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

1. Targets for the Treatment of
Alzheimer's Disease
June 1, 2012
Brian S. Appleby, M.D.
Cleveland Clinic Lou Ruvo Center for Brain Health

2. Objectives
1. Describe the pathophysiology
underlying Alzheimer's disease (AD)
2. Summarize currently available AD
treatments
3. Describe investigational treatments and
potential treatment targets

3. Alzheimer's Disease
Mild
Pre-Symptomatic Cognitive
Dementia
Disease Impairment
(MCI)
Amnesia
Aphasia
Apraxia
Agnosia

4. Neuropathology
Amyloid plaques Neurofibrillary tangles
A-beta oligomers Phosphorylated tau

5. Neurotoxicity
Amyloid precursor protein (APP)
α,β,γ-secretases
a-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 Targets
Disease Modifying vs. Symptomatic Treatments

18. Intervention Stage I
Secretase Aβ oligomer
APP
Activity species
Variety of small molecule compounds

19. Intervention Stage 2
Increase innate clearance Anti-oxidant
mechanisms mechanisms
Plaque
Fibrillization Neurotoxicity
Deposition
Anti-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