
while preventing excessive T-cell activation
thereby avoiding T-cell mediated adverse
effects
33
Passive Immunization
 Monoclonal antibodies in development are designed to
target 1 of 3 domains of the Aβ protein: the n-terminus,
the middle portion, or the c-terminus.
– It is possible that efficacy, safety, or both may be
substantially different depending on the binding
domain.
 Elan/Wyeth, bapineuzumab (AAB-001) is a humanized
monoclonal antibody to N-terminus of Aβ in phase III
development
 Lilly, LY206430 (a humanized version of m266) targets A
β and is in phase II (Bales et al. Neurobiol Aging. 2004)
 Others are in development as well
34
Preclinical Data With AAB-001
(bapineuzumab)
Contralater
al
A
Ipsilateral
Intra-hippocampal anti-Aβ clears
extracellular
and intracellular Aβ aggregates
Anti-Aβ injection
Contralateral
E
1mm
500 µm
D
E
1mm
F
F
C
G
200 µm
250
Tau staining
B
Ipsilateral
1mm
G
H
250 µm
Early anti-Aβ administration clears
also non-phosphorylated tau
Reprinted with permission from Oddo S, et al. Neuron. 2004;43:321-322. 35
35
Phase 2 Trial of Bapineuzumab
Randomized, multicenter, placebo-controlled,
parallel-group, ascending-dose study
 234 patients enrolled
 Randomization: Bapineuzumab or placebo (8:7)
 Treatment: 6 infusions 13 weeks apart
– 4 dose cohorts: 0.15, 0.5, 1.0, and 2.0 mg/kg
 Final Assessment: Week 78
Salloway S, et al. Neurology. 2009. In press.
36
36
Bapineuzumab Phase II Results
 No drug-placebo differences on ADAS-cog, DAD,
NTB, CDR-SB
 Based on a post hoc analysis of E4 non-carriers,
ADAS-cog, NTB, and CDR-SB significantly favored
the drug
Salloway S, et al. Neurology. 2009.
37
Bapi phase II (Salloway et al 2009)
38
Bapineuzumab Phase 2 Results: Safety
 AEs generally mild-to-moderate,
transient, not dose-related
 % of patients with SAEs similar
between bapineuzumab and
placebo except for vasogenic
edema
– In 0.5, 1.0, and 2.0 mg/kg
cohorts
 3 deaths in bapineuzumabtreated patients, unrelated to
treatment
 Selected AEs in <5% of
bapineuzumab-treated patients:
syncope, DVT, PE, and cataract
Salloway S, et al. Neurology. 2009.
AEs in ≥5% of pts and
≥2x more frequent with
bapineuzumab vs
placebo
%
Back pain
12.1 vs 5.5
Anxiety
11.3 vs 3.6
Vomiting
9.7 vs 3.6
V E
9.7 vs 0
Hypertension
8.1 vs 3.6
Weight loss
6.5 vs 1.8
Paranoia
6.5 vs 0.9
Skin laceration
5.6 vs 2.7
Gait disturbance
5.6 vs 1.8
Muscle spasm
5.6 vs 0.9
39
Bapineuzumab and Vasogenic Edema in
phase II
12/124 (9.7%) patients on bapi (0 on placebo) developed
vasogenic edema (VE)
– Most frequently detected by MRI, with few or no
clinical symptoms, and resolved in weeks to months
– 10 ApoE4 carriers, 2 non-carriers
 2 mg/kg (6 carriers, 2 non-carriers)
 1 mg/kg (3 carriers)
 0.5 mg/kg (0 carriers)
 0.15 mg/kg (1 carrier)
– 6 of 12 patients resumed treatment with no VE
recurrence
Salloway S, et al. Neurology. 2009.
40
PIB-PET data from phase II (Rinne et al 2010)
41
Bapineuzumab: Phase III Summary
 Mild-moderate (MMSE: 16-26)
 Infusion frequency: Q13 weeks; Infusion duration: 60 minutes
 Four trials (Primary endpoints: ADAS-cog, DAD; Secondary
endpoints: NTB, CDR-SB; Other: MRI, LP)
– 301
• E4- carriers: 0.5, 1.0 mg/kg (2.0 mg/kg discontinued 4/09)
– 302
• E4+ carriers: 0.5 mg/kg
– 3000
• E4- carriers: 0.5, 1.0 mg/kg (2.0 mg/kg discontinued 4/09)
– 3001
• E4+ carriers: 0.5 mg/kg
42
Passive Immunization, cont’d: IVIg
• Beneficial results of monthly infusions of IVIg have
reported in OL study by Dodel et al of 5 patients with
mild-moderate AD (J Neurol Neurosurg Psych. 2005)
• Reported effects included increased plasma Aβ levels
and decreased CSF Aβ consistent with expectations for
increased clearance of Aβ from the brain.
• Relkin et al report similar early experience with small
OL study presented in abstract form (AAN. 2005)
• Relkin et al have conducted a phase II trial showing
encouraging effects
• ADCS/Baxter have launched a phase III trial
43
3rd generation vaccines
 2nd generation vaccines and antibodies both target
linear amino acid sequences found in APP and in
amyloid deposits.
 Antibodies against normal human proteins can cause
autoimmune side effects.
 It is difficult to make antibodies against self-proteins
because of immune suppression of auto antibodies.
 3rd generation vaccines use antibodies that target
structures specific to amyloid aggregates and that do
not react with normal human proteins.
44
Secretase Pathway
 Beta secretase (“BACE”) inhibitor
– Most attractive theoretically?
– Prior agents have failed
– Several agents in/approaching
 Gamma secretase inhibitor
– Various agents have shown the desired
biological effect
– 2 in phase II-III trials now (Lilly, BMS)
– Others pending
 Tarenflurbil (“Flurizan”), a putative gamma
secretase modulator, failed to show
benefit in phase III trial; concerns re lack
of demonstration of target engagement
45
Anti-aggregant Therapies
 Tramiprosate (“Alzhemed”) failed in phase
III trials
 Elan has compound in phase II now
46
Anti Amyloid Therapy:
Conclusions
• Many medications and immunotherapies exist that
can alter the processing of amyloid in the lab and
in animal models
• They have shown at least some ability to alter
blood, spinal fluid, PiB, and pathological
measures of different types of amyloid in normals
and/or people with AD
• Effects on MRI, FDG PET, other biomarkers in
humans unclear/unknown
• Dose ranges not established in all cases
• Clinical significance of encouraging proof of
concept biomarkers remain unknown
47
Theories of How Damage
Occurs in AD
From Inside the Cell: Tangle Formation
Axon
Microtubules
Tangles
Neuron
Tau
Proteins
Paired Helical
Filament
Dendrites
Tau proteins, which
normally stabilize
microtubules in brain cells...
undergo abnormal chemical
changes and assemble into spirals
called paired helical filaments...
thus creating tangles
that disrupt cell functions
and lead to cell death.
Sources: Dr John Trojanowski and Dr Virginia M. Y. Lee. University of Pennsylvania Medical Center.
48
Antitangle Therapies for Alzheimer’s Disease
 Minocyline
 Microtubule stabilizers
– kinase inhibitors:
• GSK 3: AstraZeneca compound in early
development, large ADCS valproate trial
was (-), ADCS lithium trial abandoned
after (-) European Li trial completed
• vaccination approaches in early
development
• CDK5
– AZD-1080
– AL-108 (NAP)
– PDE4 inhibitors
49
Methylthioninium Chloride
(rember™)
 Thought to inhibit tau aggregation by
– Blocking the formation of Tau oligomers and their
conversion to Paired helical filaments
– Solvating / dissolving Tau oligomers and paired
helical filaments into the short truncated monomers
that comprise the proteolytically stable core of the
Paired helical filaments
• Once reduced to its constituent monomers, the
truncated Tau monomers become susceptible to
proteases and are of a size that can be cleared efficiently
through the proteasomal clearance pathway
 Phase 3 trial underway
TauRx Therapeutics Ltd. Pipeline—Alzheimer’s disease. 2008.
Available at: www.taurx.com/pipeline_first.aspx. Accessed June 8, 2009.
50
Where Do We Stand in Terms of
Pharmacotherapeutic Advances?
 Disappointments
– Tarenflurbil
– Tramiprosate
– Vitamin E
– B6, B12, folate combination
– Omega 3 fatty acid
– Statins
– Glitazones
– Valproate
– Lithium
– Gingko biloba for prevention
– NSAID’s for treatment, prevention
– HRT for treatment, prevention
• But important questions remain
51
Where Do We Stand in Terms of
Pharmacotherapeutic Advances?
 Too soon to tell
– Methylthioninium Chloride (rember™)
– Huperzine (ADCS trial showed +/- results)
– Glitazones in MCI
 Phase III
 Latreperdine (dimebolin)
 Other potential antiamyloid therapies
– Bapineuzumab
– Other monoclonal Ab’s
– IVIG
– Secretase inhibitors
– RAGE inhibitor
– Antiaggregant (scyloinositol derivative)
– Insulin
52
Rational Polypharmacy
 Because the number of possible combination therapies is too
large to allow all combinations to be tested, combination and
add-on therapies will be guided by rational polypharmacy on the
basis of the following1:
– Complementary MOAs and relevant additive or synergistic
effects
– Degree of disease progression
– Potential for drug-drug interactions
– Feasible administrative schedules
– Safety
– Tolerability
 Disease modification may slow deterioration without
improvement if existing symptoms, and concomitant therapy
with symptomatic agents is anticipated1
1. Salloway S, et al. Alzheimers Dementia. 2008;4:65-79.
53
Alzheimer’s Disease: The
Treatment Horizon
 Disease-modifying therapy
 Combination disease-modifying and symptomatic
therapy
 Earlier recognition of Alzheimer’s disease
 Integration of biomarkers into clinical practice
– Spinal fluid
– Blood
– Imaging
– Genetics as well
 A host of unanswered questions
54
We Can Use Information From Multiple Sources
to Improve Diagnosis and Assess Treatment
Neuronal Activity
FDG PET
Biomarkers
Cognitive Reserve
fMRI
Diagnosis
Treatment
Brain Atrophy
Structural MRI
Plaque Load
PIB-PET
Genetic Risk
Profile
Cognitive, Functional
Profile
Why Now?
1. The urgent need
2. Suggested but unproven “healthy lifestyle”
interventions
3. Investigational AD-modifying treatments
4. The treatment of symptomatic patients may be too
little too late
5. Biomarkers of AD progression & pathology
What’s Holding Us Back?
1. Too many subjects, too much time & too much money
using clinical endpoints
2. Insufficient evidence to support the “qualification for
use” of AD biomarkers as surrogate endpoints
3. The safety & tolerability data needed to evaluate
investigational AD-modifying treatments in
presymptomatic AD trials
Biomarkers of AD Progression &
Pathology*
•
•
•
•
Structural MRI measurements
FDG PET measurements
Fibrillar Aβ PET measurements
CSF Aβ42, alone or in combination with t-tau or p-tau
levels
*in both the symptomatic & presymptomatic stages
of AD
But…
• These biomarkers need to be further characterized &
compared in RCTs
• to determine the extent to which they can be budged by
effective treatments
• to identify potentially confounding treatment effects
unrelated to AD modification
• to determine the extent to which a treatment’s effects
on biomarkers, alone or in combination, are “reasonably
likely” to predict a clinical benefit
A Proposal to Accelerate the Evaluation
of Presymptomatic AD Treatments
1. Presymptomatic AD treatment / surrogate marker
development trials in people at the highest imminent risk
of symptomatic AD
• PSEN1 carriers close to their estimated median age at
clinical onset
• 60-80 year-old APOE ε4 homozygotes
2. Infrastructure & national registry to support the
conceptualization & implementation of other
presymptomatic AD trials
3. Scientific & public policy recommendations for the
accelerated evaluation of presymptomatic AD treatments
Presymptomatic Treatment / Surrogate Marker
Development RCTs in People at the Highest Imminent
Risk of Symptomatic AD: The Opportunities
1. To evaluate promising investigational treatments in presymptomatic RCTs sooner
than otherwise possible
2. To generate data needed to support the use of biomarkers as reasonably likely
surrogate endpoints in other presymptomatic AD RCTs
•
To help provide both the means & accelerated regulatory approval pathway
needed to evaluate many different presymptomatic AD treatments at the same
time
3. To provide the best test yet of the amyloid hypothesis
4. To provide a foundation for other presymptomatic AD trials
5. To complement, contribute to & benefit from other initiatives e.g., ADNI, ADCS,
DIAN , ADC program & public policy initiatives
6. To give those at highest imminent risk for AD access to some of the promising
investigational treatments in RCTs