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
 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.
U.S. Life Expectancy at
Birth
in 1900, 1950, 2000
90
79.5
80
74.1
65.6 71.1
70

60

46.3 48.3
50
Age

40

30

20

10

0
1900 1950 2000

Source: 65+ in the United States, U.S. Census Bureau, 2005

POPULATION GROWTH OF OLDER
AMERICANS (65 Years and Older)

100000 25

80000 20

60000 15

40000 10

20000 5

0 0
00

20

40

60

80

00

20

40

Number (thousands)
19

19
19

19

19

20

20

20

YEAR Percent of Population

(Federal Interagency Forum on Aging-Related Statistics, 2004)

Estimated Percentage of People over Age
65
with Probable Alzheimer’s Disease
50 47

40

30
Percent

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.
50, the number of Americans with AD will increase to btw 11 and 16 million

Source: Evans, et al. Arch Neurol 2003; 60: 1119-1122.

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
 Inside the
Human Brain
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.
AD and the Brain
Plaques and Tangles: The Hallmarks of AD

The brains of people with AD have an abundance of two

abnormal structures:
• 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

An actual AD plaque An actual AD tangle

AD Pathogenesis
 Theproduction 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 and the Brain
Beta-amyloid Plaques

1. 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
2. beta-amyloid.
3. Beta-amyloid fragments come
together in clumps to form
plaques.

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 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
 Neuropathologic Changes
Characteristic of AD
AD

Normal

Amyloid
plaques

Tangles
Courtesy of George Grossberg M.D.; St. Louis University.
 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

 Genetics
Genetic Studies

The two main types of AD

are young-onset and late-
onset:
• 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 β ( A β ) 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.
Several other potential genes are under
investigation
Bird Genetics in Med 2008
 ApoE4 decreases the age of onset of AD

Non Alzheimer Cases (% of total)

100

80

60

40
0ApoE4

20
1ApoE4

2ApoE4
60 70 80 90
Adapted from Corder et al. Science. (1993),261,921
AgeatOnset(years)& Roses Et al. (1998) and
Michelson 00
Alzheimer’s Disease Risk Factors
Age
Age
HeadInjury
Head Injury
HighBlood
High BloodPressure
Pressure
HighCholesterol
High Cholesterol
HighHomocysteine
High Homocysteine
Diabetes
Diabetes
Diet
Diet
Education
Education
Exercise
Exercise
SocialInteraction
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
 Pr event 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
 Pr event build up of paired helical
filaments (tau focused)
o slow or prevent tau aggregation and dysfunction
o dissolve paired helical filaments
 Pr event br ain 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
‘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
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

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.
 Diagnosing 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
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

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

dividuals with MCI Cover the Range
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- 10
AD Converters 1 AD Converters 0

PiB+ 15 PiB+ 13
AD Converters 12 AD Converters 5

Villemagne et al., SNM 2008 Wolk et al., AAN 2008

 F-AV-45 Scans Spectrum of
18

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.
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 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
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,
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
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

Neil Buckholtz
NIBIB, NINDS, NIMH, NIDA, NCRR, NINR
ADNI Executive Steering Committee PI: Mike Weiner Publications Core: Biostatistics Core:

PET Core: MRI Core: Clinical Core: Administrative Core: UCSF BostonU: Green UCD: Beckett

Berkeley: Mayo: Jack UCSD: Aisen Biomarkers Core: Informatics Core: Neuropathology Core:
Jagust Mayo: Peterson UCLA: Toga WashU: Morris
UPenn: Trojanowski/Shaw

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)

Mean Cortical Thickness Change
(over 12 months)

+2%

-2%

Lateral View Medial View Holland et al.

 PET: Regional
Hypometabolism
AD MCI

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 AD 12 month CMRgl Decline in MCI

P<0.001 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
 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 ADAS-COG11 MMSE

61 612 493

Reiman et al
Banner Alzheimer
Follow-Up of PIB-Positive ADNI MCI’s

ADNI PiB MCI’s

N = 65, 12 mo. follow-up

PiB(-) 18
Converters to AD 3

PiB(+) 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 1
CDR 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 real-time public data sharing
 Collaboration: academia, industry, non-profits,
regulatory agencies world-wide
 J-ADNI

EU-ADNI
NA-ADNI

A-ADNI

WW-ADNI
 NIA-Alzheimer’s Association
Project to Redefine Diagnostic
Criteria 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

 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.
MCI
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.
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
 Where Do We Go From Here?

•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
 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 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 Factors
Age
Age
HeadInjury
Head Injury
HighBlood
High BloodPressure
Pressure
HighCholesterol
High Cholesterol
HighHomocysteine
High Homocysteine
Diabetes
Diabetes
Diet
Diet
Education
Education
Exercise
Exercise
SocialInteraction
Social Interaction
Potential Link Between
Cardiovascular
Risk Factors and Dementia

High cholesterol
Hypertension
High homocysteine
Diabetes
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
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

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 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 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

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.
Ongoing AD/MCI Prevention Clinical Trials Funded by NIA
TRIAL NAME INTERVENTION POPULATION TYPE OF TRIAL ANTICIPATED
COMPLETION DATE

ANTIOXIDANTS
PREADVISE (Prevention of Vitamin E, Selenium, Men age 60 - 90 Primary Prevention2014
Alzheimer's Disease by Vitamin Vitamin E +
E and Selenium)♦ Selenium
Vitamin E in Aging Persons With Vitamin E People age 50+ with Down Primary Prevention2012
Down Syndrome Syndrome, at high risk of
developing AD

OMEGA-3 FATTY ACIDS AND

ANTIOXIDANTS
AREDS2 (Age-Related Eye
Disease Study 2) †
Macular People age 50-85 with Primary Prevention2015
xanthophylls (lutein age-related Macular
and zeaxanthin) degeneration (AMD) in
and/or omega -3 both eyes, or advanced
fatty acids (DHA and AMD in one eye
EPA)

CARDIOVASCULAR
ASPREE (Aspirin in Reducing Aspirin Healthy adults, age 70+ Primary Prevention2017
Events in Elderly)

SPRINT-MIND (Systolic Blood
Pressure Intervention Trial-
MIND)♦
Blood pressure Adults age 55+ with Primary Prevention2017
lowering to <140 mm systolic blood pressure of
Hg versus <120 mm 130 mm Hg or higher;
Hg history of cardiovascular
disease; high risk for heart
disease
HORMONES
ELITE (Early Versus Late 17 β-estradiol Healthy early (less than 6 Primary Prevention 2014
Intervention with Estradiol) years) or late (10 years +)
menopausal women
SMART (Somatotrophics, Growth hormone People with MCI and Secondary 2011
Memory, and Aging Research releasing hormone healthy older adults age 55 Prevention
Trial) (GHRH) – 80
Testosterone Supplementation in Testosterone Older men with MCI and Secondary 2011
Men with MCI low testosterone Prevention

DIABETES
Metformin in Amnestic MCI Metformin Overweight/obese older Secondary 2012
adults with MCI Prevention
Pioglitazone & Exercise Effects Pioglitazone Overweight/obese older Secondary 2012
on Older Adults with MCI and adults with MCI Prevention
Metabolic Syndrome
EXERCISE, COGNITIVE
TRAINING
Exercise Versus Cognitive Cognitive training, People with MCI Secondary 2012
Interventions for Elders at Risk aerobic exercise Prevention
for Dementia training, cognitive
training + aerobic
exercise training

Lifestyle Interventions and Aerobic exercise, Adults age 70+ Primary Prevention 2015
Independence for Elders (LIFE) resistance, and
flexibility exercises
Memory Training Intervention in Repetition lag People with MCI Secondary 2014
Mild Cognitive Impairment training procedure Prevention
(RLTP)
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!

E-mail:
Laurie Ryan: ryanl@mail.nih.gov