Laurie Ryan, PhDProgram Director, Alzheimer’s Disease Clinical TrialsDementias of Aging BranchDivision of NeuroscienceNational Institute on Aging, National Institutes of Health

Alzheimer’s Disease (AD): Overview Progressive, degenerative CNS disorder Characterized by memory impairment plus one

or more additional cognitive disturbances Gradual decline in three key symptom

domainsActivities of daily living (ADL)Behavior and personalityCognition

Most common cause of dementia in people aged 65 and over

Other Dementias

Vascular Frontotemporal Lewy-Body Parkinson’s

2010 Alzheimer’s Facts and Figures, Alzheimer’s Association

As many as 5.3 million people in the United States are living with Alzheimer’s.

• Every 70 seconds, someone develops Alzheimer’s.

• Alzheimer's is the seventh-leading cause of death.

• The direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $172 billion each year.

0

10

20

30

40

50

60

70

80

90

1900 1950 2000

Ag

e

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

U.S. Life Expectancy at Birth in 1900, 1950, 2000

46.3 48.3

65.6 71.1

79.574.1

POPULATION GROWTH OF OLDER AMERICANS (65 Years and Older)

0

20000

40000

60000

80000

100000

YEAR

0

5

10

15

20

25

Number (thousands)Percent of Population

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

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

3.0

19

47

0

10

20

30

40

50

65-74 75-84 85+

Age Group

Perc

en

t

Source: Evans D , et al. JAMA , Vol. 262, No. 18, 1989.

Projected Number of Persons with Alzheimer’s Disease

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

In 2000, there were 4.5 million Americans with AD. By 2050, the number of Americans with AD will increase to btw 11 and 16 million11 and 16 million

AD Neuropathology

A growing body of evidence suggests that the underlying pathology precedes the onset of clinically detectable AD by a decade or more

By the time a patient is diagnosed, there is thought to be massive neuronal loss and widespread pathology

Neurons

• The brain has billions of neurons, each with an axon and many dendrites.

• To stay healthy, neurons must communicate with each other, carry out metabolism, and repair themselves.

• AD disrupts all three of these essential jobs.

Inside the Human Brain

Plaques and Tangles: The Hallmarks of AD

The brains of people with AD have an abundance of two abnormal structures:

An actual AD plaque An actual AD tangle

• beta-amyloid plaques, which are dense deposits of protein and cellular material that accumulate outside and around nerve cells

• neurofibrillary tangles, which are twisted fibers that build up inside the nerve cell

AD and the Brain

AD Pathogenesis The production and accumulation of

amyloid beta (Aβ) is increasingly thought to be central to AD pathogenesis

Generation of Aβ from amyloid precursor protein (APP) is a pivotal initiating event

Aβ aggregation triggers a variety of secondary events

Beta-amyloid Plaques

Amyloid precursor protein (APP) is the precursor to amyloid plaque.

1. APP sticks through the neuron membrane.

2. Enzymes cut the APP into fragments of protein, including beta-amyloid.

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

1.

2.

3.

AD and the Brain

Neurofibrillary Tangles

Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles.

AD and the Brain

AD PathogenesisTau hyperphosphorylationFormation of neurofibrillary tanglesSynaptic degenerationOxidative injuryInflammationDemyelinationApoptosisTransmitter deficits

Diagram of the cascade of events currently hypothesized to comprise the pathophysiology of AD.

Salloway, S. et al. Alzheimer's and Dementia 2008; 4: 65-79

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

Neuropathologic ChangesNeuropathologic ChangesCharacteristic of ADCharacteristic of AD

AD

AmyloidAmyloidplaquesplaques

Normal

TanglesTangles

Cognitive ContinuumCognitive Continuum

Mild CognitiveMild CognitiveImpairmentImpairment

NormalNormal

Alzheimer's DiseaseAlzheimer's Disease

CP926864- 35

Figure 3 Proposed model relating imaging, pathologyand clinical presentation over an individual’s adult lifetime.The lifetime clinical course of the disease is divided into pre-symptomatic,prodromal and dementia phases.

Jack et al. Brain 2009: 132; 1355–1365

Genetic Studies

The two main types of AD are young-onset and late-onset:

Genetics

• Young-onset AD is rare, usually affecting people aged 30 to 60 and usually running in families. Researchers have identified mutations in three genes that cause young-onset AD.

• Late-onset AD is more common. It usually affects people over age 65. The primary risk factor for AD is age.

Rare, early onset autosomal-dominant forms of the disease are caused by mutations in 3 genes (APP, Presenilin 2, Presenilin 1) all of which alter production of the amyloid A) peptide; less than 5% of all AD cases.

Bertram and Tanzi, Nature Reviews Neuroscience 2008

LOAD is thought to be multi-factorial.

However, ApoE is the only clearly identified genetic risk factor;

E4 allele influences age at onset of AD, but is neither necessary nor sufficient for the disease.

Bird Genetics in Med 2008

Several other potential genes are under investigation

100100

Non

Alz

hei

mer

Cas

es (

% o

f to

tal)

0 ApoE4

1 ApoE4

2 ApoE4

6060

8080

4040

2020

Age at Onset (years) Adapted from Corder et al. Science. (1993),261,921 & Roses Et al. (1998) and Michelson 00

ApoE4 decreases the age of onset of AD

6060 7070 8080 9090

Alzheimer’s Disease Risk FactorsAlzheimer’s Disease Risk Factors

Age

Head Injury

High Blood Pressure

High Cholesterol

High Homocysteine

Diabetes

Diet

Education

Exercise

Social Interaction

Age

Head Injury

High Blood Pressure

High Cholesterol

High Homocysteine

Diabetes

Diet

Education

Exercise

Social Interaction

Currently FDA Approved Treatments for AD The U.S. Food and Drug Administration

(FDA) has approved two types of medications to treat cognitive symptoms of AD.

Provide temporary cognitive improvement and deferred decline in some patients

Currently Approved Treatments for AD Cholinesterase Inhibitors*

Donepezil (Aricept)Rivastigmine (Exelon)Galantamine (Razadyne)

Memantine (Namenda)#

*Cholinesterase inhibitors are drugs that block the activity of an enzyme in the brain: cholinesterase. Cholinesterase breaks apart acetylcholine, a neurotransmitter vital for the transmission of nerve impulses. Cholinesterase inhibitors reduce the action of cholinesterase, thus making more acetylcholine available to neurons.#N-Methyl-D-aspartate (NMDA) antagonist; thought to be a neuroprotective agent that blocks excitotoxicty; May have a potentially disease modifying effect

Disease Modification An improved understanding of the

pathogeneses of AD has led to the identification of numerous therapeutic targets designed to alter Aβ or tau accumulation

Many of these targets have been validated in proof of concept studies in preclinical animal models, and a number are being tested in human clinical trials.

Avenues for New AD Therapies Prevent build up of plaque (anti-amyloid)

o slow or prevent amyloid production by inhibiting clipping enzymes or by vaccine therapy

o slow aggregation into plaqueso dissolve plaqueso increase clearance

Prevent build up of paired helical filaments (tau focused)o slow or prevent tau aggregation and dysfunctiono dissolve paired helical filaments

Prevent brain cell dysfunction and deatho slow or prevent oxidative stress, inflammation, reduced blood flowo increase levels of protective molecules in braino maintain viable connections between cells

‘Cocktail’ Approach

Likely that multimodal therapy or ‘cocktail’ may be needed to significantly impact the clinical course of AD.

E.g. a cocktail of therapies that target tau, Aβ, inflammation and cognitive symptoms, may be more efficacious than monotherapy.

NINCDS/ADRDA Criteria for Probable NINCDS/ADRDA Criteria for Probable Alzheimer’s DiseaseAlzheimer’s Disease________________________________________________________________________________

Dementia established by clinical examination; confirmed by cognitive screening tests

Deficits in two or more areas of cognition Progressive worsening of memory and other cognitive

functions No disturbance of consciousness Onset between 40 and 90, most often after 65 Absence of systemic disorders or other brain disease

that could account for the deficits and progression

McKhann et al. Neurol 1984;34:939-944

Diagnosing AD

Experienced physicians in specialized AD centers can now diagnose AD with up to 90 percent accuracy. Early diagnosis has advantages:

• Doctors can rule out other conditions that may cause dementia.

• If it is AD, families have more time to plan for the future.

• Treatments can start earlier, when they may be more effective.

• It helps scientists learn more about the causes and development of AD.

Physicians today use a number of tools to diagnose AD:• a detailed patient history

• information from family and friends

• physical and neurological exams and lab tests

• neuropsychological tests

• imaging tools such as CT scan, or magnetic resonance imaging (MRI). PET scans are used primarily for research purposes

Diagnosing AD

Increasing Role of Imaging & Biomarkers in AD treatment trials and detection

Many studies have shown changes in the brain of normal aging and in AD

Structural MRI shows shrinkage, esp. of median temporal lobe and cortex

FDG PET shows reduced metabolism AD Biomarkers can improve diagnosis

and reflect disease progression Great potential for use in clinical trials

and for early detection

PET Imaging of Amyloid Deposits in Alzheimer’s Disease vs. Normal Controls

Klunk, et al. Ann Neurol 2004

PET imaging with the tracer, Pittsburgh Compound-B (PIB), can provide quantitative information on amyloid deposits in living subjects.

Individuals with MCI Cover the Range Individuals with MCI Cover the Range of Amyloid Load of Amyloid Load

Positive Amyloid PIB Scan Predicts Clinical Positive Amyloid PIB Scan Predicts Clinical Progression of MCI patients to ADProgression of MCI patients to AD

PiB+ 15

AD Converters 12

PiB- 13

AD Converters 1

Melbourne Cohort

N=28, 21 mo. follow-up

PiB+ 13

AD Converters 5

PiB- 10

AD Converters 0

Pittsburgh Cohort

N=23, 24 mo. follow-up

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

18F-AV-45 Scans Spectrum of Pathology

AVID

Biochemical Biomarkers Cerebrospinal Fluid (CSF): AD in its earliest

stages may cause changes in CSF levels of beta-amyloid and tau, two proteins that form abnormal brain deposits strongly linked to the disease.

Plasma, Urine: investigations underway on whether pre-symptomatic AD causes consistent, measurable changes in urine or blood levels of tau, beta-amyloid or other biomarkers.

A Serum Protein–Based Algorithm for the Detection of Alzheimer Disease: O’Bryant et al. Arch Neurol. 2010;67(9):1077-1081 Identified protein biomarkers in the blood that can be

used to distinguish between individuals with and without AD.

Compared protein patterns in blood samples from 197 patients with AD and 203 without AD and incorporated into an algorithm for detecting AD cases in a test group.

Results suggest this algorithm may accurately classify most Alzheimer's cases — particularly when combined with APOE status and demographic data. Validation in an independent sample is needed.

Hypothetical Model of Dynamic Biomarkers of the Alzheimer’s Pathological Cascade

Clifford R Jack, Jr, David S Knopman, William J Jagust, Leslie M Shaw, Paul S Aisen, Michael W Weiner, Ronald C Petersen, and John Q Trojanowski

Volume 9, Issue 1, January 2010, Pages 119-128

Figure 2.  Dynamic biomarkers of the Alzheimer's pathological cascadeAβ is identified by CSF Aβ42 or PET amyloid imaging. Tau-mediated neuronal injury and dysfunction is identified by CSF tau or fluorodeoxyglucose-PET. Brain structure is measured by use of structural MRI. Aβ=β-amyloid. MCI=mild cognitive impairment.

Figure 5. Modulators of biomarker temporal relationships(A,B) Relative to a fixed age (here, 65 years), the hypothesised effect of APOE 4 is to shift β-amyloid plaque deposition and the neurodegenerative cascade both to an earlier age compared with 4 non-carriers. (C) The hypothesised effect of the presence of different diseases and genes on cognition: C−=cognition in the presence of comorbidities (eg, Lewy bodies or vascular disease) or risk amplification genes; C+=cognition in patients with enhanced cognitive reserve or protective genes; Co=cognition in individuals without

comorbidity or enhanced cognitive reserve.

Authors acknowledge that well-validated biomarkers do not currently exist for some important features of the disease. This includes reliable chemical biomarkers of specific toxic oligomeric forms of soluble Aβ and imaging measures of soluble Aβ or diffuse plaques, PET ligands that specifically measure the burden of NFTs and other tau abnormalities.

Thus, they note, the biomarker model of disease is just that—a model of the stages of disease that can be assessed with currently validated biomarkers, and not a comprehensive model of all pathological processes in AD.

Need For Validated Biomarkers For AD Need For Validated Biomarkers For AD TrialsTrials

Current trials use clinical/cognitive outcome measures : slow rate of change over time, do not easily determine

disease modifying effects of treatmenttrials require large sample sizelarge sample size, are time intensive time intensive and

costlycostly Imaging and Biochemical Biomarkers – hope to

improve speed and efficiency improve speed and efficiency of clinical trialsBiomarkers useful in Phase 2 to make decisions

about Phase 3 (e.g. doses)Biomarkers useful in Phase 3

○ Provide additional evidence to support primary outcome findings

○ Provide evidence for “disease modification” and not simply symptomatic improvement

Goals of ADNI: Goals of ADNI: Longitudinal Multi-Site Observational StudyLongitudinal Multi-Site Observational Study

Major goal is collection of data and samples to establish a brain imaging, biomarker, and clinical database in order to identify the best markers for following disease progression and monitoring treatment response

Determine the optimum methods for acquiring, processing, and distributing images and biomarkers in conjunction with clinical and neuropsychological data in a multi-site context

“Validate” imaging and biomarker data by correlating with neuropsychological and clinical data.

Rapid public access of all data and access to samples

STUDY DESIGN-ADNI1

MCI (n= 400): 0, 6, 12, 18, 24, 36 months AD (n= 200): 0, 6, 12, 24 months Controls (n= 200): 0, 6, 12, 24, 36 months

Clinical/neuropsychological evaluations, MRI (1.5 T) at all time points

FDG PET at all time points in 50% 3 T MRI at all time points in 25% PIB sub-study on 120 subjects Blood and urine at all time points from all subjects;

CSF from 50% of subjects 0, 1 yr, 2 yr (subset); DNA and immortalized cell lines from all subjects

GWAS study

ADNI Public-Private Partnership Structure

Neil Buckholtz

PI: Mike WeinerAdministrative Core: UCSF

Biostatistics Core:UCD: Beckett

Biomarkers Core:UPenn: Trojanowski/Shaw

MRI Core:Mayo: Jack

Clinical Core:UCSD: AisenMayo: Peterson

PET Core:Berkeley: Jagust

Informatics Core:UCLA: Toga

Publications Core:BostonU: Green

Neuropathology Core:WashU: Morris

57 Clinical Sites: ADNI PIs and Cores

ADNI Executive Steering Committee

Private/Philanthropic+

Public

NIBIB, NINDS, NIMH, NIDA, NCRR, NINR

FDA

ADNI Progression RatesADNI Progression Rates

Year Normal MCI MCI AD

0-1 1.4% (0.0-3.2) 16.0% (11.3-20.4)

1-2 2.4% (0.0-4.7) 23.9% (19.0-29.5)

2-3 0.0% (0.0-3.4) 9.1% (5.8-13.5)

Mean Cortical Thickness Change (over 12 months)

Holland et al.

+2%

-2%

Lateral View Medial View

PET: Regional Hypometabolism

AD MCI

Kewei Chen, Ph.D., Eric M. Reiman, M.D.Kewei Chen, Ph.D., Eric M. Reiman, M.D.

Banner Alzheimer's InstituteBanner Alzheimer's Institute

Translational Genomics Research InstituteTranslational Genomics Research Institute

University of ArizonaUniversity of Arizona

Arizona Alzheimer’s ConsortiumArizona Alzheimer’s Consortium

Phoenix, Arizona, USAPhoenix, Arizona, USA

12 month CMRgl Decline in AD

P<0.001

12 month CMRgl Decline in MCI

P<0.001

Kewei Chen, Ph.D., Eric M. Reiman, M.D.Kewei Chen, Ph.D., Eric M. Reiman, M.D.

Banner Alzheimer's InstituteBanner Alzheimer's Institute

Translational Genomics Research InstituteTranslational Genomics Research Institute

University of ArizonaUniversity of Arizona

Arizona Alzheimer’s ConsortiumArizona Alzheimer’s Consortium

Phoenix, Arizona, USAPhoenix, Arizona, USA

Number of AD patients per group needed to detect a 25% treatment effect in a 12-month clinical trial

FDG PET ADAS-COG11 MMSE 61 612 493

Use of Imaging and Biomarkers Increases Power of AD Progression Analysis

Reiman et alBanner Alzheimer Institute

Follow-Up of PIB-Positive ADNI MCI’s

PiB(+) 47

Converters to AD 21

PiB(-) 18

Converters to AD 3

ADNI PiB MCI’s N = 65, 12 mo. follow-up

ADNI GO

EMCI: 200 new subjects Continued follow-up of LMCI and controls

from ADNI 1 All subjects to have LP, AV-45 amyloid

imaging, FDG-PET, vMRI Some adjustments to cognitive

assessment Additional analysis funds

Mild Cognitive Impairment

NormalNormal MCIMCI ADAD

00 0.50.5 11CDRCDR

3004153-1

ADNI 1ADNI 1(LMCI)(LMCI)

ADNI 2ADNI 2((EMCI)EMCI)

ADNI 2 Continue to follow all EMCI, LMCI and NC

from ADNI 1 and ADNI GO for 5 more years Enroll:

100 additional EMCI (supplements 200 from GO)150 new controls, LMCI, and AD

MRI at 3, 6, months and annually F18 amyloid (AV-45)/FDG every other year LP on 100% of subjects at enrollment Genetics

Summary: ADNI Standardization: imaging, biomarkers Neuroscience: relationships among biomarker

trajectories elucidate neurobiology Trials: new understanding of biomarkers has

facilitated interventional studies in very early AD Data sharing: ADNI has demonstrated the power

of real-time public data sharing Collaboration: academia, industry, non-profits,

regulatory agencies world-wide

NA-ADNINA-ADNI

J-ADNIJ-ADNI

EU-ADNIEU-ADNI

WW-ADNIWW-ADNI

A-ADNIA-ADNI

OVERALL GOALS

TO BETTER DEFINE THE NATURAL HISTORY OF ALZHEIMER’S DISEASE FROM ASYMPTOMATIC STAGES TO FULL BLOWN DEMENTIA TO ATTEMPT TO RELATE THE CLINICAL SYMPTOMS, AS THEY EMERGE, TO THE UNDERLYING PATHOPHYSIOLOGY TO USE PRESENT KNOWLEDGE TO BETTER DIAGNOSE THE DISEASE

TO DEFINE A RESEARCH AGENDA THAT WILL HELP TO EXTEND OUR KNOWLEDGE TO BETTER REACH THESE GOALS

NIA-Alzheimer’s AssociationProject to Redefine Diagnostic

Criteria for Alzheimer’s Disease

Current AD Diagnostic Criteria The current criteria for the diagnosis of AD

were established by a National Institute of Neurological Disorders and Stroke (NINDS)/Alzheimer's Disease and Related Disorders Association (ADRDA) workgroup in 1984.

Almost universally adopted, useful; they have survived without modification for more than 25 years. However, the AD field has evolved greatly since then.

NINCDS/ADRDA Criteria for Probable NINCDS/ADRDA Criteria for Probable Alzheimer’s DiseaseAlzheimer’s Disease________________________________________________________________________________

Dementia established by clinical examination; confirmed by cognitive screening tests

Deficits in two or more areas of cognition Progressive worsening of memory and other cognitive

functions No disturbance of consciousness Onset between 40 and 90, most often after 65 Absence of systemic disorders or other brain disease

that could account for the deficits and progression

McKhann et al. Neurol 1984;34:939-944

The NIA/Alzheimer's Association working groups were organized around the three stages of Alzheimer's disease that are commonly thought to exist today – pre-clinical Alzheimer's, mild cognitive impairment (MCI) due to Alzheimer's, and Alzheimer's dementia.

Alzheimer's dementia – The group is revising the existing criteria for diagnosing Alzheimer's to include possible biomarkers and other assessments that may aid in diagnosis.

Mild Cognitive Impairment – The group is refining the MCI criteria, which will help to indicate cognitive change before dementia and better differentiate MCI from Alzheimer's.

Pre-Clinical – The group is laying out a research agenda to identify methods of assessment that may help predict risk for developing the disease.

AD Dementia Clinical Criteria for All Cause Dementia

Dementia is diagnosed when there are clinical and cognitive symptoms that:○ Interfere with the ability to function independently at work or at usual

activities; and○ Represent a decline from prior levels of functioning and performing; and○ Are not explained by delirium nor major psychiatric disorder;

Probable AD dementia: Patient meets the clinical and cognitive criteria for dementia and

does not have evidence of alternate diagnoses, particularly cerebrovascular disease.

Probability can be enhanced by factors including a documented longitudinal decline and positive evidence from biomarkers, or they may be an AD mutation carrier.

○

AD Dementia Pathologically proved AD dementia:

Patient meets the clinical and cognitive criteria for AD dementia during life and then have proven AD by pathological examination.

Possible AD dementia: Patients who have an atypical course; i.e., those who

meet other clinical/ cognitive criteria, but for whom information on the course of progression is lacking or uncertain. It also includes those who meet clinical and cognitive criteria but who are negative for biomarkers. Includes those with mixed presentation.

MCI Four clinical and cognitive criteria for MCI due to

AD were developed — similar but slightly different from original criteria for MCI:Concern regarding a change in cognition: Concern

about a change in cognition from prior level (patient, an informant, or a skilled clinician).

Impairment in 1 or more cognitive domains: Performance should be lower than would be expected from the patient's age and education. Memory impairment is clearly the most common but other domains may be impaired, may be impairments in more than 1 domain.

MCIPreservation of independence in functional

abilities: Have the ability to maintain independence of function with minimal aids and assistance ; may have mild problems with complex tasks such as paying bills, preparing meals, or shopping, etc.

Not demented: The cognitive changes should be sufficiently mild that there is no evidence of impairment in social or occupational function.

MCI MCI of a neurodegenerative etiology: The

patient meets the clinical and cognitive criteria for the disorder, and biomarkers may not have been tested, they may have been tested and are ambiguous, or biochemical/molecular biomarkers may be negative.

MCI of the Alzheimer type: The patient meets clinical and cognitive criteria for the disorder, plus has positive findings from 1 of the "downstream" biomarkers of structural or functional change, e.g., MRI evidence of hippocampal atrophy, or FDG PET alterations. No biochemical/molecular biomarkers, or equivocal findings

MCI Prodromal Alzheimer's dementia: The

highest level of certainty, in which the patient meets the clinical and cognitive criteria for MCI, plus has biomarker evidence to suggest underlying AD pathology.

Pre-Clinical AD

Propose operational research criteria for the study of preclinical AD.

These criteria are intended to provide a common language to advance the scientific understanding of the preclinical stages of AD and a foundation for the evaluation of preclinical AD treatments.

Pre-Clinical AD Working Group: Model of the clinical trajectory of AD. The stage of preclinical AD precedes MCI and encompasses both asymptomatic individuals in whom the pathophysiological process has already begun but who are clinically indistinguishable from the profile of normal or “typical” aging, as well as individuals who have demonstrated subtle decline from their own baseline that exceeds that expected in typical aging, but would not yet meet criteria for MCI.

Pre-Clinical AD Working Group: Hypothetical model of the pathophysiological sequence leading to cognitive impairment in AD. This model postulates that amyloid-β accumulation is an “upstream” event in the cascade that results synaptic dysfunction, which may lead directly to cognitive impairment and/or trigger “downstream” neurodegeneration and cell loss. Specific host factors, such as brain and cognitive reserve, or other brain diseases may mediate the response to amyloid toxicity and pace of progression towards the clinical manifestations of AD.

Pre-Clinical AD Stage 1: Biomarker evidence of amyloid-β accumulation

(Stage 1 = asymptomatic cerebral amyloidosis) Elevated tracer retention on PET amyloid imaging and/or low Aβ42

on CSF assay

Stage 2: Biomarker evidence of synaptic dysfunction and or early neurodegeneration (Stage 2 = evidence of amyloid positivity + presence of one or more additional AD markers) Elevated CSF tau or phospho-tau Hypometabolism in an AD-like pattern (i.e. posterior cingulate,

precuneus, and/or temporo-parietal cortices) on FDG-PET Cortical thinning/grey matter loss in AD-like anatomic distribution

(i.e. lateral and medial parietal, posterior cingulate and lateral temporal cortices) and/or hippocampal atrophy on volumetric MRI

Pre-Clinical AD Stage 3: Evidence of subtle cognitive decline, but

does not meet criteria for MCI or dementia (Stage 3 = amyloid positivity + markers of neurodegeneration + very early cognitive symptoms) Demonstrated cognitive decline over time on standard

cognitive tests, but not meeting criteria for MCI Subtle impairment on challenging cognitive tests, particularly

accounting for level of innate ability or cognitive reserve but not meeting criteria for MCI

• WORKGROUPS ARE REVISING THE REPORTS AFTER CONSIDERING FEEDBACK FROM THE SCIENTIFIC COMMUNITY

• FINAL REPORTS WILL BE DRAFTED AND SUBMITTED FOR PUBLICATION – WINTER 2011

• A PAPER SUMMARIZING THE RECOMMENDATIONS FOR DOCTORS IN NON- RESEARCH SETTINGS IS BEING DRAFTED FOR A MEDIAL JOURNAL WITH WIDE READERSHIP

• THE RECOMMENDATIONS WILL BE REVISITED AS NEW EVIDENCE ACCUMULATES AND BIOMARKERS ARE VALIDATED – CURRENTLY BIOMARKERS ARE NOT USED ROUTINELY IN PRACTICE, ONLY FOR RESEARCH

Where Do We Go From Here?

Primary prevention strategies intend to avoid the development of disease

Secondary prevention strategies attempt to diagnose and treat an existing disease in its early stages before it results in significant morbidity (slow/delay progression to AD in individuals with MCI/prodromal AD)

NIH State-of-the-Science Conference Statement onPreventing Alzheimer’s Disease and Cognitive Decline

April 26–28, 2010NATIONAL INSTITUTES OF HEALTHOffice of the Director

NIH State-of-the-Science Conference Statement on Preventing Alzheimer’s Disease and Cognitive Decline

“Currently, firm conclusions cannot be drawn about the association of any modifiable risk factor with cognitive decline or Alzheimer’s disease. Highly reliable consensus-based diagnostic criteria for cognitive decline, mild cognitive impairment, and Alzheimer’s disease are lacking, and available criteria have not been uniformly applied. Evidence is insufficient to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimer’s disease. We recognize that a large amount of promising research is under way; these efforts need to be increased and added to by new understandings and innovations (as noted in our recommendations for future research).”

AD Risk FactorsAD Risk Factors

Age

Head Injury

High Blood Pressure

High Cholesterol

High Homocysteine

Diabetes

Diet

Education

Exercise

Social Interaction

Age

Head Injury

High Blood Pressure

High Cholesterol

High Homocysteine

Diabetes

Diet

Education

Exercise

Social Interaction

Potential Link Between Potential Link Between Cardiovascular Cardiovascular Risk Factors and DementiaRisk Factors and Dementia

High cholesterol

Hypertension

High homocysteine

Diabetes

Lifestyle Therapies Tested inLifestyle Therapies Tested inAnimals for Cognitive Decline and ADAnimals for Cognitive Decline and AD

Interventions

• Behavioral enrichment • Dietary antioxidants• Exercise

Results

• Improved learning ability in older animals• Prevention of brain cell dysfunction and death• Prevention of buildup of plaque and amyloid

Aged Canine Model Cotman et al. evaluated the effect of behavioral enrichment (ENR)

(social and cognitive enrichment and exercise), an antioxidant diet targeting mitochondrial function (AOX), and the combination of the ENR and AOX interventions in the aged canine.

The combined AOX/ENR treatment appeared to have additive or synergistic effects on preserving cognitive function, as well as on several neurobiological endpoints.

The AOX/ENR intervention also counteracted oxidative stress, improved mitochondrial function, preserved neuron number, and increased availability of growth factors such as BDNF. However, interventions had little, if any, effect on Abeta levels.

e.g., Cotman CW, Head E. The canine (dog) model of human aging and disease: dietary, environmental and immunotherapy approaches. J Alzheimers Dis. 2008;15(4):685–707.

Hypothesize that improved mitochondrial function, achieved by the AOX diet, is a key factor in the synergistic/additive effect of the combined intervention on cognitive function.

Improved mitochondrial function positions the aged brain to better respond to behavioral interventions; neurons with healthy mitochondria are more able to benefit from ENR.

The AOX and ENR interventions may engage molecular mechanisms that enhance ―cognitive reserve, allowing the canine to maintain intact cognitive abilities despite the continued presence of Abeta in the brain.

Suggest that strategies to improve overall neuronal heath, esp., mitochondrial function, may be critical for the effectiveness of behavioral-based interventions, as well as the effectiveness of some pharmacological-based strategies.

e.g., Cotman CW, Head E. The canine (dog) model of human aging and disease: dietary, environmental and immunotherapy approaches. J Alzheimers Dis. 2008;15(4):685–707.

Human Observational Lifestyle Studies: Diet, Exercise Mediterranean Diet (MeDi) adherence and physical

activity (PA) on AD riskProspective multi-ethnic cohort study of 1880

community-dwelling elders without dementia living in New York, New York, with both diet and physical activity information available

Results: Risk for incident AD was lower for both higher MeDi adherence and more PA.

Adoption of both physical activity and healthy nutrition seem to be independently associated with low risk for AD

Scarmeas, N. et al. JAMA 2009;302:627-637

Figure 2. Alzheimer Disease (AD) Incidence by High or Low Physical Activity Levels and Mediterranean-Type Diet Adherence Scores

Scarmeas, N. et al. JAMA 2009;302:627-637

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 ExerciseHuman Studies of Aerobic Exercise

Epidemiology or observational studies show association between aerobic exercise and development of AD

Short term clinical trials show improvements in executive function

Short term trials show increased brain volume (MRI) and functional activity (fMRI)

Human Lifestyle Therapies: Exercise

Home-based Physical Activity170 community-dwelling older adults from the Perth

Metropolitan area, who were free of dementia, but had subjective memory complaints or Mild Cognitive Impairment

Randomized controlled trial of a 24-week physical activity intervention vs. usual care conducted between 2004 and 2007 in metropolitan Perth, Western Australia. Assessors of cognitive function were blinded to group membership.

Results: Modest improvement in cognition over 18 months. The effect of exercise was apparent by 6 months and persisted at the 12 and 18-months assessments

Lautenschlager et al JAMA 2008

Table 2. Effects of the Intervention and Time on Cognitive Outcomes, Mood, and Quality of Life of Participants (Intention-to-Treat Method Using Multiply Imputed Data)a.

Lautenschlager, N. T. et al. JAMA 2008;300:1027-1037

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 functionKrueger et al. Exp Aging Res. 2009 ; 35(1): 45–60.

The Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) Study

5,000 persons assessed – 2,832 randomized

Three training groups (speed, reasoning, episodic memory) and a matched control group

Ten 60- to 75-minute sessions over 5 to 6 weeks

Willis et al (2006) JAMA 296:2805

Human Lifestyle Therapies: Cognitive Training

ACTIVE Results

Improved in the domain trained; maintained at 2 years

Cognitive training in any domain was maintained 5 years post training

Five year follow-up revealed reasoning training resulted in less functional decline

Human Lifestyle Studies: Education The cognitive reserve hypothesis suggests that at a particular level of

AD pathology, highly educated individuals are less likely to manifest clinical symptoms of dementia vs. less-educated individuals.

To investigate whether education can help explain a clinical diagnosis of no dementia within 1 year of death among individuals with neuropathologic diagnoses of AD, samples of participants (age 65+ years at last clinical assessment) meeting each of three neuropathologic criteria for AD were constructed using data from the National Alzheimer's Coordinating Center Minimum and Neuropathology Data Sets.

RESULTS: Regardless of the neuropathologic criteria used, education is predictive of dementia status among individuals with neuropathologic AD. These results support the theory that individuals with greater cognitive reserve, as reflected in years of education, are better able to

cope with AD brain pathology without observable deficits in cognition.

Roe et al. Neurology. 2007 Jan 16;68(3):223-8

Human Lifestyle Therapies: Dietary Supplements

Ginkgo Evaluation of Memory (GEM) Study : 3,069 community volunteers aged 75 years or older with normal cognition (n = 2587) or MCI (n = 482) at study entry were assessed every 6 months for incident dementia. Intervention Twice-daily dose of 120-mg extract of G biloba

(n = 1545) or placebo (n = 1524). Results - Main Outcome: not effective in reducing either the overall

incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI.

Results - Secondary Outcome: did not result in less cognitive decline in older adults with normal cognition or with MCI

DeKosky, S. T. et al. JAMA 2008;300:2253-2262; Snitz, B. E. et al. JAMA 2009;302:2663-2670

Human Lifestyle Therapies: Dietary Supplements

Memory Improvement With Docosahexaenoic Acid (DHA) Study (MIDAS): Randomized, double-blind, placebo-controlled trial of 485 cognitively healthy subjects, aged ≥55

900 mg/d of DHA orally or matching placebo for 24 weeks.

Results: After 24 weeks, individuals in the DHA group had significantly fewer errors on a visuospatial memory test compared with the placebo group

K. Yurko-Mauro et al. Alzheimer’s & Dementia 6 (2010) 456–464

Human Lifestyle Studies: Diabetes Treatment

Diabetes Medications:Postmortem study: 124 older adult diabetic patients

and 124 non-diabetic older adult controls

Found that those treated with both insulin and oral diabetic agents had significantly fewer amyloid plaques (as much as 80 percent) than patients with other medication statuses (none, or only insulin or oral anti-diabetic medication) or non-diabetic controls

Beeri et al., Neurology. 2008; 71(10): 750–757

NIA Ongoing Prevention Trials Currently supports 37 active clinical trials, including both pilot and

large scale trials, of a wide range of interventions to prevent, slow, or treat AD and/or MCI.

7 primary and 6 secondary prevention trials. Of the 7 primary prevention trials, 2 are NIA-funded cognitive/AD measure add-ons to large NIH primary prevention trials that address a variety of other primary outcomes.

One such trial is NHLBI’s Systolic Blood Pressure Intervention Trial (SPRINT), which will evaluate the health effects of lowering systolic blood pressure from 140 to 120. The add-on study, SPRINT-MIND, funded by NIA and NINDS, will assess the effect of lowering systolic blood pressure specifically on cognitive decline and development of MCI and AD. The study will also use brain imaging to measure treatment effects on brain structure, including white matter lesions typical of vascular disease.

TRIAL NAME INTERVENTION POPULATION TYPE OF TRIAL ANTICIPATED COMPLETION DATE

ANTIOXIDANTSPREADVISE (Prevention of Alzheimer's Disease by Vitamin E and Selenium)♦

Vitamin E, Selenium, Vitamin E + Selenium

Men age 60 - 90 Primary Prevention

2014

Vitamin E in Aging Persons With Down Syndrome

Vitamin E People age 50+ with Down Syndrome, at high risk of developing AD

Primary Prevention

2012

OMEGA-3 FATTY ACIDS AND ANTIOXIDANTS

AREDS2 (Age-Related Eye Disease Study 2) †

Macular xanthophylls (lutein and zeaxanthin) and/or omega -3 fatty acids (DHA and EPA)

People age 50-85 with age-related Macular degeneration (AMD) in both eyes, or advanced AMD in one eye

Primary Prevention

2015

CARDIOVASCULARASPREE (Aspirin in Reducing Events in Elderly)

Aspirin Healthy adults, age 70+ Primary Prevention

2017

SPRINT-MIND (Systolic Blood Pressure Intervention Trial-MIND)♦

Blood pressure lowering to <140 mm Hg versus <120 mm Hg

Adults age 55+ with systolic blood pressure of 130 mm Hg or higher; history of cardiovascular disease; high risk for heart disease

Primary Prevention

2017

Ongoing AD/MCI Prevention Clinical Trials Funded by NIAOngoing AD/MCI Prevention Clinical Trials Funded by NIA

HORMONES

ELITE (Early Versus Late Intervention with Estradiol)

17 β-estradiol Healthy early (less than 6 years) or late (10 years +) menopausal women

Primary Prevention

2014

SMART (Somatotrophics, Memory, and Aging Research Trial)

Growth hormone releasing hormone (GHRH)

People with MCI and healthy older adults age 55 – 80

Secondary Prevention

2011

Testosterone Supplementation in Men with MCI

Testosterone Older men with MCI and low testosterone

Secondary Prevention

2011

DIABETES

Metformin in Amnestic MCI Metformin Overweight/obese older adults with MCI

Secondary Prevention

2012

Pioglitazone & Exercise Effects on Older Adults with MCI and Metabolic Syndrome

Pioglitazone Overweight/obese older adults with MCI

Secondary Prevention

2012

EXERCISE, COGNITIVE TRAINING

Exercise Versus Cognitive Interventions for Elders at Risk for Dementia

Cognitive training, aerobic exercise training, cognitive training + aerobic exercise training

People with MCI Secondary Prevention

2012

Lifestyle Interventions and Independence for Elders (LIFE)

Aerobic exercise, resistance, and flexibility exercises

Adults age 70+ Primary Prevention

2015

Memory Training Intervention in Mild Cognitive Impairment

Repetition lag training procedure (RLTP)

People with MCI Secondary Prevention

2014

AD Resources

NIA Alzheimer’s Disease Education and Referral Center (ADEAR)

Toll-free information line, 1-800-438-4380Web site (English & Spanish) :

www.nia.nih.gov/alzheimers

Alzheimer’s Association

Web site: www.alz.org

Thank You!

E-mail:

Laurie Ryan: ryanl@mail.nih.gov