1. AD Research Update Steven H. Ferris, PhD Friedman Professor and Director NYU Alzheimer’s Disease Center Silberstein Alzheimer’s Institute Center for Cognitive Neurology

2. Combining Two Important Developments 1.Potential for very early detection of AD –“Preclinical AD”: Very early pathology in brain, no clinical symptoms (5-15 years) –Amyloid Tau/Synaptic loss Subtle impairment 2.Development and clinical testing of “disease modifying” treatments to slow progression –e.g., anti-amyloid, anti-tau compounds, other neuroprotective agents

3. What is available for early detection? Biomarkers: Great potential for very early detection of AD However… –Invasive –Costly EBAD Study New cognitive tests for early detection National Institute on Aging/Alzheimer's Association Diagnostic Guidelines for Alzheimer's Disease: Criteria for preclinical Alzheimer’s Disease (Sperling et al., 2011 (Adapted from Jack et al., 2010)

4. Current NYU Research on Preclinical Detection of AD Center for Brain Health (CBH) biomarker studies –CSF studies: β-amyloid and P-Tau –Neuroimaging: MRI, PET-amyloid, PET-tau EBAD Study: Early cognitive detection of AD –Normal elderly receive sensitive cognitive battery –Validation using PET-amyloid, MRI (and CSF Aβ and tau)

5. Amyloid Precursor Protein Amyloid  monomer Amyloid  oligomers Amyloid Plaques NFTs (tau) Inflammation Oxidative stress Neuronal loss, neurotransmitter loss, cognitive deficit Secretase Inhibitors Selective A  lowering agents Anti-aggregation Anti-fibril Passive Immunization Active Immunization Antioxidants Anti-inflammatory agents Anti-tau aggregation/phosphorylation Symptomatic Drugs Anti-cholinesterases; NMDA antagonists Nicotinic agonists, memory enhancers AD Treatment Targets

6. Immunotherapy Strategies Passive immunity: –Bapineuzumab (Janssen AI): Monoclonal antibodies; Phase III trials in AD: No clinical benefits –Solanezumab (Lilly): Monoclonal Antibodies; Phase III trials in AD: Possible benefit--only in mild AD –Gammagard [IVIG] (Baxter/ADCS): Human Aß antibodies; Phase III trial in AD: No clinical benefits –Other antibodies: Genentech/Roche, Eisai, Biogen Active “vaccines” –Aß fragments (Janssen AI, Pfizer, others; Phase I-II)

7. Other Anti-Amyloid Strategies γ-Secretase inhibitors/modulators –Semagacestat (Lilly): Phase III in AD halted, No clinical benefits –BMS-708163 (BMS): Phase II in AD and MCI, No clinical benefits ß-Secretase (BACE) inhibitors –MK8931 (Merck): Phase II in AD; Prodromal AD –E2609 (Eisai): Phase I in AD

8. Conclusions Major advances in early detection can identify presymptomatic AD Important clinical trials of disease modifying agents that may slow progression (amyloid, tau, other neuroprotective targets) Pre-symptomatic detection coupled with effective disease slowing agents will facilitate future prevention

9. Clinical Trials at NYU BACE Inhibitor (MK-8931) ↓ amyloid production; Phase IIb, oral, AD and prodromal AD (MCI) TMS + Cognitive Remediation: Brain stimulation + cognitive training in AD (weekdays, 6-weeks) Ketonergic metabolism (Axona):  brain metabolism Insulin sensitizer-Pioglitazone (Takeda): 5-year prevention trial; normal elderly with genetic risk for AD Amyloid antibody-BAN2401 (Eisai): MCI and mild AD ----------------------------------------------------------------------------------------------------------- Intranasal Insulin (ADCS): MCI and mild AD A4 trial of Solanezamab (ADCS): Prevention in preclinical AD Solanezamab in mild AD: Confirmation of prior results 14861B (Lundbeck): Mild-moderate AD Anti-tau compound-T-817(ADCS/Toyama): Mild-moderate AD Crenezumab (Genentech): Mild-moderate AD; Prodromal AD (MCI) Nicotinic agonist (EnVivo): Mild-moderate AD

10. NYU Alzheimer’s Disease Center Silberstein Alzheimer’s Institute Center on Cognitive Neurology Clinical Trials: 212-263-5708 ADC Participation: 212-263-8088 Center for Brain Health: 212-263-7563 Barlow Center: 212-263-3210

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