Prospects for New Treatments for Alzheimer’s Disease

1. Prospects for New Treatments for Alzheimer’s Disease Alex Osmand, Ph.D. Research Scientist Department of Biochemistry and Cellular and Molecular Biology University of Tennessee June 2012

2. An idiosyncratic view of Alzheimer’s Disease Present-day treatments for Alzheimer’s Disease Prospects for new treatments Preventive measures Future directions June 2012

3. Frau Auguste Deter, admitted: November 25, 1901; d. April 8,1906 Alzheimer A (1907) AllgemeineZeitschriftfürPsychiatrie und Psychisch-GerichtlicheMedizin64: 146-148. ÜbereineeigenartigeErkrankung der Hirnrinde. [Tr: About an unusual disease of the cortex of the brain.] June 2012

4. Graeber et al. (1998) Alzheimer (1911) Plaques and tangles in the cortex of the brain of AugusteDeter June 2012

5. From Fuller, S.C. Am. J. Insanity (1911) and J. Nerv. Ment. Dis. (1912) June 2012

6. A B C Amyloid plaques (A-beta [Aβ], brown) and neurofibrillary tangles (tau, black) in early onset familial Alzheimer’s disease (46 y, WF). A: cortex; B: hippocampus; C: cholinergic nucleus June 2012

7. Early onset Alzheimer’s disease in a Tennessee family 1999 d46 d83 d25 79 d52 57 51 47 40 51 49 55 48 46 39 38 47 45 43 42 49 d46 43 32 28 27 15 12 25 21 34 30 19 8 6 6 4 June 2012

8. Prevalence rate (%) of AD, by age, in the US (Government Accounting Office, 1998) June 2012

9. Braak staging of the neurofibrillary (tangle) changes seen in AD: N = 2,661 Cases devoid of changes (n=582, 21.9%) Stages III and IV (n=453, 17.0%) Stages I and II (n=1480, 55.6%) Stages V and VI (n=146, 5.5%) From Braak and Braak, 1997 June 2012

10. Braak staging of the amyloid changes seen in AD: N = 2,661 Amyloid deposits of stage B (n=428, 16.1%) Cases devoid of amyloid (n=1513, 56.8%) Amyloid deposits of stage A (n=428, 16.1%) Amyloid deposits of stage C (n=292, 11.0%) From Braak and Braak, 1997 June 2012

11. Neurofibrillary pathology in individuals under 30 (Braak and Del Tredici, 2011) Age locus coeruleus NFT Staging AT8 entorhinal cortex

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13. Effect of ApoE4 gene on chance of remaining unaffected by Alzheimer’s disease ApoE gene frequencies From Roses and Saunders, 1994 June 2012

14. axon axon Multifactorial basis of Alzheimer’s disease pathogenesis after Huang and Mucke, 2012 June 2012

15. This view of Alzheimer’s Disease: • slow lifelong progression of neurofibrillary change universal • catastrophic changes in old age associated with Aβ deposition toxic forms of Aβ • age of onset determined, in part, by apolipoprotein E genotype specifically apoE4 • acceleration of disease progression involving prion-like processes as the disease spreads along predictable pathways through the brain entorhinal cortex (memory) → cortex (executive functions) June 2012

16. “Ask your doctor if taking a pill to solve all your problems is right for you?” June 2012

17. Present-day treatments for Alzheimer’s Disease Cholinesterase inhibitors/cholinergic agonists Cholinergic hypothesis Davies P, Maloney AJF.  Selective loss of central cholinergic neurons in Alzheimer's disease.  Lancet.1976;2:1403. Glutamate antagonist Excitotoxicity as a contributing factor Olney JW et al., Excitotoxic neurodegeneration in Alzheimer disease: new hypothesis and new therapeutic strategies. Arch Neurol1997; 54 (10): 1234-1240 June 2012

18. Present-day treatments for Alzheimer’s Disease • Donepezil (Aricept, 1996)* mild to moderate and moderate to severe ADcholinesterase inhibitor - once daily tablet, 5, 10, or 23 mg • Rivastigmine (Exelon, 2000)* mild to moderate AD cholinesterase inhibitor - twice daily capsule or solution, 3 to 12 mg two versions of patch • Galantamine (Razadyne, 2001)* mild to moderate AD cholinesterase inhibitor - twice daily tablet or solution, or slow release capsule, 16 to 24 mg daily • Memantine (Namenda, 2003) moderate to severe ADglutamate antagonist (blocker) – twice daily tablet or solution or extended release tablet, 10 to 28 mg daily • * available as generic drug June 2012

19. Recently failed Phase III clinical trials for AD Dimebon 2012-2010 Semagacestat 2010 Phenserine 2009 Flurizan 2008 Alzhemed 2007 Omega-3 fatty acids 2006 Vitamin E 2005 Clioquinol 2005 NSAIDs 2003 Estrogen 2003 A vaccination 2002 June 2012

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22. Treatment effects in AD transgenic mice June 2012

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27. It is generally the rule that new treatments make their first appearances in animal models and it is possible (probable) that the next candidates for clinical trials are buried within these tables. June 2012

28. Genetic and environmental causes Disease-promoting alterations Neurodegenerative disease “everything is genetic and everything is environmental” June 2012

29. Prevention - Delay – (Treatment) - Cure normal aging MCI prevent cure AD Cognitive function delay AD Age/Time ‘late midlife’ June 2012

30. Preventive measures • Diet • dietary risk factors: high fat, low fish consumption, low B vitamins, low fruit and vegetables, low alcohol • Exercise • risk factors: low physical and mental activity • ApoE4 • structure correction June 2012

31. Projected effect of risk factor reduction on AD prevalence Barnes and Yaffe, Lancet Neurology, 2011 June 2012

32. “I say it’s government-mandated broccoli, and I say the hell with it.” June 2012

33. Should the US government mandate Americans buy broccoli? At the US supreme court hearing on the healthcare law, Justice Antonin Scalia made a comparison between the individual insurance mandate and a hypothetical federal requirement for citizens to buy broccoli. Well, should they? YES 57.4% NO 42.6% guardian.co.uk June 2012

34. “Any history of physical activity in your family?” June 2012

35. Protective factors for Alzheimer’s disease • Non-modifiable • Age • ApoE genotype • Family history of dementia • Absence of mild cognitive impairment • Gender • Modifiable • Educational achievement • Mental activity • Physical activity (avoid head injuries) • Avoidance of risks for cardiac disease, diabetes, and hypertension • Diet rich in antioxidants and B vitamins, fruits and vegetables, some fish • Avoidance of high fat diet and obesity • Avoidance of smoking • Low level of alcohol consumption after Friedland, 2006 June 2012

36. One Apoε4 gene male female Two Apoε4 genes male female No Apoε4 gene male female APOE-ε4 count predicts age when prevalence of AD increases, then declines: The Cache County Study. Breitner, J. et al. Neurology. 53(2):321-331(1999) June 2012

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38. A comprehensive approach to Alzheimer’s disease: • block genetic risk factors, when known e.g. apoε4 gene effect modifiers • eliminate disease causing proteins toxic forms of Aβ, hyperphosphorylated tau [immunotherapies] • block detrimental brain cell reactions e.g. anti-inflammatory agents • neuroprotective strategies neurotrophic factors, e.g. cerebrolysin • improve neuronal network communication • enhance repair neuronal plasticity, stem cells Mucke, 2012 June 2012

39. Future directions • Alzheimer’s Disease Research Summit 2012 (NIH-NIA) • Longer term: e.g. impact of biotechnology stem cells, shRNA, individual genome • Predictive medicine, rather than reactive • P4 Medicine: Predictive, Preventive, Personalized, Participatory (Leroy Hood, 2006) • Success of particular treatments or approaches unpredictable • Changing risks for AD – up or down? June 2012

40. Trends in the incidence of AD – the Rotterdam study Schrijvers et al. June 2012

41. Trends in the incidence of AD The National Health and Retirement Study Rochester, Minnesota June 2012

42. Alois Alzheimer (1864-1915) June 2012