Your SlideShare is downloading. ×
0
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
100 Years of Alzheimer's Disease: Prevention, Cure, Care
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

100 Years of Alzheimer's Disease: Prevention, Cure, Care

1,390

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
1,390
On Slideshare
0
From Embeds
0
Number of Embeds
3
Actions
Shares
0
Downloads
28
Comments
0
Likes
0
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide
  • 10
  • 10
  • 2 2
  • Transcript

    • 1. 100 Years of Alzheimer’s Disease: Prevention, Cure, Care
      • Marilyn S. Albert, PhD
      • Department of Neurology
      • Johns Hopkins University
    • 2. Summary - Epochs of Progress
      • 100 years ago – unknown as a disease
      • 30 years ago – no research effort
      • 15 years ago – no known genes associated with AD, limited understanding of biological pathways
      • 10 years ago – no animal models of disease
      • 5 years ago – no prevention trials funded, limited ability to identify persons at high risk, limited knowledge about factors that promote brain health
    • 3. Overview of Recent Progress Hope for Tomorrow
      • Genetics Provides Clues for Drug Development
      • Clinical Research Emphasizes Importance of Early Diagnosis
      • Technology Provides Methods for Tracking Evolution of Disease
      • Population Studies Provide Clues to Factors that Promote Brain Health
    • 4. Status of Alzheimer’s Disease 30 Years Ago
      • AD considered a rare disease (early onset)
      • Handful of investigators interested in the area (research budget virtually zero)
      • AD considered untreatable and hopeless
      • No specialized clinical professionals or clinical facilities
      • No broadly accepted criteria for diagnosis or methods of assessment
      • No sources of information and support for patients and families
    • 5. Major Accomplishments 1970s-1980s
      • AD associated with specific pathological changes in the brain (clinical pathological correlations)
      • AD associated with specific biochemical changes in the brain (acetylcholine deficiency)
      • Consensus on clinical and pathological criteria for diagnosis
    • 6. Pathophysiology of AD ~ 1975-1990s
      • Neuritic plaques
      • Neurofibrillary tangles
      • Synaptic & neuronal loss
      • Neurotransmitters ( acetylcholine )
      • temporal parietal frontal
    • 7.  
    • 8.  
    • 9. ‘ Definite’ Diagnosis of AD ‘gold standard’
      • Presence of dementia during life
      • Examination of brain tissue to determine prevalence of neuritic plaques and neurofibrillary tangles
    • 10.  
    • 11. Clinical Diagnosis of AD ‘ Probable or Possible AD’
      • History of progressive decline in two or more areas of cognition (e.g., memory, language, spatial ability, executive function)
      • Laboratory tests to identify treatable or structural causes of dementia (e.g., CBC, TFTs, LFTs, RPR, CT or MRI)
      • Consciousness not clouded (i.e., absence of acute confusion)
      • ~ 90 % accurate
      • McKhann et al., 1984
    • 12. Pathophysiology of AD ~ 1975-1990s
      • Neuritic plaques
      • Neurofibrillary tangles
      • Synaptic & neuronal loss
      • Neurotransmitters ( acetylcholine )
      • temporal parietal frontal
    • 13. Current Treatments for AD
      • Aricept (donepezil): 5-10mg qd *
      • Exelon (rivastigmine): 3-6mg bid *
      • Reminyl (galantamine): 4-12mg bid *
      • Ebixa (memantine): 5-20mg qd
      • ~ 6 month improvement in function
      • * - cholinesterase inhibitors
    • 14.  
    • 15.  
    • 16. A Disease Modifying Agent Would Alter Rate of Progression
      • No Treatment
      Time Cognitive Function Early Treatment
    • 17. Major Accomplishments 1990s
      • Molecular structure of the hallmark brain abnormalities (plaques and tangles) identified
      • Genetic mutations identified that cause early onset form of disease (Ch. 21, 14, 1 – APP, PS1, PS2)
      • Genetic variant identified that increases susceptibility to disease (APOE)
    • 18. Molecular pathology of AD: plaques
      • Primary component is Aß, a 40 or 42 amino acid peptide derived from APP
      • Numerous other components including apoE and a2M
      • Sponge-like aggregate in the neuropil includes cellular elements
      • Glial response near many plaques
    • 19. Molecular pathology of AD: tangles
      • Paired helical filaments by EM
      • Microtubule associated protein tau is major component
      • 20-25 phosphorylation sites identified
      • Kinases are a therapeutic target
    • 20. Search for Genetic Factors that Cause Alzheimer’s Disease
      • Identify families in which AD occurs in large numbers across multiple generations
      • Obtain clinical information and blood for genetic analysis from families
      • Identify location of gene shared by individuals with disease vs those without
      • Determine specific genetic mutation that causes disease
    • 21.  
    • 22. Role of Genetics in AD
      • Early Onset AD
        • (Onset < 60 - 65 yrs)
          • Chromosome 21 - APP Gene
          • Chromosome 14 - PS1 Gene
          • Chromosome 1 - PS2 Gene
      • Late Onset AD
        • (Onset > 60 - 65 yrs)
          • Chromosome 19 - APOE Gene
            • 3 alleles - APOE 2, 3, 4
            • APOE-4 increases susceptibility
              • to AD
    • 23. Development of Mice Carrying Major Genes for AD sac Y Y Y Y Y Mice Appear Normal Plaques Develop Memory Deficit Emerges
    • 24. Spatial Memory Task
    • 25. Alzheimer’s Disease Genes Early Onset AD (Onset <60 years)
    • 26. A β misfolding into “amyloid”
    • 27. Dominant Genes Suggest Mechanism - based on ‘Amyloid Hypothesis’ -
      • Dominant AD genes increase production of beta-amyloid protein (A ß 1-42) - beta secretase and gamma secretase
      • Beta amyloid protein accumulates, generating neuritic plaques
      • Neurofibrillary tangle formation accelerates
      • Synaptic and neuronal loss progresses
    • 28. Role of Genetics in AD
      • Early Onset AD
        • (Onset < 60 - 65 yrs)
          • Chromosome 21 - APP Gene
          • Chromosome 14 - PS1 Gene
          • Chromosome 1 - PS2 Gene
      • Late Onset AD
        • (Onset > 60 - 65 yrs)
          • Chromosome 19 - APOE Gene
            • 3 alleles - APOE 2, 3, 4
            • APOE-4 increases susceptibility
              • to AD
    • 29. Search for Improved Treatments - based on ‘Amyloid Hypothesis’ – APOE Gene Findings
      • APOE-4 allele appears to decrease clearance of A ß 1-42
      • Interaction between vascular risk and risk for AD: increase in cholesterol increases accumulation of A ß 1-42
    • 30. Impact of Other Factors in Cell Death
      • Inflammation in response to accumulation of amyloid and tau
      • Oxidation facilitating further injury
      • Cell viability – protective agents that promote response to injury, cell connectivity, blood flow
    • 31. Medication Types Under Study by Pharmaceutical Companies
      • Anti-amyloid aggregation
      • Anti-tau aggregation
      • Improve cellular response to injury (oxidation, inflammation)
      • Novel treatments – need information on safety and indication of effectiveness
    • 32. Clinical Trials of Medications Potential for Disease Modification
      • Alzemed
      • Flurizan
      • Rosiglitazone
      • Vaccine – Monoclonal antibody (AAB-001)
    • 33. A Disease Modifying Agent Would Alter Rate of Progression
      • No Treatment
      Time Cognitive Function Early Treatment
    • 34. Major Accomplishments
      • Understanding that disease takes a long time to evolve over time
      • Development of methods for studying disease before symptoms are severe enough to warrant diagnosis of AD
      • Applications of technology to study of very early disease
    • 35. Disease Progression Patho- physiology Progression of Neurodegenerative Diseases Normal Prodromal Clinical Dx
    • 36.  
    • 37.  
    • 38. Changes in Brain in Very Mild AD Neuropathologic Data
      • Formation of neuritic plaques and neurofibrillary tangles neuronal loss
      • >30% neuronal loss in entorhinal cortex (major input to hippocampus)
      • Gradual spread of plaques and tangles and neuronal loss throughout brain (e.g. superior temproral cortex, anterior cingulate, inferior parietal cortex
    • 39. Evolution of Pathology in Alzheimer’s Disease CONTROL PRODROMAL AD CLINICAL AD Cognitive Performance 100% Disease Progression years A β NFT/TAU Inflammation
    • 40. Mild Cognitive Impairment MCI
      • memory complaint / corroborated by informant
      • not demented
        • preserved general cognitive function
        • normal activities of daily living
      • memory impaired for age and education (tends to be   1.5 SD)
      • Petersen et al., 1999
    • 41. Individuals With MCI Develop Clinical AD At A Much Higher Rate Than Normal Elderly
    • 42. Disease Progression Cognitive Function Therapeutic Implications of Disease Course Normal Prodromal Clinical Dementia Prevent Onset Slow Progression Treat Symptoms & Slow Decline
    • 43. Disease Progression Cognitive Function Progression of Alzheimer’s Disease Normal Prodromal Clinical Dementia Min V Mild MCI Rx
    • 44. Disease Progression Cognitive Function Progression of Alzheimer’s Disease Normal Prodromal Clinical Dementia Min V Mild MCI Rx
    • 45. Disease Progression Cognitive Function Progression of Alzheimer’s Disease Normal Prodromal Clinical Dementia Min V Mild MCI Rx
    • 46. Major Accomplishments
      • Technological advances make imaging feasible for tracking evolution of disease
      • Technological advances make measurement of proteins in brain feasible for tracking evolution of disease
      • Recognition that careful tracking of disease may be essential for finding better treatments
    • 47.  
    • 48. Entorhinal/Hippocampal ROI’s Entorhinal Cortex Hippocampus
    • 49. Need Better Biomarkers for Clinical Trials
      • Need measurement of outcome within a reasonable period of time
      • Biomarkers under consideration – imaging measures and /or measures from blood and urine
        • MRI
        • PET
        • Plasma A ß
    • 50. Need Better Biomarkers for Clinical Trials
      • Measures need to be standardized across sites
        • Reliable (measured in the same way across sites)
        • Feasible (can be measured in large numbers of subjects)
      • Optimal measures may vary with stage of disease and modality (e.g., MRI, PET, etc)
    • 51. Alzheimer’s Disease Neuroimaging Initiative
      • Funded jointly by government, industry, foundations
      • Planned jointly by academic centers and industry
      • N ovel methods of assessment – imaging (MRI and PET), blood, CSF
      • International effort – ADNI sites in US and Canada, Collaborating consortia in Europe and Australia
      • Goal to help industry find better drugs faster
    • 52.  
    • 53. European ADNI Consortium Stockholm – Wahlund/Winblad Munich – Hampel Bio co-PI Brescia – Frisoni Project PI Toulouse – Vellas Clinical PI Amsterdam – Barkhof/Scheltens MR imag PI Copenhagen - Waldemar Gotheborg – Blennow Bio co-PI Participating Sites
    • 54. Australia ADNI Consortium Perth Melbourne PARTICIPATING SITES
    • 55. Major Accomplishments
      • Completion of population studies that identify risk factors for AD
      • Understanding that life style factors that are modifiable may alter risk for AD
      • Start of national campaigns to alter risk factors for AD (Alzheimer’s Australia, UK, US)
    • 56. Predictors of Maintenance of Cognition
      • Many large community-based observational studies conducted since early 1990s
      • Primary study design
        • Examine wide range of factors among individuals with good function
        • Follow participants over time
        • Identify factors that predict maintenance of cognitive function
    • 57. Predictors of Maintenance of Cognition
      • Community-based Observational Studies
      • Nature of Populations Studied
        • Emphasize participants unimpaired when first studied
        • Examine elderly only (e.g., 70-80 at baseline) as well as middle aged individuals followed into elderly age range
        • Geographically diverse (U.S., Canada, Europe; Urban, Rural)
    • 58. Examples: Longitudinal Studies n=15,000
      • MacArthur Study of Successful Aging
      • Chicago Health & Aging Project
      • North Manhattan Aging Study
      • Canadian Study of Health & Aging (Canada)
      • Kungsholmen Project (Sweden)
      • Berlin Aging Study (Germany)
      • Rotterdam Study (Netherlands)
      Albert et al., 1995 Schmand et al., 1997 Laurin e al., 2001 Scarmeas et al., 2001 Verghese et al., 2003 Wilson et al., 2003, 2005 Weuve et al., 2004 Rovio et al., 2005
    • 59. Predictors of Maintenance of Cognition
      • Physical activity
      • Mental activity
      • Social engagement
      • Vascular risk factors
      • Statistical analysis suggests that these factors may be additive
      • Genetics
    • 60. Physical Activity and Maintenance of Cognition
      • Physical activity – activities involved in daily living
        • Blocks walked
        • Stairs climbed
        • Objects lifted
        • Total kilocalories expended
      • Relationship after adjusting for potential confounders (co-morbid conditions, functional limitations, smoking, etc)
    • 61. Physical Activity Potential Mechanisms
      • Stimulation of chemicals that protect and repair the brain (e.g., Brain Derived Neurotrophic Factor - BDNF)
      • Stimulation of new nerve cells (i.e. neurogenesis)
      • Reduced accumulation of amyloid (increased neprilysin, increased expression of genes for learning and memory, cell survival)
    • 62. Mental Activity and Maintenance of Cognition
      • Educational Experience - relationship after adjusting for socioeconomic status
      • Daily activities that are mentally stimulating– crossword puzzles, books, lectures
    • 63. Mental Activity Potential Mechanisms
      • Development of increased connections among nerve cells
      • Compensation - Alternate brain pathways for performing tasks and solving problems
    • 64. Psychosocial Factors and Maintenance of Cognition
      • Social engagement
      • Feelings of self-worth
      • Feelings of self-efficacy
      • Mood and anxiety
    • 65. Psychosocial Factors Potential Mechanisms
      • Modulation of stress hormones
      • Increased likelihood of compliance with healthy life-style
    • 66. Vascular Risk Factors and Maintenance of Cognition
      • Blood Pressure
      • Diabetes
      • Cholesterol
      • Weight
      • Smoking
    • 67. Vascular Risk Factors Potential Mechanisms
      • Small and large artery disease
      • Disruption of blood brain barrier
      • Inflammation and oxidative stress
    • 68. Vascular Risk Factors
      • Effects may be additive or multiplicative
      • Intervention strategies provide multiple potential benefits (heart and brain)
      • Minority populations may demonstrate the greatest benefit as risk factors are more prevalent
    • 69. Combination of Factors Appears Most Effective
      • Ex. Mental and physical activity in combination
        • Statistical demonstration of combined effect
        • Animal model - physical activity in enriched environment (rodents)
        • Human model – tai chi, exercise bicycle while reading
    • 70. Increasing Interest
      • Alzheimer’s Australia – ‘Mind Your Mind’ campaign
      • Alzheimer’s Society UK – ‘Mind Your Head’ campaign
      • Alzheimer’s Association, US – ‘Maintain Your Brain’ campaign
      • U.S. National Institutes of Health – Cognitive and Emotional Health Project
    • 71. General Conclusions: Predictors of Maintenance of Cognition
      • A complex interaction of factors predicts maintenance of cognitive function in older persons
      • Evidence suggests combination of factors is more effective than any one factor alone
      • Results have implications for intervention efforts aimed at minimizing or preventing cognitive decline in older age
      • The most effective interventions will likely combine educational activities, physical training, and psychosocial approaches
    • 72. Predicting Maintenance of Cognition
      • What activity best combines all predictive factors -------------SHOPPING
    • 73. Overview of Recent Progress Hope for Tomorrow
      • Genetics Provides Clues for Drug Development
      • Clinical Research Emphasizes Importance of Early Diagnosis
      • Technology Provides Methods for Tracking Evolution of Disease
      • Population Studies Provide Clues to Factors that Promote Brain Health
    • 74. Summary - Epochs of Progress
      • 100 years ago – unknown as a disease
      • 25 years ago – no research effort
      • 15 years ago – no known genes associated with AD, limited understanding of biological pathways
      • 10 years ago – no animal models of disease
      • 5 years ago – no prevention trials funded, limited ability to identify persons at high risk, limited knowledge about factors that promote brain health
    • 75. Strategy that Maximized Progress
      • Identification of research areas that required improved funding
      • Recruitment of outstanding scientists into field
      • Communication to Government regarding importance of problem: No Time To Lose – Invest in Research
      • Speaking with One Voice regarding strategy

    ×