1. Advances in Alzheimer's Disease: New Technologies and New Ethical Issues Steven T. DeKosky, MD James Carroll Flippin Professor of Medical Science Vice President and Dean University of Virginia School of Medicine Charlottesville, VA USA National Press Foundation Washington, DC May 24, 2011

2. Disclosures Consultant/Advisory Boards : Bristol Myers Squibb, Eisai, Lilly, Merck, Novartis, Pfizer, PsychoGenics Research Grants: –Elan, Forest, Janssen, Novartis Special acknowledgements : Stephen Post, Stony Brook University Robert Green, Boston University

3. Outline of Discussion From rare disease to coming epidemic Technology and research breakthroughs –The value of basic research –Examples in Alzheimer’s Disease Ethical issues arising Advances in technology and their effects on AD research, therapies, and caregiving

4. Case Study 46 year old married female –General good health; on no medications –No major medical problems –Sub-acute onset of pathological jealousy –Onset of dysnomia (calls a pitcher a ‘milk pourer’) –Difficulties with short term memory –General medical examination normal –Neurological examination normal except for mental status –Progressive cognitive decline, death 4 years later

5. Alzheimer’s original patient: Auguste D. “I have lost myself.”

6. Alzheimer’s original patient: Auguste D. Alzheimer’s Disease Memory loss Language disturbances Visuospatial deficits “Frontal-Dysexecutive”: Impaired judgment, motivation, insight, decreased social cognition Neuropsychiatric symptoms: depression, anxiety, sleep disturbance psychosis The anatomical/circuitry correlates of these behaviors are now largely identified

7. From Clinic to Community: characterizing the clinical picture of AD Alois Alzheimer Germany, 1907: single case report rare, unusual disease of middle-aged “pre-senile dementia” Martin Roth and colleagues Newcastle, 1964: community survey fairly common disease of elderly “senile dementia” Majority of cases of dementia in late life are AD, with many cases showing additional co-morbidities

8. 1976 Katzman editorial: an alarm is sounded Katzman, R. The prevalence and malignancy of Alzheimer disease. A major killer. Archives of Neurology, 1976 Predicted a massive increase in the number of cases of Alzheimer’s Disease in the 21 st century No clear difference between presenile and senile onset with respect to symptoms or pathology Stimulated research in aging and AD brain

9. Sloane, et al., Ann. Rev. Public Health 2002. 23:213–31 Prevalence of Mild, Moderate/Severe and Total Cases of AD: 2000-2050 Assume no new therapy 12 10 8 6 4 2 0 200020102020203020402050 Number of Cases (in millions) Mild Mod/Severe

10. Increasing Global Burden of AD: Cultures differ in their dealing with dementia

11. Technology & Alzheimer Breakthroughs “Heavy metal” (silver) stains and Alzheimer Radioassay for ChAT (Fonnum) in 1975 Protein purification techniques Gene sequencing Neuroimaging: CT, MRI, PET Computing power to calculate…and to share!

12. Categories of Ethics Questions in AD (and other late life dementias) Moral, cultural and socio-political issues Respect and autonomy –balance of responsibility to individual vs. society, e.g., driving privileges End of Life Care –Comfort, feeding, withholding nutrition or water Diagnosis and Truthtelling The Role of Biomarkers –Confirmation of Diagnosis, Earlier Diagnosis, Risk Assessment in Normals

13. Moral, Cultural, and Socio-Political Issues Affirmation of and respect for people with AD and other disorders involving loss of self (e.g., “deeply forgetful”) –Example, South Korea efforts to honor people with dementia –Justice and protection Whose responsibility are the Deeply Forgetful? Family? Society? Government? –South Korea’s view… all of them Respite for family caregivers –Increased morbidity and mortality Ethicists: Cultivate a ‘culture of acceptance’ –The glass is half full (celebrate what is still available to others, not continue to mourn for what is lost)

14. Biomarkers Diagnostic Confirmation Increased Accuracy in MCI Risk Assessment in Asymptomatic People What are they? How should they be used? Research or general availability?

15. Alzheimer’s Disease: Course, Prevention, Treatment Strategies Disease Progression NormalAD Pre- symptomatic AD Mild Cognitive Impairment ClinicalState

16. Linking Clinical Symptoms With Degree of Pathology Disease Progression No Disease No Symptoms Early Brain ChangesNoSymptoms AD Brain ChangesMildSymptomsMild, Moderate, or SevereImpairment NormalAD Pre- symptomatic AD Mild Cognitive Impairment ClinicalState BrainPathologicState SecondaryPrevention/ Early Tx TreatmentPrimaryPrevention Intervention

17. Major Pathological Changes in AD Brain shrinkage (atrophy) Neuritic Plaques –altered metabolism of APP –Deposition of beta amyloid Neurofibrillary Tangles –Cytoskeletal pathology [girders and trusses] –Altered metabolism of tau protein Neuronal death in specific brain regions (why some regions and not others?) Specific Neurotransmitter deficits (especially ACh, serotonin, norepinephrine, glutamate)

18. NeuroFibrillary Tangles & Neuritic Plaques Inflammatory surround Compacted amyloid core Neurofibrillary tangles The ‘inflammatory surround’ consists of distorted and degenerating synaptic processes, activated microglia, and astrocytic processes

19. Tau (Microtubule Associated Protein MAP2): Axonal Dissolution and Dysfunction in AD

20. Tangle (NFT) & Plaque (NP) Distribution In AD at Autopsy: The Static View of the 1980s-90s NFT NP S. Arnold, Cortex, 1991

21. Biochemical pathway of neurofibrillary degeneration Delacourte A, et al. Neurology. 1999;52:1158-1165. S9c S8 S6 S4 S3 Stages S0 S1 S2 S3 S4 S5 S6 S7 S8 S9a S9b,c S10 A35A28A34A38A20A21A22, 10, 39A44A4A18A17 Distribution of PHF-Tau + entorhinal + hippocampus + anterior temporal ctx + mid temporal + anterior frontal, superior temporal, inferior parietal + Broca area + motor cortex + occipital areas n=3 trans- entorhinal n=30 n=4 n=16 n=10 n=12 n=11 n=15 n=5 n=6 n=13 n=27All cortical areas affected. Brodmann areas + inferior temporal

22. Types of Biomarkers Genetic –"Risk alleles" e.g. ApoLiprotein E; APOE Biochemical –CSF Beta amyloid, tau, phosph-tau Neuroimaging –MRI, FDG-PET, amyloid imaging

23. APOE and Alzheimer’s Disease normal population: in AD: normal population: in AD: E2 7%7% E379%40-50% E414%40-50% ALLELE FREQUENCY: Potential mechanisms: Impaired removal of beta amyloid Diminished neural regeneration Allele frequency twice as high in Africans & African Americans as in Caucasians (~40% v 22%)

24. Genetic Biomarkers APOE is the major risk gene in AD REVEAL study, now 10 years on, has tracked individuals views and reactions to have genetic status “revealed.” Results benign thus far No other genes of near-equal power are likely to be discovered

25. REVEAL Conclusions Disclosure of APOE does not seem harmful –may actually reduce anxiety for some who find they are e4- Persons alter their LTC insurance purchasing learning their APOE genotype –If widespread would have insurance industry implications APOE4+ carriers –more likely to make changes (vitamins, exercise) even knowing such changes are not proven – Also more likely to purchase unregulated neutraceuticals The impact is less than expected –people come into the study with a baseline perception of their own risk –seem to have a psychological inertia

26. Structural and Biochemical Biomarkers Biochemical: CSF Beta amyloid, tau, phosph-tau –Diagnostic as well as predictive value Neuroimaging: MRI, FDG-PET, amyloid imaging –Used for diagnostic confirmation in a symptomatic person, for earlier definitive diagnosis in mild or uncertain symptoms (e.g., MCI), and for detection of AD pathology in asymptomatic individuals.

27. Evolution of Neuroimaging Computed Tomography MRI Volumetric MRI FDG Glucose PET Co-registration of MRI Functional MRI Amyloid Imaging 1970s 1980s 1990s 2000s

29. Evolution of Volume Mapping www.loni.ucla.edu/~thompson/AD_4D/dynamic.html. Helmuth L. Science. 2002;297:1260-1262. 39 Enhancing ability to assess variability of structural change AND response to medications.

30. Ethics Issues With Biomarkers Diagnostic information We can ascertain with high probability whether AD pathology is present in the brain How much to tell research participants about unvalidated research results?

31. CSF Aβ42 Amyloid imaging FDG-PET MRI hipp CSF tau Cog Fxn Best markers across a broad range are MRI and FDG-PET

33. Biomarkers for Earlier Diagnosis Lancet Neurol 2007; 6: 734–46 “They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid β or tau proteins. “

34. CSF in Alzheimer’s Disease: Low Aβ and High Tau AβAβTau Concentration (pg/mL) Sunderland T, et al. JAMA. 2003;289:2094-2103.

35. CSF in MCI has elevated tau, decreased β- amyloid Hansson et al.,2006

36. Imaging Amyloid in vivo in Humans Amyloid Cascade Hypothesis: –Amyloid deposition begins years before clinical symptoms Ability to image brain amyloid will impact: –Diagnosis (sensitivity and specificity TBD) –Prognosis (different patterns of progression?) –Monitoring anti-amyloid therapeutic interventions –Efficiency of drug development Current ligands, more in development: –PiB (GE), AV-45 (AVID/Lilly), Bayer PiB: Now in use in over 60 centers around the world F18-PiB in development at both GE and Pittsburgh –Just as accurate as C11-PiB

37. PIB PET in AD and Control

38. Amyloid Imaging Agents AV45 (AVID/Lilly) Florbetapir (Amyvid) Florbetaben (Bayer)

40. PIB Retention Distribution Volume Ratio (DVR) 1.06 1.64 1.04 1.62 2.59 2.48 Frontal DVR C-8 C-2 MCI-2 MCI-10 MCI-4 AD-2

41. Prediction of Outcome Utilizing PiB Imaging in MCI: PiB+ Cases Develop AD; PiB- Cases Do Not 23/26 patients have had follow-up ADRC evaluations Mean f/u: 24.0 months (6-57 months) 13 PiB positive (Mean f/u: 23.6 months) 10 PiB negative (Mean f/u: 24.5 months) Wolk, et al., 2009

42. Prevalence of Plaques Precede DAT

43. Mean Cortical PIB Binding in Nondemented Controls and AD (N=41) scBP -0.200 0.000 0.200 0.400 0.600 0.800 1.000 1.200202223494951565758585959596060606161626464667172727475757576777777798081838384858686727373797981848586 Mintun et al, 2006, Neurology Subject AGE ADControls

44. 2 yrs Longitudinal Change in PiB Retention in a Questionably Positive Control over Two Years

45. PiB Binding (amyloid plaque density) in Cognitively Normal Elderly and AD Aizenstein et al., Arch. Neurol. 2008; 65: 1509-1517

46. Heterogeneity of Amyloid Binding in Asymptomatic Normal Elderly Courtesy of Reisa Sperling, Harvard Univ.

47. How will disease-modifying medications affect the field? Immediate pressure to identify subjects as early as possible Amyloid scans beginning at age 50, repeated every 5 years, as for colon cancer Public Health Message: “At 50, get evaluated head to tail! Have your colonoscopy and your PiB Scan.”

48. Operational Research Criteria for Preclinical AD Not intended as clinical diagnostic criteria Prognostic utility of these biomarkers in individual subjects remains unclear Not all individuals with neuroimaging evidence of AD changes will develop clinical symptoms during life –30% of non-demented 80+ year olds have evidence of AD in the brain at autopsy

49. Overview of Phase III AD Trials Negative Phase III: –Xaliproden (5HT1A agonist with neurotrophic effects in vitro) –Tramiprosate (GAG anti-aggregant) –Tarenflurbil (R flurbiprofen, gamma secretase modulator) –Rosiglitazone (Peroxisome proliferators activated receptor PPAR-ү) –Leuprolide (LHRH endocrine) –Dimebon (5HT6 antagonist, H1 antagonist + mitochondrial transition pore) –Semagacestat (gamma secretase inhibitor) Phase III in progress –Bapineuzumab (passive immunotherapy; monoclonal Ab N-terminal ) –Solanezumab (passive immunotherapy; monoclonal mid domain Ab) –IVIG (passive immunotherapy; polyclonal pooled Abs) –Dimebon (5HT6 antagonist, H1 antagonist + mitochondrial transition pore) –Tau Rx (methylene blue, anti tau aggregant)

50. Phase II Bapineuzemab Study Salloway et al., 2009 “Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.”

51. 11C-PiB PET assessment of change in amyloid-β load in patients with AD treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study Rinne et al., Lancet Neurology 2010

52. Loss of amyloid on PET Scan— how much is enough? Rinne et al., Lancet Neurology 2010

53. Revised Diagnostic Criteria Preliminary recommendations from the NIA/Alzheimer’s Association Workgroup Pre-Clinical AD Mild Cognitive Impairment Alzheimer’s Disease DeKosky et al Revision of the criteria for Alzheimer’s disease: A symposium Alzheimers Dement 2011;7:e1-e12.