alzheimer’s diseasealzheimer’s disease rachelle s. doody, md, phd effie marie cain chair in...
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Alzheimer’s Disease
Rachelle S. Doody, MD, PhD Effie Marie Cain Chair in Alzheimer’s Disease
Research
Director
Alzheimer’s Disease and Memory Disorders Center
Baylor College of Medicine
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Key Questions
What causes AD?
How do you know when someone has AD?
When do you have to intervene in order to prevent or effectively treat AD?
What are current treatments?
What is the status of treatments under development?
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Classic Elements of Alzheimer Neuropathology
Neuritic (Senile) Plaques Central element:
β-amyloid
Neurofibrillary Central element:
hyperphosphorylated tau
From: http://www.neuropat.dote.hu/alzheim.htm
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What causes AD? Plaques and tangles?
Loss of reserve?
Biochemistry of aging?
“Weak” genetic background?
Bad habits?
Chronic inflammation?
All of the above?
Doody Alzheimer’s Dementia Ed Doody RS Carma Publishing, 2008
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Risk factors for AD Age, menopause
Genetics: Apo E 4, TOMM 40, CR1, CLU, PICALM, SORL1 , TREM 2 Genetic risk is probably cumulative
Elevated glucose or diabetes
Elevated cholesterol
Elevated homocysteine
Major head injury with LOC
Chronic inflammation?
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What do we know about preventing AD?
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Large (N>2K) AD Prevention Trials
Study Population Treatment Study Design Results GuidAge SML Ginkgo
Biloba Randomized, PC, 5 years incidence
Primary NS Those on >4 years 50% decrease
GEMS ≥ Age 75 Normal or MCI
Ginkgo Biloba
Randomized, PC, 5 years incidence
NS
WHIMS PM Women ≥ 65
Estrogen ± Progesterone
Randomized, PC, 3 arm, 5 year Incidence MCI or dementia and cognitive change
Worse in treated groups. Early termination
ADAPT ≥Age 70 +FHx in first degree relative
NSAIDs, Naproxen and Celecoxib
Randomized, PC, 3 arm cognitive change
Worse in Naproxen group. Early termination (1.5/7 years)
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Possible Preventive Measures
Weight control/Dietary factors
Exercise (mental & physical)
Normalizing Blood pressure Blood sugar Cholesterol Vitamin B12 and Homocysteine levels Preventing immune over-activation?
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Planned AD Prevention Trials Study Population Treatment Study Design
Alz Prevention Initiative
FAD esp Colombian
Crenezumab Delay AAO, reduce incidence of AD
DIAN FAD Solanezumab, Gantanerubab, Lilly BACE inhibitor
Delay AAO, reduce cognitive loss
ADCS A4 Trial
NC with Aβ, stratified by APO E
Solanezumab Prevent worsening of cognition on composite
Sargramostim Prevention of AD
MCI Sargramostim (GM CSF)
Prevent progression to AD
TOMM 40 /Pioglitazone
NC with high and low risk
Pioglitazone (low dose)
Qualify biomarker algorithm. Prevent MCI due to AD.
ADCS Exercise Study MCI Structured exercise program
Prevent progression to AD
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Speculation Regarding Prevention of AD
Public health measures may reduce the number of cases but will not prevent disease
Individuals with pre-symptomatic disease will already be biologically conditioned to respond differently to different treatments (endophenotype theory)
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How do we know when someone has AD?
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Markers of Asymptomatic AD? Strong AD genetic mutations Multiple biological markers of AD neuropathology Multiple neuroimaging markers C/W AD
Variable Biomarkers of AD neurodegeneration Neuroimaging (metabolic, functional, structural)
Weak One or more AD risk factors (genetic and non-
genetic)
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Stan
dard
ized
Dif
fere
nce
Estimated Yr From Expected Symptom Onset
-2
-1
0
1
2
-35 -30 -25 -20 -15 -10 -5 0 5 10 15
Aβ deposition
CSF tau
CDR - SOB
CSF Aβ42
HippocampalVolumeGlucose Metabolism
Clinical, Cognitive Structural, Metabolic, and Biochemical Changes as a Function of Estimated Years
from Expected Symptom Onset
Modified from Bateman et al NEJM 2012;367(9):795-804
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Role of Biomarkers in Diagnosis For deposition of beta amyloid (Aβ)
• Low CSF Aβ1-42
• Positive PET amyloid imaging For downstream neuronal degeneration and
injury • Elevated CSF tau (total and phosphorylated) • Decreased FDG uptake on PET in
temporoparietal cortex and post. cingulate • Disproportionate atrophy on structural MR
images in medial, basal, lateral temporal lobe, and medial parietal cortex
•14
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Amyloid imaging slides Negative Scan Positive Scan
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New Research Criteria for Preclinical AD
Stage Description Aβ PET or CSF
Neuronal Injury Tau, FDG PET sMRI
Subtle Cognitive Change
1 Asx cerebral amyloid
Positive
Negative Negative
2 1 + downstream neurodegeneration
Positive Positive Negative
3 2 + subtle cognitive/behavioral decline
Positive Positive Positive
Sperling etal Alz & Dem 2011;7:280-292
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Developing Treatments for Early Preclinical AD
Amyloid accumulation in the brain is not the same thing as AD
Have to use biomarkers to select patients and as the outcome since there are no clinical symptoms
Very high screen failure rates ie > 80%
Risk factors are uncontrolled
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Early Symptomatic AD: Mild Cognitive Impairment
A set of mild cognitive disorders
Amnestic MCI likely a transitional state between normal and clinical AD
Non-amnestic MCI may also evolve to AD
“Diagnosing” MCI takes skill and objective test measures
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MCI Subtypes Cognitive Complaint
Not normal for age Not demented
Cognitive decline Essentially normal functional activities
MCI
Memory impaired?
Amnestic MCI Non-Amnestic MCI
Memory Impairment only?
Single nonmemory Cognitive domain
Impaired?
Amnestic MCI Single Domain
Amnestic MCI Multiple Domain
Non-Amnestic MCI Multiple Domain
Non-Amnestic MCI Single Domain
Yes
Yes
Yes
No
No No
Peterson RC. Continuum. 2004;10:9-28.
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How is aMCI determined? Patient and/or informant notices a
change
Demonstrable problem with delayed verbal recall on testing (-1.5 SD)
Originally, no second domain
Normal activities of daily living
Petersen etal Arch Neurol 1999; Petersen and Doody et al Arch Neurol 2001, Rountree et al Dementia 2007
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New Research Criteria for MCI due to AD Diagnosis/ Liklihood
Biomarker Probability of AD
Aβ (PET or CSF) Neuronal injury (tau, FDG, sMRI)
MCI core Uninformative Conflicting/Undetermined/Untested
Conflicting/Undetermined/Untested
MCI due to AD Intermediate
Intermediate Positive Untested
Untested Positive
MCI due to AD High
Highest Positive Positive
MCI due to AD Unlikely
Lowest Negative Negative
Albert etal Alz & Dem 2011;7:270-279
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Neuropathology is not as widespread
Compensatory mechanisms, including cholinergic sprouting, may play a role
Data show that response to AD therapies and probably safety profiles differ and did not support FDA approval for routine treatment of MCI with AD drugs
MCI is Different From Early AD
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Pharmacologic Interventions for aMCI Donepezil Rivastigmine Galantamine
Long-term ‘conversion’ trials
ADCS
(3 years) InDDEx
(3-4 years) Gal 11 and Gal 18
(2 years)
‘Symptomatic’ trials
401 (24 weeks)
412 (52 weeks) - -
Co-Primary outcomes Negative Negative Negative
Other
Significant short-term delay in conversion in
ADCS
+ve outcomes on modified
ADAS-cog in 401 & 412
- -
Salloway S, et al. Neurology. 2004;63:651–657 Petersen RC, et al. N Engl J Med. 2005;352:2379-88 Feldman HH, et al. Lancet Neurol. 2007;6:501-12; Winblad etal Neurology 2008;70:202402035 Doody R, et al.Neurology 2009;72:1555-61
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Developing Therapies for MCI
No clear regulatory pathway and no FDA approved drugs
High screen failure rates ,ie >70%
No strong biomarkers of progression or surrogate markers of treatment effect
Cognitive measures more challenging than for AD (so effect sizes small)
Large, long studies required
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Former AD Research Criteria
Core clinical criteria for Dementia and AD Insidious onset and clear progression
– Amnestic: most common; should include impairments in learning and recall
– Nonamnestic » Language—eg, word-finding difficulties » Visuospatial—eg, object agnosia, impaired face
recognition » Executive function—eg, impaired reasoning,
judgment
Exclusions—eg, significant vascular disease, other dementias
•25
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New Research Criteria for AD Diagnosis Biomarker
Probability of AD Aβ (PET or CSF) Neuronal Injury
(tau, FDG-PET, sMRI
Probale AD Dementia
Clinical Uninformative Unavail, Confl, Indet Unavail, Confl, Indet
Pathophysiol Evid Intermediate Unavail, Indet. Positive
Intermediate Positive Unavail, Indet.
High Positive Positive
Possible AD (Atypical Clinical)
Clinical Uninformative
Unavail, Confl, Indet
Unavail, Confl, Indet
Pathophysiol Evid High, could be secondary
Positive Positive
Dementia—Unlikely AD Lowest Negative Negative
McKhann etal Alz & Dem 2011;7:263-269
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Current Approved AD Therapies
Cholinesterase Inhibitors (donepezil/Aricept; rivastigmine/Exelon; galantamine/Reminyl) NMDA Receptor Antagonist
(memantine/Namenda) Anti-oxidant Vitamins? (Vitamin E 1000
IU; Vitamin C 1000 mg) Medications for Behavioral and
Psychological Symptoms of Dementia
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AD Treatments Treatment Indication Evidence Side Effects Other
Donepezil Mild-Moderate, Severe
Multiple R DB PC trials 3-12 months.
Low incidence GI esp diarrhea and nausea
ODT and Generic available
Rivastigmine Mild-Moderate Multiple R DB PC trials 6 months.
Low to moderate GI incl anorexia, diarrhea and vomiting
Start doses not effective. Patch available.
Galantamine Mild-Moderate Multiple R DB PC trials 6 months.
Low incidence GI esp diarrhea and nausea
ER available for QD. Start dose not effective. Generic
Memantine Moderate-Severe Multiple R DB PC trials 6 months.
Few AE’s Four step titration to this dose
Vitamin E One moderate to severe trial
Few AE’s Controversy re: Survival data
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Molecular Targets for Current AD Therapies
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How Were Current Treatments Developed?
Three to six month randomized, Double-Blind,Placebo-C ontrolled trials
Mild-moderate or Moderate-severe AD populations
At least two clinical outcome measures, usually cognition and global functioning
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How Effective are Current Treatments? Results of pivotal trials confirmed in
meta-analyses and effectiveness studies
Little information regarding longitudinal benefit, especially beyond one year
Our studies suggest that persistent treatment changes the natural history
Doody etal AD Res and Therapy, 2010 Rountree etal AD Res and Therapy 2010, Atri et al Neurobiol Aging in press
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Medical Foods
Must meet a distinctive nutritional need of a specific population
Prescribed by an MD AxonaTM (Ketasyn), approved Souvenaid, under development
Not a nutraceutical (dietary supplement)
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Update on Drug Development
It is global
It is is based upon diverse mechanisms
It is shifting to earlier disease stages
It is hampered by patent life and cost issues
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Strategies for Antidementia Drugs
Drugs/nutraceuticals based upon risk Neurotransmitter-based therapies Metabolic/Neuroprotective drugs Amyloid modulating drugs Tau modulating drugs APO E modifying drugs Glial modulating drugs
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AD Trials Based on Risk Factors
Nonsteroidal anti-inflammatory drugs do not slow progression
Estrogen may increase the risk after age 65 and does not slow progression
Vitamins to lower blood homocysteine did not slow progression
Statins did not slow progression
DHA did not slow progression
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Lesson Learned From Risk Factor Modification Studies
There may be endophenotypes of AD; may respond to different treatments
Controlling risk factors after clinical disease is already symptomatic may not slow the progression
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Neurotransmitter-based therapies under development for AD
Acetylcholine/Cholinergic: ST 101, AF 267B, MK 7622, AZD 3480, MEM 3454, EVP-6124, Posiphen, Huperzine Serotonin: 5 HT4 partial agonists, 5 HT1A
agonists/antagonists, 5HT6 antagonists Norepinephrine/Dopamine: MAO A and MAO B
inhibitors GABA: GABAB antagonists Glutamate: AMPA potentiators Glycine: partial agonists
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Antioxidants (Vit E, Vit C, alpha lipoic acid, CoQ10,)
Phosphodiesterase inhibitors
PPARγ Agonists and Intranasal insulin
Sir1 activators or sirtuins eg Resveratrol
Growth factors (BDNF, NGF)
Dimebon
Metabolic/Mitochondrial/Neurotrophic Targets for Alzheimer’s Disease
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Senile Plaque Formation
Secretion Aggregation Fibrillogenesis
Microglial cell
Reactive astrocyte
Neural cell
Courtesy of Steven Arnold, MD. Anti-inflammatories
Anti-amyloid drugs
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Anti-amyloid Strategies as Prevention or Treatment
β-secretase inhibitors (or antibodies) γ-secretase inhibitors Anti-aggregants or chelators Immunization
α-secretase
N β-amyloid C
β-secretase γ-secretase
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Toxicity of Amyloid
Scientists debate the “species” of amyloid responsible for damage and for symptoms
Increasing evidence that abnormally folded proteins (including A beta) act as “corruptive protein templates”
Jucker etal Ann Neurol 2011; 70:532-540 Stohr etal Proc Natl Acad Sci 2012;
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Immunotherapy with AN1792 Reduces Amyloid Plaques in 18-mo
Old Transgenic Mice
Schenk D, et al. Nature 1999;400:173
a b
200 µm
Human study halted because of subacute meningoencephalitis Gilman etal Neurology 2005;64:1553-1562;
Orgogozo et al Neurology 2003;61:46-54
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Anti-amyloid strategies Passive Antibodies and IV Ig
(Bapineuzumab,Solanezumab, Crenezumab, Gantanerumab, PF 04360365, SAR228810)
Active monoclonal antibody vaccines (ACC-001, CAD-106, V950)
Anti-fibril, anti-aggregation, altered cleavage (Curcumin, Scyllo-Inositol, PBT2, ST-101)
Gamma/Beta secretase inhibitors (Semagacestat, Avagacestat, MK 8931, LY 288671)
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Recent Antibody Studies Bapineuzumab
Two large negative Phase 3 studies with > 1000 each
No clinical benefits in any group or subgroup examined
Lowered P-tau
Solaneuzumab Two large negative Phase
3 studies with > 1000 each
Benefits on cognition (esp. mild) and ADL (combined)
Lowered free Aβ40 in CSF, large increases Aβ40 and 42 in plasma
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H&E PHFtau PHFtau
Neurofibrillary Tangle Formation
Microtubule
Abnormal phosphorylation
Overactive kinase(s)
Hypoactive phosphatase(s)
Senile plaque
Dendrites
Neurofibrillary tangle
Neuron death
Axon
Neuropil threads
Tau PHFs PHFs
Courtesy of Steven Arnold, MD. W/modifications
Gsk inhibitors? /Taxols?
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Spread of Tangles
Hyperphosphorylated tau is relased by neurons and taken up trans-synaptically by adjacent cells
It triggers tangle formation in nearby neurons
Liu etal PLoS One 2012;7(2):e3130 De Calignon etal Neuron 2012:73(4):685-697
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Anti-tangle approaches
Micro-tubule stabilizers, eg NAP (AL-108) or Methylene blue (Rember) Kinase inhibitors (GSK3α, GSK3β, CDK
5) eg AZD-1080, Li, Minocycline Phosphodiesterase-4 Inhibitors Immunotherapies
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APO E enhancing strategies
Bexarotene, approved for cutaneous T-cell lymphoma, rapidly reduces soluble amyloid in WT and TG mice Increases transcription of ApoE by binding of
Retinoid X Receptors (RXR) to nuclear receptors Rate of drug metabolism increases over time Pancreatitis, hypothyroidism, LFT’s, lipids, insulin
Cramer etal Science 2012;335:1503-1506
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Glial Modulating Drugs
Affect glial cells directly (G CSF and GM CSF, Nitro-flurbiprofen, ONO-2506, Tacrolimus)
RAGE receptor antagonists (TTP 488)
TNF alpha antagonists (Enbrel)
None proven effective
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Conclusions AD is treatable
There are lots of strong theories that have treatment implications for AD
Prevention and treatment trials should proceed in parallel
Therapy will likely be tailored to stage as well as personal genetic and risk profile
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Challenges going forward
Defining populations
Recruiting enough subjects
Endpoints for preclinical studies
Funding so many diverse approaches