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

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

June 2012 Frau Auguste Deter, admitted: November 25, 1901; d. April 8,1906 Alzheimer A (1907) Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medizin 64: Über eine eigenartige Erkrankung der Hirnrinde. [Tr: About an unusual disease of the cortex of the brain.]

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

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

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 A B C

June 2012 Early onset Alzheimer’s disease in a Tennessee family

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

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

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

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

June 2012

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

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

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

June 2012 Present-day treatments for Alzheimer’s Disease 1.Cholinesterase inhibitors/cholinergic agonists Cholinergic hypothesis Davies P, Maloney AJF. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet.1976;2: Glutamate antagonist Excitotoxicity as a contributing factor Olney JW et al., Excitotoxic neurodegeneration in Alzheimer disease: new hypothesis and new therapeutic strategies. Arch Neurol 1997; 54 (10):

June 2012 Present-day treatments for Alzheimer’s Disease Donepezil (Aricept, 1996)* mild to moderate and moderate to severe AD cholinesterase 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 AD glutamate antagonist (blocker) – twice daily tablet or solution or extended release tablet, 10 to 28 mg daily * available as generic drug

June 2012 Dimebon Semagacestat2010 Phenserine 2009 Flurizan 2008 Alzhemed 2007 Omega-3 fatty acids 2006 Vitamin E 2005 Clioquinol 2005 NSAIDs 2003 Estrogen 2003 A  vaccination 2002 Recently failed Phase III clinical trials for AD

June 2012

Treatment effects in AD transgenic mice

June 2012

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 Genetic and environmental causes Disease- promoting alterations Neurodegenerative disease “everything is genetic and everything is environmental”

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

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

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

June 2012 Should the US government mandate Americans buy broccoli? At the US supreme court hearing on the healthcare lawAt 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 “Any history of physical activity in your family?”

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

June 2012

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

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

June 2012 Alois Alzheimer ( )