Friedman Professor and Director
NYU Alzheimer’s Disease Center
Silberstein Alzheimer’s Institute
Center for Cognitive Neurology

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

• 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)

• 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 A β and tau)

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

• 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 A ß 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)

• 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

• 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

• 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 sensitizerPioglitazone (Takeda): 5-year prevention trial ; normal elderly with genetic risk for AD
• Amyloid antibody-BAN2401 (Eisai): MCI and mild AD
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• 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 compoundT-817(ADCS/Toyama): Mild-moderate AD
• Crenezumab (Genentech): Mild-moderate AD; Prodromal AD (MCI)
• Nicotinic agonist (EnVivo): Mild-moderate AD

Silberstein Alzheimer’s Institute
Center on Cognitive Neurology
ADC Participation: 212-263-8088
Center for Brain Health: 212-263-7563

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