what do we know about prevention and diagnosis (dr. laurie ryan)
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What Do We Know About Prevention and DiagnosisDr. Laurie RyanNational Institute on Aging, Division of NeuroscienceTRANSCRIPT
Laurie Ryan, PhDProgram Director, Alzheimer’s Disease Clinical TrialsDementias of Aging BranchDivision of NeuroscienceNational Institute on Aging, National Institutes of Health
Alzheimer’s Disease (AD): Overview Progressive, degenerative CNS disorder Characterized by memory impairment plus one
or more additional cognitive disturbances Gradual decline in three key symptom
domainsActivities of daily living (ADL)Behavior and personalityCognition
Most common cause of dementia in people aged 65 and over
Other Dementias
Vascular Frontotemporal Lewy-Body Parkinson’s
2010 Alzheimer’s Facts and Figures, Alzheimer’s Association
As many as 5.3 million people in the United States are living with Alzheimer’s.
• Every 70 seconds, someone develops Alzheimer’s.
• Alzheimer's is the seventh-leading cause of death.
• The direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $172 billion each year.
0
10
20
30
40
50
60
70
80
90
1900 1950 2000
Ag
e
Source: 65+ in the United States, U.S. Census Bureau, 2005
U.S. Life Expectancy at Birth in 1900, 1950, 2000
46.3 48.3
65.6 71.1
79.574.1
POPULATION GROWTH OF OLDER AMERICANS (65 Years and Older)
0
20000
40000
60000
80000
100000
YEAR
0
5
10
15
20
25
Number (thousands)Percent of Population
(Federal Interagency Forum on Aging-Related Statistics, 2004)
Estimated Percentage of People over Age 65with Probable Alzheimer’s Disease
3.0
19
47
0
10
20
30
40
50
65-74 75-84 85+
Age Group
Perc
en
t
Source: Evans D , et al. JAMA , Vol. 262, No. 18, 1989.
Projected Number of Persons with Alzheimer’s Disease
Source: Evans, et al. Arch Neurol 2003; 60: 1119-1122.
In 2000, there were 4.5 million Americans with AD. By 2050, the number of Americans with AD will increase to btw 11 and 16 million11 and 16 million
AD Neuropathology
A growing body of evidence suggests that the underlying pathology precedes the onset of clinically detectable AD by a decade or more
By the time a patient is diagnosed, there is thought to be massive neuronal loss and widespread pathology
Neurons
• The brain has billions of neurons, each with an axon and many dendrites.
• To stay healthy, neurons must communicate with each other, carry out metabolism, and repair themselves.
• AD disrupts all three of these essential jobs.
Inside the Human Brain
Plaques and Tangles: The Hallmarks of AD
The brains of people with AD have an abundance of two abnormal structures:
An actual AD plaque An actual AD tangle
• beta-amyloid plaques, which are dense deposits of protein and cellular material that accumulate outside and around nerve cells
• neurofibrillary tangles, which are twisted fibers that build up inside the nerve cell
AD and the Brain
AD Pathogenesis The production and accumulation of
amyloid beta (Aβ) is increasingly thought to be central to AD pathogenesis
Generation of Aβ from amyloid precursor protein (APP) is a pivotal initiating event
Aβ aggregation triggers a variety of secondary events
Beta-amyloid Plaques
Amyloid precursor protein (APP) is the precursor to amyloid plaque.
1. APP sticks through the neuron membrane.
2. Enzymes cut the APP into fragments of protein, including beta-amyloid.
3. Beta-amyloid fragments come together in clumps to form plaques.
1.
2.
3.
AD and the Brain
Neurofibrillary Tangles
Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles.
AD and the Brain
AD PathogenesisTau hyperphosphorylationFormation of neurofibrillary tanglesSynaptic degenerationOxidative injuryInflammationDemyelinationApoptosisTransmitter deficits
Diagram of the cascade of events currently hypothesized to comprise the pathophysiology of AD.
Salloway, S. et al. Alzheimer's and Dementia 2008; 4: 65-79
Courtesy of George Grossberg M.D.; St. Louis University.
Neuropathologic ChangesNeuropathologic ChangesCharacteristic of ADCharacteristic of AD
AD
AmyloidAmyloidplaquesplaques
Normal
TanglesTangles
Cognitive ContinuumCognitive Continuum
Mild CognitiveMild CognitiveImpairmentImpairment
NormalNormal
Alzheimer's DiseaseAlzheimer's Disease
CP926864- 35
Figure 3 Proposed model relating imaging, pathologyand clinical presentation over an individual’s adult lifetime.The lifetime clinical course of the disease is divided into pre-symptomatic,prodromal and dementia phases.
Jack et al. Brain 2009: 132; 1355–1365
Genetic Studies
The two main types of AD are young-onset and late-onset:
Genetics
• Young-onset AD is rare, usually affecting people aged 30 to 60 and usually running in families. Researchers have identified mutations in three genes that cause young-onset AD.
• Late-onset AD is more common. It usually affects people over age 65. The primary risk factor for AD is age.
Rare, early onset autosomal-dominant forms of the disease are caused by mutations in 3 genes (APP, Presenilin 2, Presenilin 1) all of which alter production of the amyloid A) peptide; less than 5% of all AD cases.
Bertram and Tanzi, Nature Reviews Neuroscience 2008
LOAD is thought to be multi-factorial.
However, ApoE is the only clearly identified genetic risk factor;
E4 allele influences age at onset of AD, but is neither necessary nor sufficient for the disease.
Bird Genetics in Med 2008
Several other potential genes are under investigation
100100
Non
Alz
hei
mer
Cas
es (
% o
f to
tal)
0 ApoE4
1 ApoE4
2 ApoE4
6060
8080
4040
2020
Age at Onset (years) Adapted from Corder et al. Science. (1993),261,921 & Roses Et al. (1998) and Michelson 00
ApoE4 decreases the age of onset of AD
6060 7070 8080 9090
Alzheimer’s Disease Risk FactorsAlzheimer’s Disease Risk Factors
Age
Head Injury
High Blood Pressure
High Cholesterol
High Homocysteine
Diabetes
Diet
Education
Exercise
Social Interaction
Age
Head Injury
High Blood Pressure
High Cholesterol
High Homocysteine
Diabetes
Diet
Education
Exercise
Social Interaction
Currently FDA Approved Treatments for AD The U.S. Food and Drug Administration
(FDA) has approved two types of medications to treat cognitive symptoms of AD.
Provide temporary cognitive improvement and deferred decline in some patients
Currently Approved Treatments for AD Cholinesterase Inhibitors*
Donepezil (Aricept)Rivastigmine (Exelon)Galantamine (Razadyne)
Memantine (Namenda)#
*Cholinesterase inhibitors are drugs that block the activity of an enzyme in the brain: cholinesterase. Cholinesterase breaks apart acetylcholine, a neurotransmitter vital for the transmission of nerve impulses. Cholinesterase inhibitors reduce the action of cholinesterase, thus making more acetylcholine available to neurons.#N-Methyl-D-aspartate (NMDA) antagonist; thought to be a neuroprotective agent that blocks excitotoxicty; May have a potentially disease modifying effect
Disease Modification An improved understanding of the
pathogeneses of AD has led to the identification of numerous therapeutic targets designed to alter Aβ or tau accumulation
Many of these targets have been validated in proof of concept studies in preclinical animal models, and a number are being tested in human clinical trials.
Avenues for New AD Therapies Prevent build up of plaque (anti-amyloid)
o slow or prevent amyloid production by inhibiting clipping enzymes or by vaccine therapy
o slow aggregation into plaqueso dissolve plaqueso increase clearance
Prevent build up of paired helical filaments (tau focused)o slow or prevent tau aggregation and dysfunctiono dissolve paired helical filaments
Prevent brain cell dysfunction and deatho slow or prevent oxidative stress, inflammation, reduced blood flowo increase levels of protective molecules in braino maintain viable connections between cells
‘Cocktail’ Approach
Likely that multimodal therapy or ‘cocktail’ may be needed to significantly impact the clinical course of AD.
E.g. a cocktail of therapies that target tau, Aβ, inflammation and cognitive symptoms, may be more efficacious than monotherapy.
NINCDS/ADRDA Criteria for Probable NINCDS/ADRDA Criteria for Probable Alzheimer’s DiseaseAlzheimer’s Disease________________________________________________________________________________
Dementia established by clinical examination; confirmed by cognitive screening tests
Deficits in two or more areas of cognition Progressive worsening of memory and other cognitive
functions No disturbance of consciousness Onset between 40 and 90, most often after 65 Absence of systemic disorders or other brain disease
that could account for the deficits and progression
McKhann et al. Neurol 1984;34:939-944
Diagnosing AD
Experienced physicians in specialized AD centers can now diagnose AD with up to 90 percent accuracy. Early diagnosis has advantages:
• Doctors can rule out other conditions that may cause dementia.
• If it is AD, families have more time to plan for the future.
• Treatments can start earlier, when they may be more effective.
• It helps scientists learn more about the causes and development of AD.
Physicians today use a number of tools to diagnose AD:• a detailed patient history
• information from family and friends
• physical and neurological exams and lab tests
• neuropsychological tests
• imaging tools such as CT scan, or magnetic resonance imaging (MRI). PET scans are used primarily for research purposes
Diagnosing AD
Increasing Role of Imaging & Biomarkers in AD treatment trials and detection
Many studies have shown changes in the brain of normal aging and in AD
Structural MRI shows shrinkage, esp. of median temporal lobe and cortex
FDG PET shows reduced metabolism AD Biomarkers can improve diagnosis
and reflect disease progression Great potential for use in clinical trials
and for early detection
PET Imaging of Amyloid Deposits in Alzheimer’s Disease vs. Normal Controls
Klunk, et al. Ann Neurol 2004
PET imaging with the tracer, Pittsburgh Compound-B (PIB), can provide quantitative information on amyloid deposits in living subjects.
Individuals with MCI Cover the Range Individuals with MCI Cover the Range of Amyloid Load of Amyloid Load
Positive Amyloid PIB Scan Predicts Clinical Positive Amyloid PIB Scan Predicts Clinical Progression of MCI patients to ADProgression of MCI patients to AD
PiB+ 15
AD Converters 12
PiB- 13
AD Converters 1
Melbourne Cohort
N=28, 21 mo. follow-up
PiB+ 13
AD Converters 5
PiB- 10
AD Converters 0
Pittsburgh Cohort
N=23, 24 mo. follow-up
Wolk et al., AAN 2008 Villemagne et al., SNM 2008
18F-AV-45 Scans Spectrum of Pathology
AVID
Biochemical Biomarkers Cerebrospinal Fluid (CSF): AD in its earliest
stages may cause changes in CSF levels of beta-amyloid and tau, two proteins that form abnormal brain deposits strongly linked to the disease.
Plasma, Urine: investigations underway on whether pre-symptomatic AD causes consistent, measurable changes in urine or blood levels of tau, beta-amyloid or other biomarkers.
A Serum Protein–Based Algorithm for the Detection of Alzheimer Disease: O’Bryant et al. Arch Neurol. 2010;67(9):1077-1081 Identified protein biomarkers in the blood that can be
used to distinguish between individuals with and without AD.
Compared protein patterns in blood samples from 197 patients with AD and 203 without AD and incorporated into an algorithm for detecting AD cases in a test group.
Results suggest this algorithm may accurately classify most Alzheimer's cases — particularly when combined with APOE status and demographic data. Validation in an independent sample is needed.
Hypothetical Model of Dynamic Biomarkers of the Alzheimer’s Pathological Cascade
Clifford R Jack, Jr, David S Knopman, William J Jagust, Leslie M Shaw, Paul S Aisen, Michael W Weiner, Ronald C Petersen, and John Q Trojanowski
Volume 9, Issue 1, January 2010, Pages 119-128
Figure 2. Dynamic biomarkers of the Alzheimer's pathological cascadeAβ is identified by CSF Aβ42 or PET amyloid imaging. Tau-mediated neuronal injury and dysfunction is identified by CSF tau or fluorodeoxyglucose-PET. Brain structure is measured by use of structural MRI. Aβ=β-amyloid. MCI=mild cognitive impairment.
Figure 5. Modulators of biomarker temporal relationships(A,B) Relative to a fixed age (here, 65 years), the hypothesised effect of APOE 4 is to shift β-amyloid plaque deposition and the neurodegenerative cascade both to an earlier age compared with 4 non-carriers. (C) The hypothesised effect of the presence of different diseases and genes on cognition: C−=cognition in the presence of comorbidities (eg, Lewy bodies or vascular disease) or risk amplification genes; C+=cognition in patients with enhanced cognitive reserve or protective genes; Co=cognition in individuals without
comorbidity or enhanced cognitive reserve.
Authors acknowledge that well-validated biomarkers do not currently exist for some important features of the disease. This includes reliable chemical biomarkers of specific toxic oligomeric forms of soluble Aβ and imaging measures of soluble Aβ or diffuse plaques, PET ligands that specifically measure the burden of NFTs and other tau abnormalities.
Thus, they note, the biomarker model of disease is just that—a model of the stages of disease that can be assessed with currently validated biomarkers, and not a comprehensive model of all pathological processes in AD.
Need For Validated Biomarkers For AD Need For Validated Biomarkers For AD TrialsTrials
Current trials use clinical/cognitive outcome measures : slow rate of change over time, do not easily determine
disease modifying effects of treatmenttrials require large sample sizelarge sample size, are time intensive time intensive and
costlycostly Imaging and Biochemical Biomarkers – hope to
improve speed and efficiency improve speed and efficiency of clinical trialsBiomarkers useful in Phase 2 to make decisions
about Phase 3 (e.g. doses)Biomarkers useful in Phase 3
○ Provide additional evidence to support primary outcome findings
○ Provide evidence for “disease modification” and not simply symptomatic improvement
Goals of ADNI: Goals of ADNI: Longitudinal Multi-Site Observational StudyLongitudinal Multi-Site Observational Study
Major goal is collection of data and samples to establish a brain imaging, biomarker, and clinical database in order to identify the best markers for following disease progression and monitoring treatment response
Determine the optimum methods for acquiring, processing, and distributing images and biomarkers in conjunction with clinical and neuropsychological data in a multi-site context
“Validate” imaging and biomarker data by correlating with neuropsychological and clinical data.
Rapid public access of all data and access to samples
STUDY DESIGN-ADNI1
MCI (n= 400): 0, 6, 12, 18, 24, 36 months AD (n= 200): 0, 6, 12, 24 months Controls (n= 200): 0, 6, 12, 24, 36 months
Clinical/neuropsychological evaluations, MRI (1.5 T) at all time points
FDG PET at all time points in 50% 3 T MRI at all time points in 25% PIB sub-study on 120 subjects Blood and urine at all time points from all subjects;
CSF from 50% of subjects 0, 1 yr, 2 yr (subset); DNA and immortalized cell lines from all subjects
GWAS study
ADNI Public-Private Partnership Structure
Neil Buckholtz
PI: Mike WeinerAdministrative Core: UCSF
Biostatistics Core:UCD: Beckett
Biomarkers Core:UPenn: Trojanowski/Shaw
MRI Core:Mayo: Jack
Clinical Core:UCSD: AisenMayo: Peterson
PET Core:Berkeley: Jagust
Informatics Core:UCLA: Toga
Publications Core:BostonU: Green
Neuropathology Core:WashU: Morris
57 Clinical Sites: ADNI PIs and Cores
ADNI Executive Steering Committee
Private/Philanthropic+
Public
NIBIB, NINDS, NIMH, NIDA, NCRR, NINR
FDA
ADNI Progression RatesADNI Progression Rates
Year Normal MCI MCI AD
0-1 1.4% (0.0-3.2) 16.0% (11.3-20.4)
1-2 2.4% (0.0-4.7) 23.9% (19.0-29.5)
2-3 0.0% (0.0-3.4) 9.1% (5.8-13.5)
Mean Cortical Thickness Change (over 12 months)
Holland et al.
+2%
-2%
Lateral View Medial View
PET: Regional Hypometabolism
AD MCI
Kewei Chen, Ph.D., Eric M. Reiman, M.D.Kewei Chen, Ph.D., Eric M. Reiman, M.D.
Banner Alzheimer's InstituteBanner Alzheimer's Institute
Translational Genomics Research InstituteTranslational Genomics Research Institute
University of ArizonaUniversity of Arizona
Arizona Alzheimer’s ConsortiumArizona Alzheimer’s Consortium
Phoenix, Arizona, USAPhoenix, Arizona, USA
12 month CMRgl Decline in AD
P<0.001
12 month CMRgl Decline in MCI
P<0.001
Kewei Chen, Ph.D., Eric M. Reiman, M.D.Kewei Chen, Ph.D., Eric M. Reiman, M.D.
Banner Alzheimer's InstituteBanner Alzheimer's Institute
Translational Genomics Research InstituteTranslational Genomics Research Institute
University of ArizonaUniversity of Arizona
Arizona Alzheimer’s ConsortiumArizona Alzheimer’s Consortium
Phoenix, Arizona, USAPhoenix, Arizona, USA
Number of AD patients per group needed to detect a 25% treatment effect in a 12-month clinical trial
FDG PET ADAS-COG11 MMSE 61 612 493
Use of Imaging and Biomarkers Increases Power of AD Progression Analysis
Reiman et alBanner Alzheimer Institute
Follow-Up of PIB-Positive ADNI MCI’s
PiB(+) 47
Converters to AD 21
PiB(-) 18
Converters to AD 3
ADNI PiB MCI’s N = 65, 12 mo. follow-up
ADNI GO
EMCI: 200 new subjects Continued follow-up of LMCI and controls
from ADNI 1 All subjects to have LP, AV-45 amyloid
imaging, FDG-PET, vMRI Some adjustments to cognitive
assessment Additional analysis funds
Mild Cognitive Impairment
NormalNormal MCIMCI ADAD
00 0.50.5 11CDRCDR
3004153-1
ADNI 1ADNI 1(LMCI)(LMCI)
ADNI 2ADNI 2((EMCI)EMCI)
ADNI 2 Continue to follow all EMCI, LMCI and NC
from ADNI 1 and ADNI GO for 5 more years Enroll:
100 additional EMCI (supplements 200 from GO)150 new controls, LMCI, and AD
MRI at 3, 6, months and annually F18 amyloid (AV-45)/FDG every other year LP on 100% of subjects at enrollment Genetics
Summary: ADNI Standardization: imaging, biomarkers Neuroscience: relationships among biomarker
trajectories elucidate neurobiology Trials: new understanding of biomarkers has
facilitated interventional studies in very early AD Data sharing: ADNI has demonstrated the power
of real-time public data sharing Collaboration: academia, industry, non-profits,
regulatory agencies world-wide
NA-ADNINA-ADNI
J-ADNIJ-ADNI
EU-ADNIEU-ADNI
WW-ADNIWW-ADNI
A-ADNIA-ADNI
OVERALL GOALS
TO BETTER DEFINE THE NATURAL HISTORY OF ALZHEIMER’S DISEASE FROM ASYMPTOMATIC STAGES TO FULL BLOWN DEMENTIA TO ATTEMPT TO RELATE THE CLINICAL SYMPTOMS, AS THEY EMERGE, TO THE UNDERLYING PATHOPHYSIOLOGY TO USE PRESENT KNOWLEDGE TO BETTER DIAGNOSE THE DISEASE
TO DEFINE A RESEARCH AGENDA THAT WILL HELP TO EXTEND OUR KNOWLEDGE TO BETTER REACH THESE GOALS
NIA-Alzheimer’s AssociationProject to Redefine Diagnostic
Criteria for Alzheimer’s Disease
Current AD Diagnostic Criteria The current criteria for the diagnosis of AD
were established by a National Institute of Neurological Disorders and Stroke (NINDS)/Alzheimer's Disease and Related Disorders Association (ADRDA) workgroup in 1984.
Almost universally adopted, useful; they have survived without modification for more than 25 years. However, the AD field has evolved greatly since then.
NINCDS/ADRDA Criteria for Probable NINCDS/ADRDA Criteria for Probable Alzheimer’s DiseaseAlzheimer’s Disease________________________________________________________________________________
Dementia established by clinical examination; confirmed by cognitive screening tests
Deficits in two or more areas of cognition Progressive worsening of memory and other cognitive
functions No disturbance of consciousness Onset between 40 and 90, most often after 65 Absence of systemic disorders or other brain disease
that could account for the deficits and progression
McKhann et al. Neurol 1984;34:939-944
The NIA/Alzheimer's Association working groups were organized around the three stages of Alzheimer's disease that are commonly thought to exist today – pre-clinical Alzheimer's, mild cognitive impairment (MCI) due to Alzheimer's, and Alzheimer's dementia.
Alzheimer's dementia – The group is revising the existing criteria for diagnosing Alzheimer's to include possible biomarkers and other assessments that may aid in diagnosis.
Mild Cognitive Impairment – The group is refining the MCI criteria, which will help to indicate cognitive change before dementia and better differentiate MCI from Alzheimer's.
Pre-Clinical – The group is laying out a research agenda to identify methods of assessment that may help predict risk for developing the disease.
AD Dementia Clinical Criteria for All Cause Dementia
Dementia is diagnosed when there are clinical and cognitive symptoms that:○ Interfere with the ability to function independently at work or at usual
activities; and○ Represent a decline from prior levels of functioning and performing; and○ Are not explained by delirium nor major psychiatric disorder;
Probable AD dementia: Patient meets the clinical and cognitive criteria for dementia and
does not have evidence of alternate diagnoses, particularly cerebrovascular disease.
Probability can be enhanced by factors including a documented longitudinal decline and positive evidence from biomarkers, or they may be an AD mutation carrier.
○
AD Dementia Pathologically proved AD dementia:
Patient meets the clinical and cognitive criteria for AD dementia during life and then have proven AD by pathological examination.
Possible AD dementia: Patients who have an atypical course; i.e., those who
meet other clinical/ cognitive criteria, but for whom information on the course of progression is lacking or uncertain. It also includes those who meet clinical and cognitive criteria but who are negative for biomarkers. Includes those with mixed presentation.
MCI Four clinical and cognitive criteria for MCI due to
AD were developed — similar but slightly different from original criteria for MCI:Concern regarding a change in cognition: Concern
about a change in cognition from prior level (patient, an informant, or a skilled clinician).
Impairment in 1 or more cognitive domains: Performance should be lower than would be expected from the patient's age and education. Memory impairment is clearly the most common but other domains may be impaired, may be impairments in more than 1 domain.
MCIPreservation of independence in functional
abilities: Have the ability to maintain independence of function with minimal aids and assistance ; may have mild problems with complex tasks such as paying bills, preparing meals, or shopping, etc.
Not demented: The cognitive changes should be sufficiently mild that there is no evidence of impairment in social or occupational function.
MCI MCI of a neurodegenerative etiology: The
patient meets the clinical and cognitive criteria for the disorder, and biomarkers may not have been tested, they may have been tested and are ambiguous, or biochemical/molecular biomarkers may be negative.
MCI of the Alzheimer type: The patient meets clinical and cognitive criteria for the disorder, plus has positive findings from 1 of the "downstream" biomarkers of structural or functional change, e.g., MRI evidence of hippocampal atrophy, or FDG PET alterations. No biochemical/molecular biomarkers, or equivocal findings
MCI Prodromal Alzheimer's dementia: The
highest level of certainty, in which the patient meets the clinical and cognitive criteria for MCI, plus has biomarker evidence to suggest underlying AD pathology.
Pre-Clinical AD
Propose operational research criteria for the study of preclinical AD.
These criteria are intended to provide a common language to advance the scientific understanding of the preclinical stages of AD and a foundation for the evaluation of preclinical AD treatments.
Pre-Clinical AD Working Group: Model of the clinical trajectory of AD. The stage of preclinical AD precedes MCI and encompasses both asymptomatic individuals in whom the pathophysiological process has already begun but who are clinically indistinguishable from the profile of normal or “typical” aging, as well as individuals who have demonstrated subtle decline from their own baseline that exceeds that expected in typical aging, but would not yet meet criteria for MCI.
Pre-Clinical AD Working Group: Hypothetical model of the pathophysiological sequence leading to cognitive impairment in AD. This model postulates that amyloid-β accumulation is an “upstream” event in the cascade that results synaptic dysfunction, which may lead directly to cognitive impairment and/or trigger “downstream” neurodegeneration and cell loss. Specific host factors, such as brain and cognitive reserve, or other brain diseases may mediate the response to amyloid toxicity and pace of progression towards the clinical manifestations of AD.
Pre-Clinical AD Stage 1: Biomarker evidence of amyloid-β accumulation
(Stage 1 = asymptomatic cerebral amyloidosis) Elevated tracer retention on PET amyloid imaging and/or low Aβ42
on CSF assay
Stage 2: Biomarker evidence of synaptic dysfunction and or early neurodegeneration (Stage 2 = evidence of amyloid positivity + presence of one or more additional AD markers) Elevated CSF tau or phospho-tau Hypometabolism in an AD-like pattern (i.e. posterior cingulate,
precuneus, and/or temporo-parietal cortices) on FDG-PET Cortical thinning/grey matter loss in AD-like anatomic distribution
(i.e. lateral and medial parietal, posterior cingulate and lateral temporal cortices) and/or hippocampal atrophy on volumetric MRI
Pre-Clinical AD Stage 3: Evidence of subtle cognitive decline, but
does not meet criteria for MCI or dementia (Stage 3 = amyloid positivity + markers of neurodegeneration + very early cognitive symptoms) Demonstrated cognitive decline over time on standard
cognitive tests, but not meeting criteria for MCI Subtle impairment on challenging cognitive tests, particularly
accounting for level of innate ability or cognitive reserve but not meeting criteria for MCI
• WORKGROUPS ARE REVISING THE REPORTS AFTER CONSIDERING FEEDBACK FROM THE SCIENTIFIC COMMUNITY
• FINAL REPORTS WILL BE DRAFTED AND SUBMITTED FOR PUBLICATION – WINTER 2011
• A PAPER SUMMARIZING THE RECOMMENDATIONS FOR DOCTORS IN NON- RESEARCH SETTINGS IS BEING DRAFTED FOR A MEDIAL JOURNAL WITH WIDE READERSHIP
• THE RECOMMENDATIONS WILL BE REVISITED AS NEW EVIDENCE ACCUMULATES AND BIOMARKERS ARE VALIDATED – CURRENTLY BIOMARKERS ARE NOT USED ROUTINELY IN PRACTICE, ONLY FOR RESEARCH
Where Do We Go From Here?
Primary prevention strategies intend to avoid the development of disease
Secondary prevention strategies attempt to diagnose and treat an existing disease in its early stages before it results in significant morbidity (slow/delay progression to AD in individuals with MCI/prodromal AD)
NIH State-of-the-Science Conference Statement onPreventing Alzheimer’s Disease and Cognitive Decline
April 26–28, 2010NATIONAL INSTITUTES OF HEALTHOffice of the Director
NIH State-of-the-Science Conference Statement on Preventing Alzheimer’s Disease and Cognitive Decline
“Currently, firm conclusions cannot be drawn about the association of any modifiable risk factor with cognitive decline or Alzheimer’s disease. Highly reliable consensus-based diagnostic criteria for cognitive decline, mild cognitive impairment, and Alzheimer’s disease are lacking, and available criteria have not been uniformly applied. Evidence is insufficient to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimer’s disease. We recognize that a large amount of promising research is under way; these efforts need to be increased and added to by new understandings and innovations (as noted in our recommendations for future research).”
AD Risk FactorsAD Risk Factors
Age
Head Injury
High Blood Pressure
High Cholesterol
High Homocysteine
Diabetes
Diet
Education
Exercise
Social Interaction
Age
Head Injury
High Blood Pressure
High Cholesterol
High Homocysteine
Diabetes
Diet
Education
Exercise
Social Interaction
Potential Link Between Potential Link Between Cardiovascular Cardiovascular Risk Factors and DementiaRisk Factors and Dementia
High cholesterol
Hypertension
High homocysteine
Diabetes
Lifestyle Therapies Tested inLifestyle Therapies Tested inAnimals for Cognitive Decline and ADAnimals for Cognitive Decline and AD
Interventions
• Behavioral enrichment • Dietary antioxidants• Exercise
Results
• Improved learning ability in older animals• Prevention of brain cell dysfunction and death• Prevention of buildup of plaque and amyloid
Aged Canine Model Cotman et al. evaluated the effect of behavioral enrichment (ENR)
(social and cognitive enrichment and exercise), an antioxidant diet targeting mitochondrial function (AOX), and the combination of the ENR and AOX interventions in the aged canine.
The combined AOX/ENR treatment appeared to have additive or synergistic effects on preserving cognitive function, as well as on several neurobiological endpoints.
The AOX/ENR intervention also counteracted oxidative stress, improved mitochondrial function, preserved neuron number, and increased availability of growth factors such as BDNF. However, interventions had little, if any, effect on Abeta levels.
e.g., Cotman CW, Head E. The canine (dog) model of human aging and disease: dietary, environmental and immunotherapy approaches. J Alzheimers Dis. 2008;15(4):685–707.
Hypothesize that improved mitochondrial function, achieved by the AOX diet, is a key factor in the synergistic/additive effect of the combined intervention on cognitive function.
Improved mitochondrial function positions the aged brain to better respond to behavioral interventions; neurons with healthy mitochondria are more able to benefit from ENR.
The AOX and ENR interventions may engage molecular mechanisms that enhance ―cognitive reserve, allowing the canine to maintain intact cognitive abilities despite the continued presence of Abeta in the brain.
Suggest that strategies to improve overall neuronal heath, esp., mitochondrial function, may be critical for the effectiveness of behavioral-based interventions, as well as the effectiveness of some pharmacological-based strategies.
e.g., Cotman CW, Head E. The canine (dog) model of human aging and disease: dietary, environmental and immunotherapy approaches. J Alzheimers Dis. 2008;15(4):685–707.
Human Observational Lifestyle Studies: Diet, Exercise Mediterranean Diet (MeDi) adherence and physical
activity (PA) on AD riskProspective multi-ethnic cohort study of 1880
community-dwelling elders without dementia living in New York, New York, with both diet and physical activity information available
Results: Risk for incident AD was lower for both higher MeDi adherence and more PA.
Adoption of both physical activity and healthy nutrition seem to be independently associated with low risk for AD
Scarmeas, N. et al. JAMA 2009;302:627-637
Figure 2. Alzheimer Disease (AD) Incidence by High or Low Physical Activity Levels and Mediterranean-Type Diet Adherence Scores
Scarmeas, N. et al. JAMA 2009;302:627-637
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Figure 3. Alzheimer Disease (AD) Incidence in Individuals by No, Some, or Much Physical Activity and Low, Middle, and High Mediterranean-Type Diet Adherence Scores
Scarmeas, N. et al. JAMA 2009;302:627-637
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Human Studies of Aerobic ExerciseHuman Studies of Aerobic Exercise
Epidemiology or observational studies show association between aerobic exercise and development of AD
Short term clinical trials show improvements in executive function
Short term trials show increased brain volume (MRI) and functional activity (fMRI)
Human Lifestyle Therapies: Exercise
Home-based Physical Activity170 community-dwelling older adults from the Perth
Metropolitan area, who were free of dementia, but had subjective memory complaints or Mild Cognitive Impairment
Randomized controlled trial of a 24-week physical activity intervention vs. usual care conducted between 2004 and 2007 in metropolitan Perth, Western Australia. Assessors of cognitive function were blinded to group membership.
Results: Modest improvement in cognition over 18 months. The effect of exercise was apparent by 6 months and persisted at the 12 and 18-months assessments
Lautenschlager et al JAMA 2008
Table 2. Effects of the Intervention and Time on Cognitive Outcomes, Mood, and Quality of Life of Participants (Intention-to-Treat Method Using Multiply Imputed Data)a.
Lautenschlager, N. T. et al. JAMA 2008;300:1027-1037
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Human Observational Lifestyle Studies: Social Engagement
Relation of social engagement to level of cognitive function in older persons from the Rush Memory and Aging Project, a clinical-pathologic study of risk factors for common chronic conditions of old age.
838 persons without dementia who had a mean age of 80.2
Results: Better cognitive function was correlated with more frequent participation in social activities, as well as with the subjects’ own perception of being well-supported socially. Even when higher levels of intellectual and physical activity were accounted for, there was still a significant correlation between social interaction and cognitive functionKrueger et al. Exp Aging Res. 2009 ; 35(1): 45–60.
The Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) Study
5,000 persons assessed – 2,832 randomized
Three training groups (speed, reasoning, episodic memory) and a matched control group
Ten 60- to 75-minute sessions over 5 to 6 weeks
Willis et al (2006) JAMA 296:2805
Human Lifestyle Therapies: Cognitive Training
ACTIVE Results
Improved in the domain trained; maintained at 2 years
Cognitive training in any domain was maintained 5 years post training
Five year follow-up revealed reasoning training resulted in less functional decline
Human Lifestyle Studies: Education The cognitive reserve hypothesis suggests that at a particular level of
AD pathology, highly educated individuals are less likely to manifest clinical symptoms of dementia vs. less-educated individuals.
To investigate whether education can help explain a clinical diagnosis of no dementia within 1 year of death among individuals with neuropathologic diagnoses of AD, samples of participants (age 65+ years at last clinical assessment) meeting each of three neuropathologic criteria for AD were constructed using data from the National Alzheimer's Coordinating Center Minimum and Neuropathology Data Sets.
RESULTS: Regardless of the neuropathologic criteria used, education is predictive of dementia status among individuals with neuropathologic AD. These results support the theory that individuals with greater cognitive reserve, as reflected in years of education, are better able to
cope with AD brain pathology without observable deficits in cognition.
Roe et al. Neurology. 2007 Jan 16;68(3):223-8
Human Lifestyle Therapies: Dietary Supplements
Ginkgo Evaluation of Memory (GEM) Study : 3,069 community volunteers aged 75 years or older with normal cognition (n = 2587) or MCI (n = 482) at study entry were assessed every 6 months for incident dementia. Intervention Twice-daily dose of 120-mg extract of G biloba
(n = 1545) or placebo (n = 1524). Results - Main Outcome: not effective in reducing either the overall
incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI.
Results - Secondary Outcome: did not result in less cognitive decline in older adults with normal cognition or with MCI
DeKosky, S. T. et al. JAMA 2008;300:2253-2262; Snitz, B. E. et al. JAMA 2009;302:2663-2670
Human Lifestyle Therapies: Dietary Supplements
Memory Improvement With Docosahexaenoic Acid (DHA) Study (MIDAS): Randomized, double-blind, placebo-controlled trial of 485 cognitively healthy subjects, aged ≥55
900 mg/d of DHA orally or matching placebo for 24 weeks.
Results: After 24 weeks, individuals in the DHA group had significantly fewer errors on a visuospatial memory test compared with the placebo group
K. Yurko-Mauro et al. Alzheimer’s & Dementia 6 (2010) 456–464
Human Lifestyle Studies: Diabetes Treatment
Diabetes Medications:Postmortem study: 124 older adult diabetic patients
and 124 non-diabetic older adult controls
Found that those treated with both insulin and oral diabetic agents had significantly fewer amyloid plaques (as much as 80 percent) than patients with other medication statuses (none, or only insulin or oral anti-diabetic medication) or non-diabetic controls
Beeri et al., Neurology. 2008; 71(10): 750–757
NIA Ongoing Prevention Trials Currently supports 37 active clinical trials, including both pilot and
large scale trials, of a wide range of interventions to prevent, slow, or treat AD and/or MCI.
7 primary and 6 secondary prevention trials. Of the 7 primary prevention trials, 2 are NIA-funded cognitive/AD measure add-ons to large NIH primary prevention trials that address a variety of other primary outcomes.
One such trial is NHLBI’s Systolic Blood Pressure Intervention Trial (SPRINT), which will evaluate the health effects of lowering systolic blood pressure from 140 to 120. The add-on study, SPRINT-MIND, funded by NIA and NINDS, will assess the effect of lowering systolic blood pressure specifically on cognitive decline and development of MCI and AD. The study will also use brain imaging to measure treatment effects on brain structure, including white matter lesions typical of vascular disease.
TRIAL NAME INTERVENTION POPULATION TYPE OF TRIAL ANTICIPATED COMPLETION DATE
ANTIOXIDANTSPREADVISE (Prevention of Alzheimer's Disease by Vitamin E and Selenium)♦
Vitamin E, Selenium, Vitamin E + Selenium
Men age 60 - 90 Primary Prevention
2014
Vitamin E in Aging Persons With Down Syndrome
Vitamin E People age 50+ with Down Syndrome, at high risk of developing AD
Primary Prevention
2012
OMEGA-3 FATTY ACIDS AND ANTIOXIDANTS
AREDS2 (Age-Related Eye Disease Study 2) †
Macular xanthophylls (lutein and zeaxanthin) and/or omega -3 fatty acids (DHA and EPA)
People age 50-85 with age-related Macular degeneration (AMD) in both eyes, or advanced AMD in one eye
Primary Prevention
2015
CARDIOVASCULARASPREE (Aspirin in Reducing Events in Elderly)
Aspirin Healthy adults, age 70+ Primary Prevention
2017
SPRINT-MIND (Systolic Blood Pressure Intervention Trial-MIND)♦
Blood pressure lowering to <140 mm Hg versus <120 mm Hg
Adults age 55+ with systolic blood pressure of 130 mm Hg or higher; history of cardiovascular disease; high risk for heart disease
Primary Prevention
2017
Ongoing AD/MCI Prevention Clinical Trials Funded by NIAOngoing AD/MCI Prevention Clinical Trials Funded by NIA
HORMONES
ELITE (Early Versus Late Intervention with Estradiol)
17 β-estradiol Healthy early (less than 6 years) or late (10 years +) menopausal women
Primary Prevention
2014
SMART (Somatotrophics, Memory, and Aging Research Trial)
Growth hormone releasing hormone (GHRH)
People with MCI and healthy older adults age 55 – 80
Secondary Prevention
2011
Testosterone Supplementation in Men with MCI
Testosterone Older men with MCI and low testosterone
Secondary Prevention
2011
DIABETES
Metformin in Amnestic MCI Metformin Overweight/obese older adults with MCI
Secondary Prevention
2012
Pioglitazone & Exercise Effects on Older Adults with MCI and Metabolic Syndrome
Pioglitazone Overweight/obese older adults with MCI
Secondary Prevention
2012
EXERCISE, COGNITIVE TRAINING
Exercise Versus Cognitive Interventions for Elders at Risk for Dementia
Cognitive training, aerobic exercise training, cognitive training + aerobic exercise training
People with MCI Secondary Prevention
2012
Lifestyle Interventions and Independence for Elders (LIFE)
Aerobic exercise, resistance, and flexibility exercises
Adults age 70+ Primary Prevention
2015
Memory Training Intervention in Mild Cognitive Impairment
Repetition lag training procedure (RLTP)
People with MCI Secondary Prevention
2014
AD Resources
NIA Alzheimer’s Disease Education and Referral Center (ADEAR)
Toll-free information line, 1-800-438-4380Web site (English & Spanish) :
www.nia.nih.gov/alzheimers
Alzheimer’s Association
Web site: www.alz.org