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

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

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

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

Cholinergic Neuron in Aging AChE CAT Choline uptake

Plaque Theory of Damage in AD From Outside the Cell Plaque Soluble peptides Insoluble peptides Reactive 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

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

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

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

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.)

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

Expanding Uses of AChEI’s Placebo-controlled Open Studies 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

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

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

Percent Remaining Outside an Institution 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)

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

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

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

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

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

Normal Enzymatic Processing Alternative Enzymatic Processing 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

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

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

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

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

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

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

Positron Emission Tomography in AD CONTROL AD PATIENT

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

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

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

Neurofibrillary Tangles in AD

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

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

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

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

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

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

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

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