Targets for the treatment of Alzheimer's disease

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

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Targets for the treatment of Alzheimer's disease

  1. 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. 2. Objectives1. Describe the pathophysiology underlying Alzheimers disease (AD)2. Summarize currently available AD treatments3. Describe investigational treatments and potential treatment targets
  3. 3. Alzheimers Disease MildPre-Symptomatic Cognitive Dementia Disease Impairment (MCI) Amnesia Aphasia Apraxia Agnosia
  4. 4. NeuropathologyAmyloid plaques Neurofibrillary tanglesA-beta oligomers Phosphorylated tau
  5. 5. NeurotoxicityAmyloid precursor protein (APP) α,β,γ-secretasesa-beta a-beta 1-40 1-42
  6. 6. Mesiotemporal Atrophy
  7. 7. Nucleus Basalis of Meynert Ach Anticholinergic AD Scopolamine Ach
  8. 8. Cholinesterase Inhibition Ach Ach Ach AchE Ach Ach Ach Ach Ach Ach Ach Ach
  9. 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. 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. 11. NO Effect on Survival Time Suh G, Am J Geri Psych 2011
  12. 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. 13. Farlow MR, Clinical Therapeutics 2010
  14. 14. Farlow MR, Clinical Therapeutics 2010
  15. 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. 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. 17. Treatment TargetsDisease Modifying vs. Symptomatic Treatments
  18. 18. Intervention Stage I Secretase Aβ oligomerAPP Activity species Variety of small molecule compounds
  19. 19. Intervention Stage 2 Increase innate clearance Anti-oxidant mechanisms mechanisms PlaqueFibrillization Neurotoxicity DepositionAnti-propagation Anti-inflammatory Antibody mediated strategies mechanisms
  20. 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. 21. Immunization Strategy Holmes C, Lancet 2008
  22. 22. No Clinicopathologic Correlation
  23. 23. No Change in Survival Time
  24. 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. 25. Bexarotine (Tg mice) *Corresponding clinical improvement Cramer P, Science 2012
  26. 26. Proteinopathies are “prionoid” Morales R, CNSND-DT 2009
  27. 27. Stop Aggregation/Stop Propagation Forlorni G, FEBS Letters 2001
  28. 28. One More Challenge…
  29. 29. 2011 Alzheimer’s Disease Facts and Figures
  30. 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. 31. Ashburn TT, Nat Rev Drug Discov 2004
  32. 32. The Power or Repositioning Ashburn TT, Nat Rev Drug Discov 2004
  33. 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

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