1. Alzheimer’s Disease: Advances and Hope Trey Sunderland, M.D. Chief, Geriatric Psychiatry Branch National Institute of Mental Health Bethesda, Maryland

2. Diagnosis and Treatment of Alzheimer’s Disease: Today and Tomorrow

3. What is the course of Alzheimer’s Disease?

4. When does AD really start?

5. What is the cause of AD?

6. Frontal Cortex Hippocampus Basal Nucleus Nucleus of Diagonal Band Medial Septal Nucleus Occipital Cortex

7. Plaque of  -Amyloid Protein in the Brain of an AD Patient

8. Neurofibrillary Tangles in AD

9. FDA Approved Therapy: Acetylcholinesterase Inhibitors (AChEI)

10. Rivastigmine in Mild to Moderate Alzheimer’s Disease (Messina J et al. Poster presented at: 3rd International Meeting of College of Psychiatric and Neurologic Pharmacists; April 6-9, 2000; Washington, DC.) -2 0 2 4 6 8 01226384452 Weeks of Treatment Mean Change from Baseline in ADAS-Cog Score Clinical Improvement Clinical Decline 6-12 mg/d 1-4 mg/d Placebo/Rivastigmine Projected Placebo All patients taking 2-12 mg/d

11. Metrifonate Effects on NPI (Cummings et al. AAN Abstract, 1998) 4 NPI Change from BL 3 2 1 0 Total Hal Depr Apathy Abe 0.8 0.6 0.4 0.2 0 -0.2 Placebo Metrifonate

12. Therapeutic Conundrums: Questions How long to treat? Do they slow progression? Are they effective in all stages of AD? Are they effective only in Alzheimer’s disease? Cholinesterase inhibitors

13. Current & Potential AD Therapies:

14. Memantine in Moderate-to-Severe Alzheimer’s Disease Reisberg et al., NEJM 384: 1333-41, 2003 MemantinePlacebo N Completers Age (Yrs) Educ (Yrs) MMSE GDS Stage: 5 6 126 (35M/91F) 97 (77%) 75.5 ± 8.2 12.3 ± 3.1 7.8 ± 3.8 47% 53% 126 (47M/79F) 84 (67%) 75.8 ± 7.3 12.9 ± 3.1 8.1 ± 3.6 49% 51%

15. Effect of Lovastatin on Serum A  * P = 0.02 ** P = 0.03 -75 Controlled-Release Lovastatin -50 -25 25 50 75 % Change in Serum A  0 Placebo n = 15 10 mg n = 20 20 mg n = 19 40 mg n = 20 60 mg n = 20 * **

16. Proportion Remaining Unaffected According to Duration of Estrogen Use (Tang MX et al. Lancet, 1996;348:429-432) 0.0 65707590 Age of Onset (Years) 0.2 0.4 0.6 0.8 1.0 Proportion Free of AD Survival Analysis Plot of Distribution by Age 80 85 95 >1 Year (mean 13.6 years) <1 Year (mean 4 months) Never Duration of estrogen

17. Anti-inflammatory Approaches

18. Alzheimer’s Disease Inflammatory Mechanisms APP Non-Fibrillar  -A4  -A4 Deposits IL-1, IL-6 Activated Microglia Neuronal Degeneration

19. NIMH Study (Protocol 01-M-0128)

20. Vaccine Therapy?

21. Anti-Amyloid Therapy? Gamma secretase inhibitors Beta secretase inhibitors - Drug(s) that blocks enzyme that triggers plaque

22. Future Therapies: ?Multidrug Approaches?

23. Would YOU want Preventative Therapy?

24. RISK vs. BENEFIT Analysis Needed (Protocol 95-M-96)

25. Family “AT RISK” Study: Biological Measures APO E Genotyping (Baseline) Structural MRI (1.5 Tesla Machine) CSF Tap (i.e.,  -amyloid, Tau, etc.)

26. What is this object?

27. Family “AT RISK” Study: Biological Measures APO E Genotyping (Baseline) Structural MRI (1.5 Tesla Machine) CSF Tap (i.e.,  -amyloid, Tau, etc.)

29. Family “AT RISK” Study: Biological Measures APO E Genotyping (Baseline) PET Scans CSF Tap (i.e.,  -amyloid, Tau, etc.)

30. Family “AT RISK” Study: Biological Measures APO E Genotyping (Baseline) Structural MRI (1.5 Tesla Machine) CSF Tap (i.e.,  -amyloid, Tau, etc.)

31. CSF  -amyloid 1-42 in AD

32. Good Consistency Across 18 Studies

33. Family “AT RISK” Study: Biological Measures APO E Genotyping (Baseline) Structural MRI (1.5 Tesla Machine) CSF Tap (i.e.,  -amyloid, Tau, etc.)

34. CSF Tau in AD

35. Excellent Consistency Across 35 Studies!

36.  -amyloid 1-42 + Tau 92% Specificity 89% Sensitivity

37. What about Normal People “At Risk”?

38. Will the therapies be available soon enough?

39. Future Therapies: Multidrug Approaches

40. Alzheimer’s Disease Predictions 2-4 Million 16 Million Years 0 Clinical Diagnosis 20406080100 Symptomatic Drugs Only 2000 Years 0 Clinical Diagnosis 20406080100 2030