100 Years of Alzheimers Disease: Prevention, Cure, Care

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100 Years of Alzheimers Disease Prevention,
Cure, Care

• Marilyn S. Albert, PhD
• Department of Neurology
• Johns Hopkins University

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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

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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

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Status of Alzheimers 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

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Major Accomplishments1970s-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

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Pathophysiology of AD 1975-1990s

• Neuritic plaques
• Neurofibrillary tangles
• Synaptic neuronal loss
• Neurotransmitters (acetylcholine)
• temporal parietal frontal

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Definite Diagnosis of ADgold standard

• Presence of dementia during life
• Examination of brain tissue to determine
  prevalence of neuritic plaques and
  neurofibrillary tangles

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Clinical Diagnosis of ADProbable 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

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Pathophysiology of AD 1975-1990s

• Neuritic plaques
• Neurofibrillary tangles
• Synaptic neuronal loss
• Neurotransmitters (acetylcholine)
• temporal parietal frontal

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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

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A Disease Modifying Agent Would Alter Rate of
Progression
Early Treatment
Cognitive Function

• No Treatment

Time
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Major Accomplishments1990s

• 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)

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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

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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

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Search for Genetic Factors that Cause Alzheimers
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

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Role of Genetics in AD
Early Onset AD (Onset lt 60 - 65 yrs) Chromosome
21 - APP Gene Chromosome 14 - PS1 Gene Chromosome
1 - PS2 Gene

• Late Onset AD
• (Onset gt 60 - 65 yrs)
• Chromosome 19 - APOE Gene
• 3 alleles - APOE 2, 3, 4
• APOE-4 increases susceptibility
• to AD

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Development of Mice Carrying Major Genes for AD
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Spatial Memory Task
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Alzheimers Disease Genes
Early Onset AD (Onset lt60 years)
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Aß misfolding into amyloid
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Dominant Genes Suggest Mechanism- based on
Amyloid Hypothesis -

• Dominant AD genes increase production of
  beta-amyloid protein (Aß 1-42) - beta secretase
  and gamma secretase
• Beta amyloid protein accumulates, generating
  neuritic plaques
• Neurofibrillary tangle formation accelerates
• Synaptic and neuronal loss progresses

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Role of Genetics in AD
Early Onset AD (Onset lt 60 - 65 yrs) Chromosome
21 - APP Gene Chromosome 14 - PS1 Gene Chromosome
1 - PS2 Gene

• Late Onset AD
• (Onset gt 60 - 65 yrs)
• Chromosome 19 - APOE Gene
• 3 alleles - APOE 2, 3, 4
• APOE-4 increases susceptibility
• to AD

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Search for Improved Treatments- based on
Amyloid Hypothesis APOE Gene Findings

• APOE-4 allele appears to decrease clearance of Aß
  1-42
• Interaction between vascular risk and risk for
  AD increase in cholesterol increases
  accumulation of Aß 1-42

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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

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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

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Clinical Trials of Medications Potential for
Disease Modification

• Alzemed
• Flurizan
• Rosiglitazone
• Vaccine Monoclonal antibody (AAB-001)

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A Disease Modifying Agent Would Alter Rate of
Progression
Early Treatment
Cognitive Function

• No Treatment

Time
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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

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Progression of Neurodegenerative Diseases
Normal
Prodromal
Clinical Dx
Patho-physiology
Disease Progression
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Changes in Brain in Very Mild ADNeuropathologic
Data

• Formation of neuritic plaques and neurofibrillary
  tangles neuronal loss
• gt30 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

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Evolution of Pathology in Alzheimers Disease
CONTROL
PRODROMAL AD
CLINICAL AD
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Inflammation
NFT/TAU
Cognitive Performance
Aß
years
Disease Progression
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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

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Individuals With MCI Develop Clinical AD At A
Much Higher Rate Than Normal Elderly
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Therapeutic Implications of Disease Course
Normal
Prodromal
Prevent Onset
Clinical Dementia
Slow Progression
CognitiveFunction
Treat Symptoms Slow Decline
Disease Progression
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Progression of Alzheimers Disease
Normal
Prodromal
Clinical Dementia
Rx
CognitiveFunction
Min
V Mild
MCI
Disease Progression
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Progression of Alzheimers Disease
Normal
Prodromal
Rx
Clinical Dementia
CognitiveFunction
Min
V Mild
MCI
Disease Progression
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Progression of Alzheimers Disease
Normal
Prodromal
Rx
Clinical Dementia
CognitiveFunction
Min
V Mild
MCI
Disease Progression
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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

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Entorhinal/Hippocampal ROIs
Entorhinal Cortex
Hippocampus
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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 Aß

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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)

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Alzheimers Disease Neuroimaging Initiative

• Funded jointly by government, industry,
  foundations
• Planned jointly by academic centers and industry
• Novel 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

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European ADNI Consortium
Stockholm Wahlund/Winblad
Gotheborg Blennow Bio co-PI
Copenhagen - Waldemar
Amsterdam Barkhof/Scheltens MR imag PI
Munich Hampel Bio co-PI
Brescia Frisoni Project PI
Toulouse Vellas Clinical PI
Participating Sites
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Australia ADNI Consortium
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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 (Alzheimers Australia, UK, US)

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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

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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)

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Examples Longitudinal Studiesn15,000

• 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

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Predictors of Maintenance of Cognition

• Physical activity
• Mental activity
• Social engagement
• Vascular risk factors
• Statistical analysis suggests that these factors
  may be additive
• Genetics

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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)

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Physical ActivityPotential 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)

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Mental Activity and Maintenance of Cognition

• Educational Experience - relationship after
  adjusting for socioeconomic status
• Daily activities that are mentally stimulating
  crossword puzzles, books, lectures

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Mental ActivityPotential Mechanisms

• Development of increased connections among nerve
  cells
• Compensation - Alternate brain pathways for
  performing tasks and solving problems

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Psychosocial Factors and Maintenance of Cognition

• Social engagement
• Feelings of self-worth
• Feelings of self-efficacy
• Mood and anxiety

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Psychosocial FactorsPotential Mechanisms

• Modulation of stress hormones
• Increased likelihood of compliance with healthy
  life-style

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Vascular Risk Factors and Maintenance of Cognition

• Blood Pressure
• Diabetes
• Cholesterol
• Weight
• Smoking

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Vascular Risk Factors Potential Mechanisms

• Small and large artery disease
• Disruption of blood brain barrier
• Inflammation and oxidative stress

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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

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Combination of FactorsAppears 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

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Increasing Interest

• Alzheimers Australia Mind Your Mind campaign
• Alzheimers Society UK Mind Your Head
  campaign
• Alzheimers Association, US Maintain Your
  Brain campaign
• U.S. National Institutes of Health Cognitive
  and Emotional Health Project

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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

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Predicting Maintenance of Cognition

• What activity best combines all predictive
  factors -------------SHOPPING

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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

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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

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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