1. ©2011 MFMER | slide-1 Alzheimer Disease: Update Neill R. Graff-Radford, MBBCh, FRCP Professor of Neurology Mayo College of Medicine

2. ©2011 MFMER | slide-2 Disclosures Dr Graff-Radford is part of multicenter treatment studies funded by Medivation, Allon, Janssen, Forrest He is chair of the DSMB for a Baxter study using IGIV He is on the Scientific Advisory Board of Codman He has funding from several NIH and State grants He is on the Editorial Board of the Neurologist and Alzheimer Research and Therapy journals

3. ©2011 MFMER | slide-3 Case One In 2001 a 71 year old women complained of some memory difficulty and was diagnosed with Mild Cognitive Impairment but her MMSE was 29/30 In 2004 her MMSE was 27/30 and she still met criteria for MCI In 2007 she declined and was diagnosed with Probable AD. MMSE 22/30 In 2009 her MMSE was 16/30 but she played 2 recitals monthly lasting 40 minutes including 9 pieces

4. ©2011 MFMER | slide-4 Knowing how but not knowing what

5. ©2011 MFMER | slide-5 Why do AD patients know how but not what? 1. It is the anatomy 2. It is a fluke in this patient 3. It is easier to remember what makes you happy 4. Alzheimer patients have excellent remote memory

6. ©2011 MFMER | slide-6 Topographic Distribution of AD Lesions Arnold et al., Cerebral Cortex 1991

7. ©2011 MFMER | slide-7 Alzheimer Disease Update New Diagnostic Criteria May Study of Aging and Diagnostic Criteria APP mutation DIAN biomarkers Bapineuzumab results for ApoE 4 patients AV45 PET scan

8. ©2011 MFMER | slide-8 R.A. Sperling et al. Alzheimer’s & Dementia;(2011) 1-13 NormalPreclinicalMCIDementia Clinical Disease Stage Abnormal Amyloid-  accumulation (CSF/PET) Synaptic dysfunction (FDG-PET/sMRI) Tau-mediated neuronal injury (CSF) Brain structure (volumnetric MRI) Cognition Clinical function

9. ©2011 MFMER | slide-9 Staging Categories for Preclinical AD Research Negative Positive Asymptomatic cerebral amyloidosis Stage 1 Positive Amyloidosis + neuronal injury + subtle cognitive/behavioral decline Stage 3 Evidence of Subtle Cognitive Change Markers of Neuronal Injury (tau, FDG, sMRI A  (PET or CSF)DescriptionStage NegativePositive Asymptomatic amyloidosis + “downstream” neuro-degeneration Stage 2 R.A. Sperling et al. Alzheimer’s & Dementia;(2011) 1-13

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11. ©2011 MFMER | slide-11 Rowe et.al. Neurobiol. of Aging 2010;3`:1275-83 60 50 40 30 20 10 0 3040 50 60 7080 90 100 Age (years) Prevalence (%) Prevalence of PiB+ve PET in HC Prevalence of plaques in HC Prevalence of AD ~15 yrs (Davies, 1988, n=110) (Braak, 1996, n=551) (Sugihara, 1995, n=123) (Tobias, 2008)

12. ©2011 MFMER | slide-12 Alzheimer Disease Update New Diagnostic Criteria Mayo Study of Aging and Diagnostic Criteria APP mutation DIAN biomarkers Bapineuzumab results for ApoE 4 patients AV45 PET scan

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14. ©2011 MFMER | slide-14 Staging Categories for Preclinical AD Research Positive Amyloidosis + neuronal injury + subtle cognitive/behavioral decline Stage 3 Negative Positive Asymptomatic cerebral amyloidosis Stage 1 Evidence of Subtle Cognitive Change Markers of Neuronal Injury (tau, FDG, sMRI) A  (PET or CSF)DescriptionStage NegativePositive Asymptomiatic amyloidosis + “downstream” neurodegeneration Stage 2 R.A. Sperling et al. Alzheimer’s & Dementia;(2011) 1-13

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16. ©2011 MFMER | slide-16 An operational approach to National Institute on Aging– Alzheimer's Association criteria for preclinical Alzheimer disease Annals of Neurology pages n/a-n/a, 9 APR 2012 DOI: 10.1002/ana.22628

17. ©2011 MFMER | slide-17 New Diagnostic Alzheimer Disease Criteria (7 changes) AD path seen in normals, MCI and AD so ‘pathophysiological process = +ve A  biomarkers (in CSF or with PET) Takes into account criteria for LBD, FTD and VD Includes structural change on MR or PET May not present with memory loss e.g. PCA, logopenic aphasia, FTD Includes known genes Includes persons below age 40 Possible AD before included MCI today Mckhann, Knopman and colleagues AD and Dementia 2011;7:263-6

18. ©2011 MFMER | slide-18 Alzheimer Disease Update New Diagnostic Criteria May Study of Aging and Diagnostic Criteria APP mutation DIAN biomarkers Bapineuzumab results for ApoE 4 patients AV45 PET scan

19. ©2011 MFMER | slide-19 Protective Gene Nature Published on line July 11, 2012

20. T Jonsson et al. Nature 000, 1-4 (2012) doi:10.1038/nature11283 A673T reduces BACE1 cleavage of APP.

21. ©2011 MFMER | slide-21 Findings in this study A coding mutation (A673T) in the APP gene protects against Alzheimer’s disease and cognitive decline in the elderly without Alzheimer’s disease. This substitution is adjacent to the aspartyl protease β- site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer’s disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer’s disease, the two may be mediated through the same or similar mechanisms.

22. ©2011 MFMER | slide-22 BACE Inhibitors in Clinical Trials LY2886721 – Phase 2 Merck has one as well but not in clinicaltrials.gov

23. ©2011 MFMER | slide-23 Lancet Neurology 2010, 9:702-16

24. ©2011 MFMER | slide-24 Alzheimer Disease Update New Diagnostic Criteria May Study of Aging and Diagnostic Criteria APP mutation DIAN biomarkers Bapineuzumab results for ApoE 4 patients AV45 PET scan

25. ©2011 MFMER | slide-25 NEJM July 23, 2012

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27. ©2011 MFMER | slide-27 DIAN Study CSF A  42 begins to decline 25 years before onset PIB PET 15 years before symptom onset Brain atrophy and increase CSF tau 15 years Hypometabolism on PET and anterograde memory 10 years Global cognitive decline (MMSE) 5 years Met dementia criteria 3 years before expected onset

28. ©2011 MFMER | slide-28 Alzheimer Disease Update New Diagnostic Criteria May Study of Aging and Diagnostic Criteria APP mutation DIAN biomarkers Bapineuzumab results for ApoE4 patients AV45 PET scan

29. ©2011 MFMER | slide-29 Lancet Neurol. 2010 Apr;9(4):363-72

30. ©2011 MFMER | slide-30 News Release July 23, 2012 In the 302 study ApoE4 +ve mild to moderate AD patients did not improve using bapineuzumab

31. ©2011 MFMER | slide-31 Alzheimer Disease Update New Diagnostic Criteria May Study of Aging and Diagnostic Criteria APP mutation DIAN biomarkers Bapineuzumab results for ApoE4 patients AV45 PET scan

32. ©2011 MFMER | slide-32 Patient information Amyvid is a radioactive diagnostic agent for PET imaging of the brain to estimate β-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s Disease (AD) and other causes of cognitive decline. The scan is interpreted as either positive or negative A positive Amyvid PET scan indicates moderate to frequent amyloid neuritic plaques The cost of performing and interpreting an Amyvid PET scan is approximately $5000.

33. ©2011 MFMER | slide-33 Indications In a patient with a dementia syndrome or mild cognitive impairment when greater certainty of amyloid deposition in the brain, and hence probable Alzheimer’s disease, would: help establish a diagnosis better determine treatment/management and prognosis defend discontinuation of work and defend documentation of full and permanent disability

34. ©2011 MFMER | slide-34 Contraindications Any person who: is cognitively normal will not have their treatment or prognosis altered with the increased confidence of a probable AD diagnosis (positive result) or a non-AD diagnosis (negative result) is not mentally prepared to handle a positive or negative result has limited financial means to pay for the scan (at least until third party payers and Medicare provides preauthorization)

35. ©2011 MFMER | slide-35 In Cognitively Normal Persons Physicians at Mayo Clinic strongly discourage cognitively normal subjects from Amyvid PET scan. At present, few Mayo Clinic physicians will agree to order an Amyvid PET for cognitively normal persons. A +ve scan means that a person has amyloid deposition in the brain. It does NOT mean a person currently has Alzheimer’s disease, or ever will develop Alzheimer’s disease It may impact a person’s psychological well-being and ability to secure some forms of insurance A –ve scan means that a person has no significant amyloid deposition but does NOT mean that a person will never develop Alzheimer’s disease It does not exclude the possibility of developing a non-Alzheimer disorder such as Lewy body disease or frontotemporal lobar degeneration