Transcript ALZHEIMER’S DISEASE: WHAT DO WE KNOW ABOUT DIAGNOSIS AND PREVENTION? National Press Foundation May 23, 2011 Laurie Ryan, PhD Program Director, Alzheimer’s Disease Clinical Trials Dementias of.

ALZHEIMER’S DISEASE:
WHAT DO WE KNOW ABOUT
DIAGNOSIS AND PREVENTION?
National Press Foundation
May 23, 2011
Laurie Ryan, PhD
Program Director, Alzheimer’s Disease Clinical Trials
Dementias of Aging Branch
Division of Neuroscience
National 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 domains
 Activities of daily living (ADL)
 Behavior and personality
 Cognition
 Most common cause of dementia in people
aged 65 and over
Other Dementias
• Vascular
• Frontotemporal
• Lewy-Body
• Parkinson’s
2011 Alzheimer’s Facts and Figures,
Alzheimer’s Association
• As many as 5.4 million people in the United States are
living with Alzheimer’s.
• Every 69 seconds, someone develops Alzheimer’s.
• Alzheimer's is the sixth-leading cause of death.
• The direct and indirect costs of Alzheimer's and other
dementias to Medicare, Medicaid and businesses amount
to more than $183 billion each year.
AN AGING POPULATION
U.S. Life Expectancy at Birth
in 1900, 1950, 2000
90
79.5
80
65.6
70
71.1
74.1
60
Age
50
46.3
48.3
40
30
20
10
0
1900
1950
Source: 65+ in the United States, U.S. Census Bureau, 2005
2000
POPULATION GROWTH OF OLDER
AMERICANS (65 Years and Older)
25
80000
20
60000
15
40000
10
20000
5
0
0
19
00
19
20
19
40
19
60
19
80
20
00
20
20
20
40
100000
YEAR
Number (thousands)
Percent of Population
(Federal Interagency Forum on Aging-Related Statistics, 2004)
Estimated Percentage of People over Age 65
with Probable Alzheimer’s Disease
47
50
40
30
19
20
10
3.0
0
65-74
75-84
85+
Age Group
Source: Evans D , et al. JAMA , Vol. 262, No. 18, 1989.
Projected Number of Persons with
Alzheimer’s Disease
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 million
Source: Evans, et al. Arch Neurol 2003; 60: 1119-1122.
From Ballard et al. 2011 Lancet; 377: 1019–31
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
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
AD Pathogenesis
• Tau hyperphosphorylation
• Formation of neurofibrillary tangles
• Synaptic degeneration
• Oxidative injury
• Inflammation
• Demyelination
• Apoptosis
• Transmitter 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
Fig. 2. Hypotheticalmodel of the Alzheimer’s disease (AD) pathophysiological sequence leading
to cognitive impairment. This model postulates that Aβ accumulation is an “upstream” event in
the cascade that is associated with “downstream” synaptic dysfunction, neurodegeneration, and
eventual neuronal loss. RA Sperling et al. http://dx.doi.org/10.1016/j.jalz.2011.03.003
Cognitive Continuum
Normal
Mild Cognitive
Impairment
Alzheimer's Disease
CP926864- 35
Figure 3 Proposed model relating imaging, pathology
and 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
Risk of AD
• Overall lifetime risk to any individual of developing
dementia is approximately 10–12% (Breitner et al Neurol
1999).
• First-degree relatives of a person with AD have a
cumulative lifetime risk of developing AD of about 15–
30%, this risk is about 2.5 times that of the background
risk (27% vs. 10.4%).
Lifetime Risk for AD
Race/Ethnicity
Genetics
Genetic Studies
The two main types of AD
are young-onset and lateonset:
• 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.
GENETIC FACTORS PREDISPOSING TO AD:
Young- Onset Alzheimer’s Disease
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
GENETIC FACTORS PREDISPOSING TO AD:
Late Onset Alzheimer’s Disease (LOAD)
• LOAD is thought to be multifactorial.
• 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.
• Several other potential genes are under
investigation
Bird Genetics in Med 2008
• Recent genome-wide association approaches have found
several additional AD susceptibility loci that are common in the
general population, but exert only very small risk effects:
• Variants in or near BIN1, CLU, CR1, and PICALM; status as novel AD risk
loci have been confirmed by extensive and independent replication data.
• Other GWAS loci: ATXN1, CD33, EXOC3L2, GAB2, MTHFD1L, and
PCDH11X, more provisional until further replication data become
available.
Bird Genetics in Med 2008; Bertram, Lill, & Tanzi, 2010 Neuron: 68; 270-271
Parental History
Mosconi et al 2010 PNAS: 107; 5949–5954
• Children of parents with LOAD, particularly those with
affected mothers, had increased Aβ load in AD-vulnerable
regions compared with controls.
• Results were independent of ApoE genotype and were
significant within the ApoE ε4+ group.
SPMs (statistical parametric mapping) showing higher PiB retention
in NL FHm subjects than in FH− and FHp subjects (Top Two Rows)
and in NLFHp subjects than in FH− subjects (Bottom Two Rows),
AD DIAGNOSIS
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.
ADVANCES IN
DIAGNOSIS:
BIOMARKERS
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
HUMAN AMYLOID
IMAGING
PET Imaging of Amyloid Deposits
in Alzheimer’s Disease vs. Normal Controls
PET imaging with the tracer, Pittsburgh Compound-B (PIB), can
provide quantitative information on amyloid deposits in living subjects.
Klunk, et al. Ann Neurol 2004
Individuals with MCI Cover the Range
of Amyloid Load
Positive Amyloid PIB Scan Predicts Clinical
Progression of MCI patients to AD
Melbourne Cohort
Pittsburgh Cohort
N=28, 21 mo. follow-up
N=23, 24 mo. follow-up
PiB-
13
PiB-
AD Converters 1
AD Converters
PiB+
PiB+
15
AD Converters 12
AD Converters
Villemagne et al., SNM 2008
Wolk et al., AAN 2008
10
0
13
5
AVID
18F-AV-45 Scans Spectrum of Pathology
BIOCHEMICAL
BIOMARKERS
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.
Volume 9, Issue 1, January 2010, Pages 119-128
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
Figure 2. Dynamic biomarkers of the Alzheimer's pathological cascade
Aβ 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 hypothesized
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.
• 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 Trials
• Current trials use clinical/cognitive outcome
measures :
slow rate of change over time, do not easily determine
disease modifying effects of treatment
• trials require large sample size, are time intensive and
costly
•
• Imaging and Biochemical Biomarkers – hope to
improve speed and efficiency of clinical trials
• Biomarkers 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
ALZHEIMER’S DISEASE
NEUROIMAGING
INITIATIVE (ADNI)
Goals of ADNI:
Longitudinal 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
Private/Philanthropic
+
Public
FDA
NIBIB, NINDS, NIMH, NIDA, NCRR, NINR
ADNI Executive Steering Committee
PET Core:
Berkeley:
Jagust
MRI Core:
Mayo: Jack
Clinical Core:
UCSD: Aisen
Mayo: Peterson
Publications Core:
PI: Mike Weiner
Administrative Core: UCSF BostonU: Green
Biomarkers Core:
UPenn: Trojanowski/Shaw
Biostatistics Core:
UCD: Beckett
Informatics Core: Neuropathology Core:
UCLA: Toga
WashU: Morris
57 Clinical Sites: ADNI PIs and Cores
ADNI 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)
Diagnosed as AD
Mean Cortical Thickness Change
(over 12 months)
Diagnosed as NC
+2%
-2%
Lateral View
Medial View
Holland et al.
PET: Regional Hypometabolism
AD
Kewei Chen, Ph.D., Eric M. Reiman, M.D.
Banner Alzheimer's Institute
Translational Genomics Research Institute
University of Arizona
Arizona Alzheimer’s Consortium
Phoenix, Arizona, USA
MCI
12 month CMRgl Decline in AD
P<0.001
Kewei Chen, Ph.D., Eric M. Reiman, M.D.
Banner Alzheimer's Institute
Translational Genomics Research Institute
University of Arizona
Arizona Alzheimer’s Consortium
Phoenix, Arizona, USA
12 month CMRgl Decline in MCI
P<0.001
Use of Imaging and Biomarkers
Increases Power of AD Progression Analysis
Number of AD patients per group needed to detect a 25% treatment effect
in a 12-month clinical trial
FDG PET
61
ADAS-COG11
612
MMSE
493
Reiman et al
Banner Alzheimer Institute
Follow-Up of PIB-Positive ADNI MCI’s
ADNI PiB MCI’s
N = 65, 12 mo. follow-up
PiB(-)
Converters to AD
PiB(+)
18
3
47
Converters to AD 21
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
Normal
MCI
AD
ADNI 2 ADNI 1
(EMCI) (LMCI)
0
0.5
CDR
1
3004153-1
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 realtime public data sharing
• Collaboration: academia, industry, non-profits, regulatory
agencies world-wide
Downloads by Country
J-ADNI
EU-ADNI
NA-ADNI
A-ADNI
WW-ADNI
http://www.adni-info.org
NIA-ALZHEIMER’S
ASSOCIATION
PROJECT TO REDEFINE
DIAGNOSTIC CRITERIA FOR
ALZHEIMER’S DISEASE
The new guidelines appear as free-access papers in
Alzheimer's and Dementia: The Journal of the Alzheimer's
Association
http://www.alz.org/research/diagnostic_criteria/
New Diagnostic Criteria and Guidelines
for Alzheimer's Disease
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
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
Alzheimer’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
AD Dementia
Clinical Criteria for Dementia:
• Dementia is diagnosed when there are cognitive or
behavioral (neuropsychiatric) 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;
• Cognitive impairment is detected and diagnosed through a
combination of (1) history-taking from the patient and a
knowledgeable informant and (2) an objective cognitive
assessment
• The cognitive or behavioral impairment involves a minimum of
two of the following domains:
• Memory, executive functioning, visuospatial, language,
personality/behavior
GM McKhann et al. http://dx.doi.org/10.1016/j.jalz.2011.03.005
AD Dementia
Probable AD:
• Meets criteria for dementia, and in addition, has the
following characteristics:
• A. Insidious onset. Symptoms have a gradual onset over
months to years, not sudden over hours or days;
• B. Clear-cut history of worsening of cognition by report or
observation;
• C. The initial and most prominent cognitive deficits are
evident on history and examination.
• Probability can be enhanced by factors including a
documented longitudinal decline and positive evidence
from biomarkers, or they may be an AD mutation carrier
GM McKhann et al. http://dx.doi.org/10.1016/j.jalz.2011.03.005
AD Dementia
Possible AD:
• Atypical course: Cognitive deficits for AD dementia, but
either has a sudden onset or demonstrates insufficient
historical detail or objective cognitive documentation of
progressive decline.
• Etiologically mixed presentation: Meets all core clinical
criteria but has evidence of a. concomitant cerebrovascular
disease; or b. features of Dementia with Lewy bodies (other
than the dementia); or c. evidence for another neurological
disease or a non-neurological medical comorbidity or
medication use that could have a substantial effect on
cognition.
GM McKhann et al. http://dx.doi.org/10.1016/j.jalz.2011.03.005
AD Dementia
Possible AD dementia with evidence of the AD
pathophysiological process:
• for persons who meet clinical criteria for a non-AD
dementia but who have either biomarker evidence of AD
pathophysiological process, or meet the
neuropathological criteria for AD.
• Aβ and neuronal injury biomarkers must be positive (a
conservative approach that may change as more information
is gained concerning the long-term outcomes of different
combinations of biomarker findings).
• Does not preclude the possibility that a second
pathophysiological condition is also present.
GM McKhann et al. http://dx.doi.org/10.1016/j.jalz.2011.03.005
AD Dementia
Pathophysiologically proved AD dementia:
• if the patient meets the clinical and cognitive criteria
for AD dementia, and the neuropathological
examination
Dementia unlikely to be due to AD:
• 1. Does not meet clinical criteria for AD dementia.
• 2. Regardless of meeting clinical criteria, a. there is
sufficient evidence for an alternative diagnosis that
rarely, if ever, overlap with AD (HD, HIV). b. both Aβ and
neuronal injury biomarkers are negative
GM McKhann et al. http://dx.doi.org/10.1016/j.jalz.2011.03.005
MCI – Core Clinical Criteria
• Four clinical/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.
MS Albert et al. http://dx.doi.org/10.1016/j.jalz.2011.03.008
MCI – Core Clinical Criteria
• Preservation 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.
MS Albert et al. http://dx.doi.org/10.1016/j.jalz.2011.03.008
MCI – Research Criteria
MS Albert et al. http://dx.doi.org/10.1016/j.jalz.2011.03.008
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.
RA Sperling et al. http://dx.doi.org/10.1016/j.jalz.2011.03.003
Fig. 1 The stage of preclinical AD precedes mild cognitive impairment (MCI) and
encompasses the spectrum of presymptomatic autosomal dominant mutation
carriers, asymptomatic biomarker-positive older individuals at risk for progression
to MCI due to AD and AD dementia, as well as biomarker-positive
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. RA Sperling et al. http://dx.doi.org/10.1016/j.jalz.2011.03.003
Fig. 2. Hypotheticalmodel of the Alzheimer’s disease (AD) pathophysiological sequence leading
to cognitive impairment. This model postulates that Aβ accumulation is an “upstream” event in
the cascade that is associated with “downstream” synaptic dysfunction, neurodegeneration, and
eventual neuronal loss. RA Sperling et al. http://dx.doi.org/10.1016/j.jalz.2011.03.003
Pre-Clinical AD
• Stage 1: Asymptomatic Amyloidosis
• Biomarker evidence of amyloid-β accumulation:
• Elevated tracer retention on PET amyloid imaging and/or low
Aβ42 on CSF assay
• Stage 2: Amyloidosis + Neurodegeneration
• Biomarker evidence of synaptic dysfunction and or early
neurodegeneration (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: Amyloidosis + Neurodegeneration +
Subtle Cognitive Decline
• Evidence of subtle cognitive decline, but does not
meet criteria for MCI or dementia (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
Note that some individuals will not progress beyond Stage 1 or Stage 2.
Individuals in Stage 3 are postulated to be more likely to progress to MCI and
AD dementia. RA Sperling et al. http://dx.doi.org/10.1016/j.jalz.2011.03.003
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
• 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 plaques
o dissolve plaques
o increase clearance
 Prevent build up of paired helical filaments
(tau focused)
o slow or prevent tau aggregation and dysfunction
o dissolve paired helical filaments
 Prevent brain cell dysfunction and death
o slow or prevent oxidative stress, inflammation, reduced blood flow
o increase levels of protective molecules in brain
o maintain viable connections between cells
AD Risk Factors
Age
Head Injury
High Blood Pressure
High Cholesterol
High Homocysteine
Diabetes
Diet
Education
Exercise
Social Interaction
AD PREVENTION
• 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 on
Preventing Alzheimer’s Disease and Cognitive Decline
April 26–28, 2010
NATIONAL INSTITUTES OF HEALTH
Office 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 consensusbased 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).”
Lifestyle Therapies Tested in
Animals 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 risk
• Prospective multi-ethnic cohort study of 1880 communitydwelling 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
Copyright restrictions may apply.
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
Copyright restrictions may apply.
Human Lifestyle Intervention: Diet
Craft et al, ICAD 2010
• Randomized high-fat/high-glycemic diet vs a low-fat/low-
glycemic diet, 4 weeks in 29 patients with MCI and 20
healthy adults. Diets were the same in terms of calories.
• Fasting plasma insulin, low-density lipoprotein, and total
cholesterol levels were all increased by the high-fat/highglycemic diet, whereas these parameters decreased with
the low-fat/low-glycemic diet, with greater effects seen
among those with MCI.
• The effect of the diets on amyloid in the CSF: The low-fat
diet moved Aβ42 levels in a beneficial direction for both
the controls and MCI; these changes also predicted
performance on tests of memory and attention.
Human 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 Activity
• 170 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
Copyright restrictions may apply.
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 function
Krueger et al. Exp Aging Res. 2009 ; 35(1): 45–60.
Human Lifestyle Therapies: Cognitive
Training
• 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
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 3 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 Interventions: Dietary
Supplements
• Memory Improvement With Docosahexaenoic Acid (DHA)
Study (MIDAS): Randomized, double-blind, placebocontrolled 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
• Research has suggested that AD and diabetes/insulin resistance
are closely related. For example, AD is associated with reduced
brain insulin signaling and low levels of insulin in cerebrospinal
fluid (CSF). These deficiencies may reduce or eliminate insulin's
beneficial roles in the brain.
• 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
Selected NIA Funded Trials from the AD Pilot
Clinical Trials Initiative
Trials Targeting Diabetes/Insulin Resistance:
• Intranasal insulin: Effects on cognition, cerebral glucose
metabolism, markers of AD pathology, neuroendocrine
functions in AD. Completed
• Insulin Sensitizing Agents:
• Pioglitazone and Exercise: Effects of the medication or
exercise on cognition, inflammation, insulin resistance
in individuals with MCI and Metabolic Syndrome.
Ongoing
• Metformin: Effects on cognition, brain metabolism in
overweight/obese individuals with MCI. Ongoing
Human Lifestyle Interventions: Intranasal Insulin
Craft, et al. ICAD 2011
• Restoring normal insulin function in the brain may provide
therapeutic benefits to adults with AD.
• The SNIFF-120 trial was a 4-month, randomized, double-
blind trial of placebo vs 2 doses of intranasal insulin (20 or
40 IU).
• 104 patients with AD or amnestic MCI participated;
patients with diabetes were excluded.
Human Lifestyle Interventions: Intranasal Insulin
Craft, et al. ICAD 2011
• Results: 20 IU dose of insulin delayed story recall
significantly improved compared to placebo, as did functional
status.
• Improvements in delayed memory recall persisted for 2 mos.
after treatment ended.
• Improved memory and functional status with insulin were
associated with an improved AD biomarker profile as
reflected by a lowered CSF Aβ40/42 ratio.
• Also, compared with placebo patients, those in the insulin
groups showed preserved glucose metabolism on FDG PET
scanning in areas affected by AD pathology.
NIA Funded Clinical 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.
NIA Funded Prevention Trial: SPRINTMIND
• Add-on to 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.
AD/MCI Prevention Clinical Trials Funded by NIA
TRIAL NAME
INTERVENTION
POPULATION
TYPE OF TRIAL
ANTICIPATED
COMPLETION DATE
ANTIOXIDANTS
PREADVISE (Prevention of
Alzheimer's Disease by Vitamin
E and Selenium)♦
Vitamin E in Aging Persons
With Down Syndrome
Vitamin E,
Selenium, Vitamin
E + Selenium
Vitamin E
Men age 60 - 90
Primary
Prevention
2014
People age 50+ with
Down Syndrome, at high
risk of developing AD
Primary
Prevention
2012
People age 50-85 with
age-related Macular
degeneration (AMD) in
both eyes, or advanced
AMD in one eye
Primary
Prevention
2015
Aspirin
Healthy adults, age 70+
Primary
Prevention
2017
Blood pressure
lowering to <140
mm Hg versus
<120 mm Hg
Adults age 55+ with
Primary
systolic blood pressure of Prevention
130 mm Hg or higher;
history of cardiovascular
disease; high risk for
heart disease
2017
OMEGA-3 FATTY ACIDS AND
ANTIOXIDANTS
AREDS2 (Age-Related Eye
Macular
Disease Study 2) †
xanthophylls (lutein
and zeaxanthin)
and/or omega -3
fatty acids (DHA
and EPA)
CARDIOVASCULAR
ASPREE (Aspirin in Reducing
Events in Elderly)
SPRINT-MIND (Systolic Blood
Pressure Intervention TrialMIND)♦
HORMONES
ELITE (Early Versus Late
Intervention with Estradiol)
17 β-estradiol
Healthy early (less than 6 Primary
years) or late (10 years +) Prevention
menopausal women
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
Metformin
Overweight/obese older
adults with MCI
Overweight/obese older
adults with MCI
Secondary
Prevention
Secondary
Prevention
2012
DIABETES
Metformin in Amnestic MCI
Pioglitazone & Exercise Effects
on Older Adults with MCI and
Metabolic Syndrome
Pioglitazone
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, 1-800-438-4380
Web site (English & Spanish) :
www.nia.nih.gov/alzheimers
Alzheimer’s Association
Web site:
www.alz.org
THANK YOU!