Targets for the treatment of Alzheimer's disease

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Overview of Alzheimer's disease treatment targets and drug development strategies

Overview of Alzheimer's disease treatment targets and drug development strategies

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  • 1. Targets for the Treatment of Alzheimers Disease June 1, 2012 Brian S. Appleby, M.D.Cleveland Clinic Lou Ruvo Center for Brain Health
  • 2. Objectives1. Describe the pathophysiology underlying Alzheimers disease (AD)2. Summarize currently available AD treatments3. Describe investigational treatments and potential treatment targets
  • 3. Alzheimers Disease MildPre-Symptomatic Cognitive Dementia Disease Impairment (MCI) Amnesia Aphasia Apraxia Agnosia
  • 4. NeuropathologyAmyloid plaques Neurofibrillary tanglesA-beta oligomers Phosphorylated tau
  • 5. NeurotoxicityAmyloid precursor protein (APP) α,β,γ-secretasesa-beta a-beta 1-40 1-42
  • 6. Mesiotemporal Atrophy
  • 7. Nucleus Basalis of Meynert Ach Anticholinergic AD Scopolamine Ach
  • 8. Cholinesterase Inhibition Ach Ach Ach AchE Ach Ach Ach Ach Ach Ach Ach Ach
  • 9. Cholinesterase 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
  • 10. Benefits• Possibly decrease neuropsychiatric symptoms• Helps maintenance of daily functional ability• Treatment effect of about 3 years• Approved for use in mild-moderate AD
  • 11. NO Effect on Survival Time Suh G, Am J Geri Psych 2011
  • 12. 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
  • 13. Farlow MR, Clinical Therapeutics 2010
  • 14. Farlow MR, Clinical Therapeutics 2010
  • 15. Donepezil 23mg vs 10mg• Greater benefits in cognition in moderate to severe AD• No benefit in functional status• Tolerability issues, 10mg->15mg->23mg
  • 16. Memantine• 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
  • 17. Treatment TargetsDisease Modifying vs. Symptomatic Treatments
  • 18. Intervention Stage I Secretase Aβ oligomerAPP Activity species Variety of small molecule compounds
  • 19. Intervention Stage 2 Increase innate clearance Anti-oxidant mechanisms mechanisms PlaqueFibrillization Neurotoxicity DepositionAnti-propagation Anti-inflammatory Antibody mediated strategies mechanisms
  • 20. Targeting 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)
  • 21. Immunization Strategy Holmes C, Lancet 2008
  • 22. No Clinicopathologic Correlation
  • 23. No Change in Survival Time
  • 24. Immunotherapy Summary• Early serious adverse effects of cerebral edema• Works from a pathophysiological perspective• No effect clinically• ? Need to treat earlier?• ? Are plaques protective “sinks”
  • 25. Bexarotine (Tg mice) *Corresponding clinical improvement Cramer P, Science 2012
  • 26. Proteinopathies are “prionoid” Morales R, CNSND-DT 2009
  • 27. Stop Aggregation/Stop Propagation Forlorni G, FEBS Letters 2001
  • 28. One More Challenge…
  • 29. 2011 Alzheimer’s Disease Facts and Figures
  • 30. Rank Cause of death 2010 Age-adjusted % change death rate 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)
  • 31. Ashburn TT, Nat Rev Drug Discov 2004
  • 32. The Power or Repositioning Ashburn TT, Nat Rev Drug Discov 2004
  • 33. Summary• 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