Dementia: Early Detection and Treatment

1. CP1185103-1 Dementia:Early Detection and Treatment Ronald C. Petersen, PhD, MD Alzheimer�s Disease Research Center Mayo Clinic College of Medicine Rochester, MN

2. CP1185103-2 Change in intellectual function Impairment in memory plus Language, attention, constructional skills, or problem solving Functional impairment Dementia

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4. CP1185103-4 History Mental status exam General neurological exam Laboratory tests Neuropsychological testing Neuroimaging Dementia Evaluation

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9. CP1185103-9 Degenerative etiology Gradual progression Neurological exam normal Clin-path correlation 80-90% Alzheimer�s Disease

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13. 13 IS THERE A BLOOD TEST FOR ALZHEIMER�S DISEASE?

14. 14 Likelihood of developing AD based on APOE genotype

15. 15 Use of APOE genotyping for AD prediction and diagnosis Not useful for prediction in cognitively normal individuals Not sensitive or specific enough to be used alone as a diagnostic test Improves the specificity of diagnosis in patients meeting criteria for dementia the incomplete penetrance of AD in APOE e4 carriers, even homozygotes, critically decreases the value of APOE genotyping in asymptomatic at-risk individualsthe incomplete penetrance of AD in APOE e4 carriers, even homozygotes, critically decreases the value of APOE genotyping in asymptomatic at-risk individuals

16. 16 Do biomarkers help in the diagnosis of AD?

17. 17 CSF ?-amyloid(1-42) and Tau The diagnostic yield may be improved by the simultaneous measurement of CSF ?-amyloid(1-42) and tau In Class II or III studies, sensitivities of 85% and specificities of 87% have been reported Galasko et al, 1998 Hulstaert et al, 1999 Shoji et al, 1998)

18. 18 CSF BIOMARKERS ABETA 42 - DECREASED TAU - INCREASED SUGGESTIVE, BUT NOT DIAGNOSTIC

19. CP1185103-19 Questions AboutAlzheimer�s Disease

20. CP1185103-20 What are Risk Factors for AD? Age Family history Apolipoprotein E Estrogen

21. CP1185103-21 Putative Protective Factors for AD Anti-inflammatory drugs Statins Antioxidants Lifestyle

22. CP1185103-22 Is AD Inherited?

23. CP1185103-23 Will I Inherit AD? Early-onset AD Autosomal dominant Ch 1, 14, 21 Late-onset AD Susceptibility polymorphisms Ch 19 APO E Ch 10 ?

24. 24 ALZHEIMER�S DISEASETREATMENTS2007

25. 25 MEMANTINE FDA APPROVED FOR MODERATE TO SEVERE PATIENTS NMDA ANTAGONIST ADD-ON THERAPY

26. 26 DISEASE MODIFYING AGENTS Antioxidants Anti-inflammatories Anti-fibril formation molecules Secretase inhibitors Immunization therapy

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29. 29 ?-Amyloid Hypothesis A? initiates damage Leads to nerve cell dysfunction and death Brain normally clears plaque Alzheimer�s brain has reduced clearance of plaque

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31. 31 Rationale for Amyloid as a Therapeutic Target in AD A?40-42 plaques are central to the diagnosis of AD All genetic variants of AD are linked to increased synthesis or deposition of A?42 In cases of sporadic AD, patients have reduced clearance of A?42 through the CSF Brain levels of A? correlate with disease severity

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34. 34 Effect of AN 1792 on A? plaque burden in the cortex of PDAPP mice

35. 35 AN1792-102 multiple ascending dose study design Multi-center, randomized, double-blind, adjuvant-controlled study in patients with mild to moderate AD Dose (n=20 per group) 4:1 active:placebo A: 50 �g AN1792 + 50 �g QS-21 or 50 �g QS-21 alone B: 50 �g AN1792 + 100 �g QS-21 or 100 �g QS-21 alone C: 225 �g AN1792 + 50 �g QS-21 or 50 �g QS-21 alone D: 225 �g AN1792 + 100 �g QS-21 or 100 �g QS-21 alone This was a multicentre, phase 1, randomised, multiple-dose, dose escalation, double-blind study conducted at four study sites in the United Kingdom and involved 80 patients with mild to moderate AD. Twenty patients were enrolled in each of four dose groups and randomly assigned in a double-blind manner to receive treatment in a 4:1, active:control ratio. In each dose group, treatment was administered as a 1 mL intradeltoid injection of QS-21 (immunogenic adjuvant, surface-active saponin, Aquila Biopharmaceuticals, Inc) alone or in combination with AN1792 at Weeks 0, 4, 12 and 24. After an interim data review to assess tolerability and immunogenicity, the study protocol was amended to add an optional extension phase (up to a total of 84 weeks after the first injection) that permitted patients to receive additional study injections at Weeks 36, 48, 60 and 72. In the extension phase, the formulation of active and control immunisations was modified by the addition of 0.4% polysorbate 80 (PS-80) to improve product stability. This was a multicentre, phase 1, randomised, multiple-dose, dose escalation, double-blind study conducted at four study sites in the United Kingdom and involved 80 patients with mild to moderate AD. Twenty patients were enrolled in each of four dose groups and randomly assigned in a double-blind manner to receive treatment in a 4:1, active:control ratio. In each dose group, treatment was administered as a 1 mL intradeltoid injection of QS-21 (immunogenic adjuvant, surface-active saponin, Aquila Biopharmaceuticals, Inc) alone or in combination with AN1792 at Weeks 0, 4, 12 and 24. After an interim data review to assess tolerability and immunogenicity, the study protocol was amended to add an optional extension phase (up to a total of 84 weeks after the first injection) that permitted patients to receive additional study injections at Weeks 36, 48, 60 and 72. In the extension phase, the formulation of active and control immunisations was modified by the addition of 0.4% polysorbate 80 (PS-80) to improve product stability.

36. 36 AN1792 Phase II Study:Summary of Encephalitis Cases Of 300 patients treated with AN1792: 18 cases (6%) encephalitis Typical clinical presentation: headache, confusion, lethargy Of the 18 cases, 13 returned to baseline status; 5 patients had neurologic deficit or clinical sequelae at trial completion

37. 37 AN1792 201 Adverse Events Encephalitis Greater risk among antibody responders Most antibody responders did not get encephalitis Encephalitis believed to be related to T cell response directed to the carboxy terminal Antibody titers may reflect immune activation Emphasize that the date is a compilation of 3 years of intense research by the 2 companies. Emphasize that the quality of the antibody was not changed after PS80,still primarily anti-N terminal Emphasize that the date is a compilation of 3 years of intense research by the 2 companies. Emphasize that the quality of the antibody was not changed after PS80,still primarily anti-N terminal

38. 38 Findings in 201 Study Antibodies to amyloid were produced Antibodies enter the brain of the patient (CSF) Antibodies bind to plaques

39. 39 Tests included in the NTB (Neuropsychological Test Battery) Memory (immediate and delayed) � 6 tests: Wechsler Memory Scale Visual Paired Associates Wechsler Memory Scale Verbal Paired Associates Rey Auditory Verbal Learning Test Executive Function � 3 tests: Wechsler Memory Scale Digit Span Controlled Word Association Test (FAS) Category Fluency Test (animals)

40. 40 Mean change on NTB over 12 months in placebo and responder groups The error bars are standard errorsThe error bars are standard errors

41. 41 Summary Part I Despite dosing cessation, 19.7% achieved pre-determined antibody levels Truncated study, most clinical measures not significant, however: NTB suggests titer-related improvements in antibody responders CSF results decreased tau levels suggest diminished cell death rate in antibody responders

42. 42 ?-Amyloid ImmunotherapyFuture Directions

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44. 44 Current Trials R Flurbiprofen Lowers abeta levels Targets gamma secretase Alzhemed Clearance of abeta fragments

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46. 46 Behavioral Control

47. 47 Behavioral Control Behavioral modification techniques Environment measures

48. 48 Behavioral Control Cholinesterase inhibitors Anxiolytics Trazodone Buspirone Neuroleptics Typical Atypical Black box warning

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50. 50 But�

51. 51 Dementia and Violence: Caregiver Risk

52. CP1185103-52 New Research Directions

53. CP1185103-53 Added to series 6-29-2003, MCAdded to series 6-29-2003, MC

54. CP1185103-54 Memory complaint Normal general cognitive function Normal activities of daily living Memory impaired for age Not demented Mild Cognitive ImpairmentCriteria

55. CP1185103-55 Mild Cognitive Impairment

56. CP1185103-56 Mild Cognitive Impairment Predictors of outcome APO-E status +E4 Learning/semantic cues Hippocampal volume

58. CP1185103-58 MCI Clinical Trials Cholinesterase inhibitors Antioxidants Anti-inflammatories Nootropics ? immunization therapies ? secretase inhibitors

59. MCI Trial with Vitamin E and Donepezil

61. Survival with P-Value Reference from Pointwise Z-Test: Donepezil vs Placebo

64. There was neither an overall effect of donepezil nor vitamin E on progression to AD over 36 months Donepezil appeared to reduce the risk of progressing from MCI to AD for up to 12 months and for 24 months in ApoE 4 subjects Donepezil had an effect on overall function, memory and language for up to 18 months Vitamin E had no effect on progression to AD and had a minor effect on secondary outcomes Amnestic MCI strongly predicted progression to AD

66. CP1185103-66 Alzheimer�s Disease Summary

67. CP1185103-67 Guidelines for AD Management Assessment Daily function Cognitive status Other medical conditions Behaviors Resassess every 6 months Identify caregiver and assess Assess decision-making capacity

68. CP1185103-68 Treatment Develop and implement ongoing plan Consider AChEI�s Treat medical conditions Refer to day care services Treat behavioral problems and mood disorders Non-pharmacological measures Pharmacological agents Refer for support Consider Alz Assoc Safe Return Prog

69. CP1185103-69 Pt and Caregiver Educ and Support Discuss dx and progression of AD Refer to support organizations Alzheimer�s Association Senior Linkage Line Discuss advance directives

70. CP1185103-70 Monitor for evidence and report all suspected abuse to Adult Protective Services or local police as required by law Required Report

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