prospects for new treatments for alzheimer’s disease
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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. An idiosyncratic view of Alzheimer’s Disease Present-day treatments for Alzheimer’s Disease - PowerPoint PPT PresentationTRANSCRIPT
June 2012
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: 146-148. 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 ofAuguste Deter
June 2012
From Fuller, S.C.Am. J. Insanity (1911)
and J. Nerv. Ment. Dis. (1912)
June 2012
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
A B
C
June 2012
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
Early onset Alzheimer’s disease in a Tennessee family
June 2012
0
10
20
30
40
50
60
65-69 70-74 75-79 80-84 85-89 90-94 >94
All AD Moderate to severe
Prevalence rate (%) of AD, by age, in the US (Government Accounting Office, 1998)
June 2012
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
From Braak and Braak, 1997
locuscoeruleus
entorhinalcortex
Age
NFT Staging AT8
Neurofibrillary pathology in individuals under 30 (Braak and Del Tredici, 2011)
June 2012
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
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;2:1403.
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): 1234-
1240
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 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
Recently failed Phase III clinical trials for AD
June 2012
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Treatment effects in AD transgenic mice
June 2012
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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 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):321-331 (1999)
One Apoε4 gene male femaleTwo Apoε4 genes male female No Apoε4 gene male female
June 2012
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 (1864-1915)