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
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

19
20
Percent

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.

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 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.
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
β ( A β ) 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- 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

AVID

F-AV-45 Scans Spectrum of

18

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,
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 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
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 Assoc
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
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
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 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).”
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 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/high-
glycemic 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, 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
• 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: SPRINT-
MIND
• 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 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!