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2-4 Million

2000. 2-4 Million. Clinical Diagnosis. 0. 20. 40. 60. 80. 100. Years. 2030. Clinical Diagnosis. 16 Million. 0. 20. 40. 60. 80. 100. Years. Symptomatic Drugs Only. Alzheimer’s Disease Predictions. Nursing Home. Alzheimer’s Disease Symptomatic Time Course. Test Results.

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2-4 Million

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  1. 2000 2-4 Million Clinical Diagnosis 0 20 40 60 80 100 Years 2030 Clinical Diagnosis 16 Million 0 20 40 60 80 100 Years Symptomatic Drugs Only Alzheimer’s Disease Predictions

  2. Nursing Home Alzheimer’s Disease Symptomatic Time Course Test Results Diagnosis of AD MCI (12-15%/yr) Diagnosis Autopsy Mild Moderate Severe 3-4 years/stage

  3. Inflammatory response Cell Amyloid damage deposition LOD? Autopsy Gene? Test Results Clinical diagnosis 0 20 40 60 80 100 Years Alzheimer’s Disease Rx Speculative Timeline

  4. Major Theories in AD Causation: Cholinergic Damage b-Amyloid Toxicity Tau Pathology Genetic Risk

  5. Cholinergic Neuron in Aging AChE CAT Choline uptake

  6. Plaque Theory of Damage in AD From Outside the Cell Plaque Reactive peptides Insoluble peptides Soluble peptides Neural cell Nucleus Chaperone proteins Beta amyloid peptides, secreted by brain cells, are normally soluble, and any excess is cleared away ... … but when they become insoluble, they collect in the space between cells, the fibrils herded together by chaperone proteins The large plaques that form damage brain cells and attract reactive cells, which cause further damage Sources: Dr. John Trojanowski and Dr. Virginia M.Y. Lee/University of Pennsylvania Medical Center

  7. Tangle Theory of Damage in AD From Outside the Cell Tangle Axon Microtubules Tau proteins Neuron Paired helical filament Dendrites Tau proteins, which normally stabilize microtubules in brain cells ... … undergo abnormal chemical changes and assemble into spirals called paired helical filaments ... … thus creating tangles that disrupt cell functions and lead to cell death Sources: Dr. John Trojanowski and Dr. Virginia M.Y. Lee/University of Pennsylvania Medical Center

  8. 2 Clinical Improvement P = 0.053 P < 0.001 1 P = 0.019 P < 0.001 P = 0.001 0 MMSE, Least Squares Mean Change from Baseline Score -1 -2 Donepezil Placebo Clinical Decline -3 0 12 24 36 48 Endpoint Study Week n = 135 n = 137 Donepezil Placebo 127 128 121 120 104 105 91 98 (135) (137) Donepezil in Mild to Moderate Alzheimer’s Disease (Winblad B et al. Poster presented at: Therapeutics of Alzheimer’s Disease Conference; 2000; Stockholm)

  9. -5 Open-Label Extension Double Blind -4 Clinical Improvement P < 0.001 -3 -2 P < 0.001 Mean (± SEM) Change from Baseline in ADAS-Cog/11 Score -1 0 1 2 Placebo/galantamine 24 mg Galantamine 24 mg/galantamine 24 mg 3 Clinical Decline 4 0 3 6 9 12 Months of Treatment Galantamine: Mean Change from Baseline in ADAS-Cog Scores (Raskind MA et al. Neurology, 2000;54:2261-2268.)

  10. Current View of Cholinergic Therapy Proven benefits: – Effective in 6-month trials Emerging benefits: – Effective for at least 12 months – Slow loss of function – Improve or delay troublesome behaviors – Delay placement in long-term care facility (Tariot PN et al. Neurology. 2000;54:2269-2276; Raskind MA et al. Neurology. 2000;54:2261-2268; Knopman D et al. Neurology. 1996:47:168-117; McLendon BM et al. J Geriatr Psychiatry Neurol. 1999;12:39-48.)

  11. Nursing Home Alzheimer’s Disease Symptomatic Time Course Test Results Diagnosis of AD MCI (12-15%/yr) Diagnosis Autopsy Mild Moderate Severe 3-4 years/stage

  12. Expanding Uses of AChEI’s Open Studies Placebo-controlled Vascular dementia Lewy body dementia Adult attention deficit hyperactivity disorder Supranuclear palsy Down’s syndrome Mild cognitive impairment Multiple sclerosis Brain injury Brain tumors Post–CABG memory loss Schizophrenia, mania REM sleep disorder Parkinson’s Dementia Autism Post-ECT confusion Pre-Surgical Prophylaxis

  13. Therapeutic Targets and Strategies Under Study , -Secretase inhibitors Vaccine Anti-inflammatories Estrogen preparations Antioxidants Statins NMDA antagonists Cholinomimetics

  14. -0.2 FAST Score Clinical Improvement 0 0.2 **p = 0.007 Change Score 0.4 0.6 Memantine Placebo Clinical Decline 0.8 0 4 12 28 Weeks in Trial Memantine in Mod-Severe AD Reisberg et al., NEJM 384: 1333-41, 2003

  15. Vitamin E Treatment Percent Remaining Outside an Institution ** 75 70 Non-NH (%) 65 60 55 Placebo Selegeline Vit E Combo (Sano et al. NEJM 336:1216-1222, 1997)

  16. 2.0 Clinical Improvement 0 -2 ADAS-Cog Change Score -4 Only 1.4 Point Change! -6 -8 Ginkgo Placebo Clinical Decline -10 0 26 52 Weeks in Trial ADAS-Cog on GINKGO (Le Bars et al. JAMA 278 (16): 1327-1332, 1997)

  17. NSAID (n = 14, mean D = +1.3%) ** Placebo (n = 14, mean D = -8.4%) 10 5 0 % Change from BL -5 -10 -15 TOKEN BOSTON MMSE ADAS Indomethacin Trial in AD (Rogers et al. Neurology 43:1609-1611, 1993)

  18. Putative Inflammatory Agents in AD Interleukin-1 (IL-1) Interleukin-6 (IL-6) Senile plaques (SPs) Neurofibrillary tangles Tumor necrosis factor  (TNF ) NF-B Microglia Amyloid  COX-2

  19. Cyclophosphamide Rx in AD:A Pilot Study Mild-to-Moderate subjects with AD Ability to give Informed Consent themselves Willing to undergo 6 monthly infusions Placebo controlled vs. 2 doses of CYCLO 15 subjects in study to this point Larry Bauer, Coordinator 301-496-3253

  20. Vaccine Therapy for AD“History & Recent Developments” AN 1792 (Elan Pharmaceuticals) - Vaccine that prevents plaque buildup in mice AN 1792vaccine administered to humans causing meningitis-like reaction (2002) Alternative vaccine approaches possible

  21. Amyloid Processing Structure of Precursor Molecule Normal Enzymatic Processing Alternative Enzymatic Processing Protease-Regulating Region Intact Beta-fragment Is released Beta-region is cut Amyloid Beta- Region Amino Terminal Carboxyl Membrane Terminal

  22. Inflammatory response Cell Amyloid damage deposition LOD? Autopsy Gene? Test Results Clinical diagnosis 0 20 40 60 80 100 Years Preventative Modifying Symptomatic Alzheimer’s Disease Diagnosis and Treatment: Speculative Timeline

  23. Family “AT RISK” Study:Entry Criteria (Protocol 95-M-96) First Degree Relative(s) with AD & Controls Over 50 Years of Age on Admission Cognitively Normal at Entry Baseline APO E Allele, Imaging & CSF Measures Interested in 8-year Follow-up Commitment Judy Bergeson, Coordinator 301-435-6058

  24. 1.0 2-3 Proportion Unaffected 0.5 3-4 3-3 3-4 APOE 4-4 APP Mutation S182 Mutation 0.0 110 100 90 80 70 60 50 40 30 20 Age (years) AD Survival Curves for ApoE Genotypes (Roses Ann. Rev. Med. 47:387-400, 1996)

  25. 80 64% 60 45% % APO E+ 40 8% 20 Controls At Risk Alzheimer Family “At Risk” Study Percentage of APO E4+ Subjects

  26. Temporal Lobe FOLLOW-UP sMRI IMAGES IN “AT RISK” STUDY Sagital Orientation Amygdala Hippocampus

  27. 1.9 1.85 1.8 1.75 1.7 Volume 1.65 AD Cutoff 1.6 APO E4(–) APO E4(+) 1.55 1. 5 1.45 Diagnosis Baseline Year 3 Year 1 sMRI Hippocampal Volumes Speculative Changes Over Time Observed (Adapted from Cohen et al. Neurology 57 (12):2223-2228, 2001)

  28. Positron Emission Tomography in AD CONTROL AD PATIENT

  29. Plaque of b-Amyloid Protein in the Brain of an AD Patient

  30. 1.200 1,000 800 600 400 200 0 AD N=131 Controls N=72 CSF b-amyloid1-42 in Older Controls and AD Subjects (Sunderland et al. JAMA 289: 2094-2103, 2003)

  31. –1.0 0.0 1.0 2.0 3.0 4.0 Results from Meta-Analysis of CSF b-amyloid1-42 Studies: EFFECT SIZE (Sunderland et al. JAMA 289: 2094-2103, 2003)

  32. Neurofibrillary Tangles in AD

  33. 1,600 1,400 1,200 1,000 pg/ml 800 600 400 200 0 Controls N=72 AD N=131 CSF tau Levels in Older Controls and AD Subjects (Sunderland et al. JAMA 289: 2094-2103, 2003)

  34. –1.0 0.0 1.0 2.0 3.0 4.0 5.0 Effective Sizes of Results from Meta-analysis of CSF Tau Studies in the World Literature (Sunderland et al. JAMA 289: 2094-2103, 2003)

  35. 1,600 1,400 1,200 1,000 CSF TAU 800 600 400 200 0 0 200 400 600 800 1,000 1,200 CSF b-amyloid 1-42 Scattergraph of CSF TAU and b-amyloid1-42 in AD and Controls (Sunderland et al. JAMA 289: 2094-2103, 2003)

  36. ? Test Results Diagnosis of AD Nursing Home MCI (12-15%/yr) Diagnosis Autopsy Mild Moderate Severe 3-4 years/stage Alzheimer’s Disease Symptomatic Time Course

  37. 2000 2-4 Million Clinical Diagnosis 0 20 40 60 80 100 Years 2030 Clinical Diagnosis 16 Million 0 20 40 60 80 100 Years Symptomatic Drugs Only Alzheimer’s Disease Predictions

  38. Alzheimer’s Disease Diagnosis and Treatment: Speculative Timeline Inflammatory response Cell Amyloid damage deposition LOD? Autopsy Gene? Test Results Clinical diagnosis 0 20 40 60 80 100 Years Preventative Modifying Symptomatic

  39. Alzheimer’s Disease Future Goals 2000 2-4 Million Clinical Diagnosis 0 20 40 60 80 100 Years 2030 Clinical Diagnosis 2-3 Million 0 20 40 60 80 100 Years ?Gene Therapy Secretase Inhib? Statins NSAIDs, HRT? & ? Vaccine? Symptomatic AChEIs Drugs + + +

  40. Early Diagnosis & Treatment: The Race is on! Research to find ways to predict and prevent Alzheimer's disease Research to find ways to treat the symptoms of Alzheimer's disease Early Diagnosis Effective Treatment Patient

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