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

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

Marilyn S. Albert, PhD

Department of Neurology

Johns Hopkins University

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

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

•

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

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

Pathophysiology of AD~ 1975-1990s

• Neuritic plaques

• Neurofibrillary tangles

• Synaptic & neuronal loss

• Neurotransmitters (acetylcholine)

temporal parietal frontal

‘Definite’ Diagnosis of AD‘gold standard’

• Presence of dementia during life

• Examination of brain tissue to determine prevalence of neuritic plaques and neurofibrillary tangles

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

Pathophysiology of AD~ 1975-1990s

• Neuritic plaques

• Neurofibrillary tangles

• Synaptic & neuronal loss

• Neurotransmitters (acetylcholine)

temporal parietal frontal

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

A Disease Modifying Agent Would Alter Rate of Progression

No Treatment

Time Time

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Early TreatmentEarly Treatment

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)

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

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

Search for Genetic Factors that Cause Alzheimer’s Disease

1. Identify families in which AD occurs in large numbers across multiple generations

2. Obtain clinical information and blood for genetic analysis from families

3. Identify location of gene shared by individuals with disease vs those without

4. Determine specific genetic mutation that causes disease

Role of Genetics in AD

Early Onset AD(Onset < 60 - 65 yrs)

Chromosome 21 - APP GeneChromosome 14 - PS1 GeneChromosome 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

sac

YYYYY

Mice Appear Normal Plaques Develop Memory Deficit Emerges

Development of Mice Carrying Major Genes for AD

Spatial Memory Task

Alzheimer’s Disease Genes

Gene GeneticMutation

BiochemicalPhenotype

APP (21) 13 CausativeMutations

Increased ratio ofA42:A40 orA generation

PSEN1 (14) 105 CausativeMutations

Increased ratio ofA42:A40

PSEN2 (1) 7 CausativeMutations

Increased ratio ofA42:A40

Early Onset AD (Onset <60 years)

Aβ misfolding into “amyloid”

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

Role of Genetics in AD

Early Onset AD(Onset < 60 - 65 yrs)

Chromosome 21 - APP GeneChromosome 14 - PS1 GeneChromosome 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

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

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

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

Clinical Trials of Medications Potential for Disease Modification

• Alzemed • Flurizan

• Rosiglitazone

• Vaccine – Monoclonal antibody (AAB-001)

A Disease Modifying Agent Would Alter Rate of Progression

No Treatment

Time Time

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Early TreatmentEarly Treatment

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

Disease Progression

Patho-physiology

Progression of Neurodegenerative Diseases

Normal

Prodromal

Clinical Dx

Changes in Brain in Very Mild ADNeuropathologic 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

Evolution of Pathology in Alzheimer’s Disease

CONTROLCONTROL PRODROMAL ADPRODROMAL AD CLINICAL ADCLINICAL AD

Co

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100%

Disease ProgressionDisease Progressionyears

Aβ

NFT/TAU

Inflammation

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

Individuals With MCI Develop Clinical AD At A Much Individuals With MCI Develop Clinical AD At A Much Higher Rate Than Normal ElderlyHigher Rate Than Normal Elderly

YEARS OF FOLLOW UP

543210

PR

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FR

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.95

.90

.85

.80

.75

.70

.65

.60

.55

.50

.45

.40

.35

.30

.25

.20

.15

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NORMAL CONTROLS

MCI SUBJECTS

Disease Progression

CognitiveFunction

Therapeutic Implications of Disease Course

Normal

Prodromal

Clinical Dementia

Prevent

Onset Slow

Progression

Treat Symptoms & Slow Decline

Disease Progression

CognitiveFunction

Progression of Alzheimer’s Disease

NormalProdromal

Clinical DementiaMin

V MildMCI

Rx


• 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

Entorhinal/Hippocampal ROI’s

Entorhinal Cortex

Hippocampus

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

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)

Alzheimer’s 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

Stockholm – Wahlund/Winblad

Munich – Hampel Bio co-PI

Brescia – Frisoni Project PI

Toulouse – Vellas Clinical PI

Amsterdam – Barkhof/Scheltens MR imag PI

Copenhagen - Waldemar

European ADNI Consortium

Gotheborg – Blennow Bio co-PI

Participating Sites

Perth

Melbourne

PARTICIPATING SITES

Australia ADNIConsortium


• 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)

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


• 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)

Examples: Longitudinal Studiesn=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., 1995Schmand et al., 1997Laurin e al., 2001Scarmeas et al., 2001

Verghese et al., 2003Wilson et al., 2003, 2005Weuve et al., 2004Rovio et al., 2005


• Physical activity • Mental activity • Social engagement• Vascular risk factors

• Statistical analysis suggests that these factors may be additive

• Genetics

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)

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)

Mental Activity and Maintenance of Cognition

• Educational Experience - relationship after adjusting for socioeconomic status

• Daily activities that are mentally stimulating– crossword puzzles, books, lectures

Mental ActivityPotential Mechanisms

• Development of increased connections among nerve cells

• Compensation - Alternate brain pathways for performing tasks and solving problems

Psychosocial Factors and Maintenance of Cognition

• Social engagement

• Feelings of self-worth

• Feelings of self-efficacy

• Mood and anxiety

Psychosocial FactorsPotential Mechanisms

• Modulation of stress hormones

• Increased likelihood of compliance with healthy life-style

Vascular Risk Factors and Maintenance of Cognition

• Blood Pressure

• Diabetes

• Cholesterol

• Weight

• Smoking

Vascular Risk Factors Potential Mechanisms

• Small and large artery disease

• Disruption of blood brain barrier

• Inflammation and oxidative stress

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

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

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

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

Predicting Maintenance of Cognition

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

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

•

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

Strategy that Maximized Progress

1. Identification of research areas that required improved funding

2. Recruitment of outstanding scientists into field

3. Communication to Government regarding importance of problem: No Time To Lose – Invest in Research

4. Speaking with One Voice regarding strategy

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

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