Targets for the treatment of Alzheimer's disease
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Targets for the Treatment of Alzheimer's Disease
Targets for the Treatment of Alzheimer's Disease
June 1, 2012
Brian S. Appleby, M.D.Cleveland Clinic Lou Ruvo Center for Brain Health
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ObjectivesObjectives
1.Describe the pathophysiology underlying Alzheimer's disease (AD)
2.Summarize currently available AD treatments
3.Describe investigational treatments and potential treatment targets
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Alzheimer's DiseaseAlzheimer's Disease
Pre-Symptomatic Disease
Mild Cognitive
Impairment(MCI)
Dementia
Amnesia
Aphasia
Apraxia
Agnosia
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NeuropathologyNeuropathology
Amyloid plaquesA-beta oligomers
Neurofibrillary tanglesPhosphorylated tau
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NeurotoxicityNeurotoxicity
Amyloid precursor protein (APP)
α,β,γ-secretases
a-beta1-40
a-beta1-42
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Mesiotemporal Atrophy Mesiotemporal Atrophy
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Nucleus Basalis of MeynertNucleus Basalis of Meynert
Ach
Ach
ADAnticholinergicScopolamine
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Cholinesterase InhibitionCholinesterase Inhibition
Ach
Ach Ach
Ach
Ach
Ach
Ach
Ach
Ach
AchAch
AchE
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Cholinesterase InhibitorsCholinesterase Inhibitors
Medication Mechanism of Action
Donepezil AChE-Inh
Galantamine AChE-Inh
Tacrine AChE-Inh
Rivastigmine
AChE-Inh + Butyl-ChE-Inh
Adverse effects=GI upset & bradycardia
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BenefitsBenefits
• Possibly decrease neuropsychiatric symptoms
• Helps maintenance of daily functional ability
• Treatment effect of about 3 years• Approved for use in mild-moderate AD
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NO Effect on Survival TimeNO Effect on Survival Time
Suh G, Am J Geri Psych 2011
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Switching ChE-Inh?Switching ChE-Inh?
• Tolerability-switch after previous ChE-Inh’s adverse effects have abated
• Lack of clinical efficacy (>2 point decrease of MMSE in first year)
• Not recommended for loss of efficacy past one year of treatment
Massoud F, Int Psychogeriatrics 2011
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Farlow MR, Clinical Therapeutics 2010
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Farlow MR, Clinical Therapeutics 2010
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Donepezil 23mg vs 10mgDonepezil 23mg vs 10mg
• Greater benefits in cognition in moderate to severe AD
• No benefit in functional status• Tolerability issues, 10mg->15mg->23mg
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MemantineMemantine
• NMDA antagonist• Approved for use of moderate-severe AD• Mild benefits in cognition and clinician’s
global assessment of change• Not efficacious in mild AD
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Treatment TargetsTreatment Targets
Disease Modifying vs. Symptomatic Treatments
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Intervention Stage IIntervention Stage I
APPSecretase
ActivityAβ oligomer
species
Variety of small molecule compounds
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Intervention Stage 2Intervention Stage 2
Fibrillization Plaque Deposition Neurotoxicity
Anti-propagation strategies
Increase innate clearance mechanisms
Antibody mediatedAnti-inflammatory
mechanisms
Anti-oxidant mechanisms
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Targeting tauTargeting tau
• Accompanying and earlier piece to AD• Target hyper-phosphorylation
pathophysiology (formation of p-tau)• Many known ways to inhibit GSK-3β
(a.k.a. lithium, methylene blue)• Applicable to other tauopathies (i.e.
frontotemporal lobar degeneration)
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Immunization StrategyImmunization Strategy
Holmes C, Lancet 2008
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No Clinicopathologic Correlation
No Clinicopathologic Correlation
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No Change in Survival TimeNo Change in Survival Time
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Immunotherapy SummaryImmunotherapy Summary
• Early serious adverse effects of cerebral edema
• Works from a pathophysiological perspective
• No effect clinically• ? Need to treat earlier? • ? Are plaques protective “sinks”
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Bexarotine (Tg mice)Bexarotine (Tg mice)
*Corresponding clinical improvement
Cramer P, Science 2012
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Proteinopathies are “prionoid”Proteinopathies are “prionoid”
Morales R, CNSND-DT 2009
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Stop Aggregation/Stop PropagationStop Aggregation/Stop Propagation
Forlorni G, FEBS Letters 2001
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One More Challenge…One More Challenge…
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2011 Alzheimer’s Disease Facts and Figures
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Rank Cause of death 2010 Age-adjusted death rate
% change from 2009
1 Heart disease 178.5 -2.4
2 Cancer 172.5 -0.6
3 Chronic lung disease 42.1 -1.4
4 Cerebrovascular disease 39 -1.5
5 Accidents 37.1 -1.1
6 Alzheimer’s disease 25 +3.3
7 Diabetes 20.8 -1
Adapted from: NVSR, 60(4)
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Ashburn TT, Nat Rev Drug Discov 2004
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The Power or RepositioningThe Power or Repositioning
Ashburn TT, Nat Rev Drug Discov 2004
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SummarySummary
• Pathophysiologic associations are well known; direct neurotoxic mechanisms are becoming better understood
• Only symptomatic treatments currently• Many different targets for future
treatments and many compounds already studied in AD models
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