Current and Future Approaches to Alzheimer’s Disease Therapy

1. Current and Future Approaches to Alzheimer’s Disease Therapy Erik Roberson, M.D., Ph.D. Department of Neurology Center for Neurodegeneration and Experimental Therapeutics

2. The Present What we have available now What we’ve learned from recent experiences The Future New approaches to treating the disease New strategies to treat the disease earlier Targeting the pathological proteins, Aβ and Tau Outline

3. Memantine Current Therapy for AD • Cholinesterase Inhibitors • Donepezil • Rivastigmine • Galantamine

4. Memantine Placebo Limitation #1: Current Drugs Have Only Modest Effects 2 0 - 2 - 4 Difference in SIB Severe Impairment Battery - 6 - 8 -10 -12 End Point 0 12 4 28 Weeks Reisberg et al. N Engl J Med. 2003;348:1333-41.

5. Limitation #2: Current Drugs Don’t Target the Key Molecules Involved In Alzheimer’s

6. Plaques (Aβ) Tangles (Tau) Plaques and Tangles: Aβ and Tau http://www.pathology.vcu.edu/education/cns/lab1.c.html

7. Aβ (beta-amyloid or amyloid-beta) • A peptide derived from cleavage of APP (amyloid precursor protein) • Believed to be the main trigger of AD • Aggregates into oligomers (2-50) and plaques Aβ

8. How Can We Target Aβ? • Prevent it from forming • Secretases are the enzymes that make Aβ • Secretase inhibitors are being developed • Get rid of it once it is formed • Antibodies against Aβ may help do this

9. Early Results with Aβ Antibodies

10. 0 2.5 We Can Now Visualize Aβ Plaques in Patients, With a PET Scan Normal AD

11. Reasons Why: Aβ Plaques Form Years BeforeOnset of Symptoms http://www.alzforum.org/images/FleisherMovie.wmv

12. Next Step: Treating Presymptomatically • Late Onset (LOAD) • Onset age 65 or older • 6.5% of elderly population (6500/100,000) • Early Onset (EOAD) • Onset age 60 or before • 40/100,000 • Can be autosomal dominant (ADEOAD) • 5/100,000 • Usually onset in 40s

13. Genes that Cause Inherited Early Onset AD Alzheimer's Disease Education and Referral Center, a service of the National Institute on Aging

14. Studies of Inherited Early Onset AD

15. Natural History of Inherited Early Onset AD ↑ CSF Aβ (declining), ↑ activation on FDG-PET Plaque deposition begins, Hippocampal atrophy, ↑CSF Tau, CSF Aβ “pseudonormal” ↓ CSF Aβ, ↓ activation on FDG-PET, ↓ episodic memory on testing Multi-domain cognitive deficits on testing First memory symptom (MCI) ↓Function (Dementia) Death >–20 –15 –10 –5 0 +3 +14 Time Relative to 1st Symptom Bateman et al. (2012) N Engl J Med 367:795

16. Similar Study of Late Onset, Sporadic AD: The A4 Study

17. Normal function: binds/stabilizes microtubules Main component of neurofibrillary tangles (aggregated tau) “Hyper”phosphorylated in AD brain Microtubule-associated Protein Tau

18. How Can We Target Tau? • Preventing it from aggregating • Preventing it from being hyperphosphorylated • Stabilizing microtubules • Blocking it from spreading • Reducing its levels

19. Memory Test Tau Reduction is Beneficial in Mouse Modelsof Alzheimer’s Disease AD Mouse + Normal Mouse AD Mouse Tau Reduction Aβ Plaques

20. Take-Home Messages • Current FDA-approved therapies for AD offer a real, but modest benefit • Newer treatments that target Aβ and Tau are on the horizon • Clinical trials are focusing on the earliest stages of disease • This is an exciting time for AD research!