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.


U.S. Life Expectancy at Birth in 1900, 1950, 2000
90 80 70 60 50

79.5 65.6 71.1 74.1




40 30 20 10 0 1900 1950 2000

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

100000 80000 60000 40000 20000 0
19 00 19 20 19 40 19 60 19 80 20 00 20 20 20 40

25 20 15 10 5 0 Number (thousands) Percent of Population


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

Estimated Percentage of People over Age 65 with Probable Alzheimer’s Disease
50 40 30 20 10 3.0 0 65-74 75-84 85+ 19 47


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.

Cognitive Continuum

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


Genetic Studies

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

• Young-onset AD is rare, usually affecting people aged 30 to 60 and usually running in families. Researchers have identified mutations in three genes that cause young-onset AD. • Late-onset AD is more common. It usually affects people over age 65. The primary risk factor for AD is age.

GENETIC FACTORS PREDISPOSING TO AD: Young- Onset Alzheimer’s Disease
Rare, early onset autosomal-dominant forms of the disease are caused by mutations in 3 genes (APP, Presenilin 2, Presenilin 1) all of which alter production of the amyloid β ( A β ) peptide; less than 5% of all AD cases.

Bertram and Tanzi, Nature Reviews Neuroscience 2008

• 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),


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.


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

Individuals with MCI Cover the Range of Amyloid Load

Positive Amyloid PIB Scan Predicts Clinical Progression of MCI patients to AD
Melbourne Cohort
N=28, 21 mo. follow-up

Pittsburgh Cohort
N=23, 24 mo. follow-up



PiBAD Converters PiB+ AD Converters
Wolk et al., AAN 2008

10 0 13 5

AD Converters 1 PiB+ 15

AD Converters 12
Villemagne et al., SNM 2008


F-AV-45 Scans Spectrum of Pathology
1 8


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

may cause changes in CSF levels of beta-amyloid and tau, two proteins that form abnormal brain deposits strongly linked to the disease.
• Plasma, Urine: investigations underway on whether

pre-symptomatic AD causes consistent, measurable changes in urine or blood levels of tau, beta-amyloid or other biomarkers.

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

used to distinguish between individuals with and without AD. • Compared protein patterns in blood samples from 197 patients with AD and 203 without AD and incorporated into an algorithm for detecting AD cases in a test group. • Results suggest this algorithm may accurately classify most Alzheimer's cases — particularly when combined with APOE status and demographic data. Validation in an independent sample is needed.

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

Hypothetical Model of Dynamic Biomarkers of the Alzheimer’s Pathological Cascade
Clifford R Jack, Jr, David S Knopman, William J Jagust, Leslie M Shaw, Paul S Aisen, Michael W Weiner, Ronald C Petersen, and John Q Trojanowski

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

Figure 5. Modulators of biomarker temporal relationships(A,B) Relative to a fixed age (here, 65 years), the hypothesized effect of APOE 4 is to shift β-amyloid plaque deposition and the neurodegenerative cascade both to an earlier age compared with 4 non-carriers.

• Authors acknowledge that well-validated biomarkers do not

currently exist for some important features of the disease. This includes reliable chemical biomarkers of specific toxic oligomeric forms of soluble Aβ and imaging measures of soluble Aβ or diffuse plaques, PET ligands that specifically measure the burden of NFTs and other tau abnormalities.
• Thus, they note, the biomarker model of disease is just that

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

Need For Validated Biomarkers For AD Trials
• Current trials use clinical/cognitive outcome measures : • slow rate of change over time, do not easily determine disease modifying effects of treatment • trials require large sample size, are time intensive and costly size • 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 and distributing images and biomarkers in conjunction with clinical and neuropsychological data in a multi-site context neuropsychological and clinical data.

• Determine the optimum methods for acquiring, processing,

• “Validate” imaging and biomarker data by correlating with

• Rapid public access of all data and access to samples

• 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 NIBIB, NINDS, NIMH, NIDA, NCRR, NINR
ADNI Executive Steering Committee
PET Core: Berkeley: Jagust MRI Core: Mayo: Jack Clinical Core: UCSD: Aisen Mayo: Peterson Publications Core: PI: Mike Weiner Administrative Core: UCSF BostonU: Green Biomarkers Core: UPenn: Trojanowski/Shaw


Biostatistics Core: UCD: Beckett

Informatics Core: Neuropathology Core: UCLA: Toga WashU: Morris

57 Clinical Sites: ADNI PIs and Cores

ADNI Progression Rates
Year 0-1 1-2 2-3 Normal  MCI 1.4% (0.0-3.2) 2.4% (0.0-4.7) 0.0% (0.0-3.4) MCI  AD 16.0% (11.3-20.4) 23.9% (19.0-29.5) 9.1% (5.8-13.5)

Mean Cortical Thickness Change (over 12 months)



Lateral View

Medial View

Holland et al.

PET: Regional Hypometabolism

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

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 61 ADAS-COG11 612 MMSE 493

Reiman et al Banner Alzheimer

Follow-Up of PIB-Positive ADNI MCI’s
N = 65, 12 mo. follow-up

PiB(-) Converters to AD PiB(+)

18 3 47

Converters to AD 21

• 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



0.5 CDR


• Continue to follow all EMCI, LMCI and NC from ADNI 1

and ADNI GO for 5 more years • Enroll:
• 100 additional EMCI (supplements 200 from GO) • 150 new controls, LMCI, and AD

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

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

elucidate neurobiology • Trials: new understanding of biomarkers has facilitated interventional studies in very early AD • Data sharing: ADNI has demonstrated the power of realtime public data sharing • Collaboration: academia, industry, non-profits, regulatory agencies world-wide

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The new guidelines appear as free-access papers in Alzheimer's and Dementia: The Journal of the Alzheimer's Assoc

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.

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.

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.

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.

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.

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.

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.

MCI – Research Criteria

MS Albert et al.

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.

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.

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.

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.

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 dissolve paired helical filaments

o slow or prevent tau aggregation and dysfunction

 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 Head Injury Head Injury High Blood Pressure High Blood Pressure High Cholesterol High Cholesterol High Homocysteine High Homocysteine Diabetes Diabetes Diet Diet Education Education Exercise Exercise Social Interaction Social Interaction


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

Lifestyle Therapies Tested in Animals for Cognitive Decline and AD
Interventions • Behavioral enrichment
• Dietary antioxidants • Exercise

• 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 behavioralbased interventions, as well as the effectiveness of some pharmacological-based strategies.

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

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

activity (PA) on AD risk • Prospective multi-ethnic cohort study of 1880 communitydwelling elders without dementia living in New York, New York, with both diet and physical activity information available • Results: Risk for incident AD was lower for both higher MeDi adherence and more PA. • Adoption of both physical activity and healthy nutrition seem to be independently associated with low risk for AD

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

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

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

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Figure 3. Alzheimer Disease (AD) Incidence in Individuals by No, Some, or Much Physical Activity and Low, Middle, and High Mediterranean-Type Diet Adherence Scores

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

Copyright restrictions may apply.

Human Lifestyle Intervention: Diet Craft et al, ICAD 2010
• Randomized high-fat/high-glycemic diet vs a low-fat/low-

glycemic diet, 4 weeks in 29 patients with MCI and 20 healthy adults. Diets were the same in terms of calories. • Fasting plasma insulin, low-density lipoprotein, and total cholesterol levels were all increased by the high-fat/highglycemic diet, whereas these parameters decreased with the low-fat/low-glycemic diet, with greater effects seen among those with MCI. • The effect of the diets on amyloid in the CSF: The low-fat diet moved Aβ42 levels in a beneficial direction for both the controls and MCI; these changes also predicted performance on tests of memory and attention.

Human Studies of Aerobic Exercise
• Epidemiology or observational studies show association

between aerobic exercise and development of AD function

• Short term clinical trials show improvements in executive • Short term trials show increased brain volume (MRI) and

functional activity (fMRI)

Human Lifestyle Therapies: Exercise
• Home-based Physical Activity • 170 community-dwelling older adults from the Perth Metropolitan area, who were free of dementia, but had subjective memory complaints or Mild Cognitive Impairment • Randomized controlled trial of a 24-week physical activity intervention vs. usual care conducted between 2004 and 2007 in metropolitan Perth, Western Australia. Assessors of cognitive function were blinded to group membership. • Results: Modest improvement in cognition over 18 months. The effect of exercise was apparent by 6 months and persisted at the 12 and 18-months assessments
Lautenschlager et al JAMA 2008

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

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

Copyright restrictions may apply.

Human Observational Lifestyle Studies: Social Engagement
• Relation of social engagement to level of cognitive function in

older persons from the Rush Memory and Aging Project, a clinical-pathologic study of risk factors for common chronic conditions of old age.

• 838 persons without dementia who had a mean age of 80.2 • Results: Better cognitive function was correlated with more

frequent participation in social activities, as well as with the subjects’ own perception of being well-supported socially. Even when higher levels of intellectual and physical activity were accounted for, there was still a significant correlation between social interaction and cognitive function
Krueger et al. Exp Aging Res. 2009 ; 35(1): 45–60.

Human Lifestyle Therapies: Cognitive Training
• The Advanced Cognitive Training for Independent

and Vital Elderly (ACTIVE) Study

• 5,000 persons assessed – 2,832 randomized • Three training groups (speed, reasoning, episodic

memory) and a matched control group

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

Willis et al (2006) JAMA 296:2805

ACTIVE Results
• Improved in the domain trained; maintained at 2 years • Cognitive training in any domain was maintained 5

years post training
• Five year follow-up revealed reasoning training

resulted in less functional decline

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

highly educated individuals are less likely to manifest clinical symptoms of dementia vs. less-educated individuals.
• To investigate whether education can help explain a clinical diagnosis of no dementia

within 1 year of death among individuals with neuropathologic diagnoses of AD, samples of participants (age 65+ years at last clinical assessment) meeting each of 3 neuropathologic criteria for AD were constructed using data from the National Alzheimer's Coordinating Center Minimum and Neuropathology Data Sets.
• RESULTS: Regardless of the neuropathologic criteria used, education is predictive of

dementia status among individuals with neuropathologic AD. These results support the theory that individuals with greater cognitive reserve, as reflected in years of education, are better able to cope with AD brain pathology without observable deficits in cognition.

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

Human Lifestyle Therapies: Dietary Supplements
• Ginkgo Evaluation of Memory (GEM) Study : 3,069

community volunteers aged 75 years or older with normal cognition (n = 2587) or MCI (n = 482) at study entry were assessed every 6 months for incident dementia.
• Intervention Twice-daily dose of 120-mg extract of G biloba (n = 1545)

or placebo (n = 1524). • Results - Main Outcome: not effective in reducing either the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI. • Results - Secondary Outcome: did not result in less cognitive decline in older adults with normal cognition or with MCI

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

Human Lifestyle Interventions: Dietary Supplements
• Memory Improvement With Docosahexaenoic Acid (DHA)

Study (MIDAS): Randomized, double-blind, placebocontrolled trial of 485 cognitively healthy subjects, aged ≥55
• 900 mg/d of DHA orally or matching placebo for 24 weeks. • Results: After 24 weeks, individuals in the DHA group had

significantly fewer errors on a visuospatial memory test compared with the placebo group

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

Human Lifestyle Studies: Diabetes Treatment
• Research has suggested that AD and diabetes/insulin resistance are closely

related. For example, AD is associated with reduced brain insulin signaling and low levels of insulin in cerebrospinal fluid (CSF). These deficiencies may reduce or eliminate insulin's beneficial roles in the brain.

• Diabetes Medications: • Postmortem study: 124 older adult diabetic patients and 124 non-diabetic older

adult controls

• Found that those treated with both insulin and oral diabetic agents had

significantly fewer amyloid plaques (as much as 80 percent) than patients with other medication statuses (none, or only insulin or oral anti-diabetic medication) or non-diabetic controls. Beeri et al., Neurology. 2008; 71(10): 750–757

Selected NIA Funded Trials from the AD Pilot Clinical Trials Initiative
Trials Targeting Diabetes/Insulin Resistance:
• Intranasal insulin: Effects on cognition, cerebral glucose

metabolism, markers of AD pathology, neuroendocrine functions in AD. Completed • Insulin Sensitizing Agents: • Pioglitazone and Exercise: Effects of the medication or exercise on cognition, inflammation, insulin resistance in individuals with MCI and Metabolic Syndrome. Ongoing • Metformin: Effects on cognition, brain metabolism in overweight/obese individuals with MCI. Ongoing

Human Lifestyle Interventions: Intranasal Insulin Craft, et al. ICAD 2011
therapeutic benefits to adults with AD.

• Restoring normal insulin function in the brain may provide

• The SNIFF-120 trial was a 4-month, randomized, double-

blind trial of placebo vs 2 doses of intranasal insulin (20 or 40 IU).
• 104 patients with AD or amnestic MCI participated;

patients with diabetes were excluded.

Human Lifestyle Interventions: Intranasal Insulin Craft, et al. ICAD 2011
• Results: 20 IU dose of insulin delayed story recall

significantly improved compared to placebo, as did functional status. • Improvements in delayed memory recall persisted for 2 mos. after treatment ended.
• Improved memory and functional status with insulin were

associated with an improved AD biomarker profile as reflected by a lowered CSF Aβ40/42 ratio. • Also, compared with placebo patients, those in the insulin groups showed preserved glucose metabolism on FDG PET scanning in areas affected by AD pathology.

NIA Funded Clinical Trials
• Currently supports 37 active clinical trials, including both

pilot and large scale trials, of a wide range of interventions to prevent, slow, or treat AD and/or MCI.
• 7 primary and 6 secondary prevention trials. Of the 7

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

NIA Funded Prevention Trial: SPRINTMIND
• Add-on to NHLBI’s Systolic Blood Pressure Intervention Trial

(SPRINT), which will evaluate the health effects of lowering systolic blood pressure from 140 to 120.
• The add-on study, SPRINT-MIND, funded by NIA and NINDS, will

assess the effect of lowering systolic blood pressure specifically on cognitive decline and development of MCI and AD.
• The study will also use brain imaging to measure treatment effects on

brain structure, including white matter lesions typical of vascular disease.

AD/MCI Prevention Clinical Trials Funded by NIA

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 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) Primary Prevention2015

CARDIOVASCULAR ASPREE (Aspirin in Reducing Events in Elderly)


Healthy adults, age 70+

Primary Prevention2017

SPRINT-MIND (Systolic Blood Pressure Intervention TrialMIND)♦

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 Intervention with Estradiol) SMART (Somatotrophics, Memory, and Aging Research Trial)

17 β-estradiol

Healthy early (less than 6 Primary Prevention 2014 years) or late (10 years +) menopausal women People with MCI and Secondary healthy older adults age 55 Prevention – 80 Older men with MCI and low testosterone Secondary Prevention 2011

Growth hormone releasing hormone (GHRH)

Testosterone Supplementation in Testosterone Men with MCI DIABETES Metformin in Amnestic MCI Pioglitazone & Exercise Effects on Older Adults with MCI and Metabolic Syndrome EXERCISE, COGNITIVE TRAINING Exercise Versus Cognitive Interventions for Elders at Risk for Dementia Cognitive training, aerobic exercise training, cognitive training + aerobic exercise training


Metformin Pioglitazone

Overweight/obese older adults with MCI Overweight/obese older adults with MCI

Secondary Prevention Secondary Prevention

2012 2012

People with MCI

Secondary Prevention


Lifestyle Interventions and Aerobic exercise, Independence for Elders (LIFE) resistance, and flexibility exercises Memory Training Intervention in Repetition lag Mild Cognitive Impairment training procedure (RLTP)

Adults age 70+

Primary Prevention 2015

People with MCI

Secondary Prevention


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

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