U.S. Department of 

Health and Human Services 

video LINK 

Watch a video about AD 

2OO9 

Progress Report on

Alzheimer’s 

Disease 

Translating New Knowledge 
2OO9 

Progress Report on

Alzheimer’s 

Disease 

Translating New Knowledge 

National Institute on Aging 

National Institutes of Health 

U.S. Department of Health and Human Services 
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)—pages 18 and 22 

The National Institute on Aging (NIA), part of the Federal Government’s National 

Institutes of Health (NIH) at the U.S. Department of Health and Human Services, has 

primary responsibility for basic, clinical, behavioral, and social research in Alzheimer’s 

disease (AD), aimed at finding ways to treat and, ultimately, prevent this disease. The Institute’s 

AD research program is integral to its mission, which is to enhance the health and well-being of 

older people. This 2009 Progress Report on Alzheimer’s Disease summarizes recent AD research 

conducted or supported by NIA and other components of NIH, including: 

National Center for Complementary and Alternative Medicine (NCCAM)—pages 34, 37, 39, and 56 

National Center for Research Resources (NCRR)—pages 16, 31, 34, 39, 47, and 51 

National Eye Institute (NEI)—page 18 

National Heart, Lung, and Blood Institute (NHLBI)—pages 25, 37, 39, and 41 

National Human Genome Research Institute (NHGRI)—pages 23 and 24 

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)—pages 27 and 37 

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)—pages 22 and 51 

National Institute of Environmental Health Sciences (NIEHS)—pages 14, 18, 26, and 38 

National Institute of General Medical Sciences (NIGMS)—pages 16 and 26 

National Institute of Mental Health (NIMH)—pages 17, 18, 19, 23, 27, and 51 

National Institute of Neurological Disorders and Stroke (NINDS)—pages 16, 17, 18, 22, 23, 25, 26, 34, 36, 37, 41, and 47 

National Institute of Nursing Research (NINR)—pages 51 and 56 

National Institute on Alcohol Abuse and Alcoholism (NIAAA)—page 26 

National Institute on Deafness and Other Communication Disorders (NIDCD)—page 32 

AD research efforts also are supported by the John E. Fogarty International Center, National Cancer 

Institute, National Institute of Allergy and Infectious Diseases, National Institute of Biomedical 

Imaging and Bioengineering, National Institute on Drug Abuse, and NIH Common Fund. 

Throughout this report, studies with no funding attribution were funded by NIA. Funding by other 

Institutes and Centers is noted. 

 

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2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 3 ’
In Remembrance 

NIA warmly remembers two groundbreaking leaders in aging and Alzheimer’s disease research who died in 2010 

as this Progress Report on Alzheimer’s Disease was being produced. 

Robert N. Butler, M.D. (1927-2010), NIA’s founding director and founder of the International Longevity 

Center USA, was a tireless advocate for older people and aging research. At NIA, he set in place a visionary research 

endeavor, building a rationale and organization for a broad program of basic, biomedical, social, and behavioral 

research that remains at the core of our efforts today. After leaving NIA, he was the founding chairman of the 

Department of Geriatrics at Mount Sinai School of Medicine. A geriatric psychiatrist, Dr. Butler was particularly 

proud of focusing public and research attention on Alzheimer’s disease and other dementias. 

William R. Markesbery, M.D. (1933-2010), considered among the top researchers in the world for the productivity and impact of his scientific study of Alzheimer’s disease, received NIH support for nearly 30 years. Dr. 

Markesbery led the University of Kentucky Sanders-Brown Center on Aging from its founding in 1979 and was 

director of the UK Alzheimer’s Disease Center. A special issue of NeuroMolecular Medicine honoring Dr. 

Markesbery’s career and legacy will be published in March 2011, edited by NIA Neurosciences Lab Chief Mark 

Mattson, Ph.D. 

Image Credits 

Covers: Human Alzheimer plaque (second image from left)—Nancy O’Rourke, Ph.D., and Stephen J. Smith, Ph.D. (Stanford 

University) and John Trojanowski, M.D., Ph.D., and Virginia M.-Y. Lee, Ph.D., M.B.A. (University of Pennsylvania) 

Other cover images—Thinkstock 

Page 12: Stacy Jannis, Jannis Productions 

Page 17: Hagmann et al., 2008 PLoS Biology. Indiana University, University of Lausanne EPFL 

Page 24: National Human Genome Research Institute, www.genome.gov/27532724 

Page 30: Paul Aisen, M.D., Alzheimer’s Disease Cooperative Study, University of California, San Diego 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 4 ’
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table of Contents
 

IntRoduCtIon.................................................

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6
 

EXECutIVE SuMMARY 7
 

A BRIEf PRIMER on AlzhEIMER’S
 

dISEASE And thE BRAIn 11
 

RESEARCh AdVAnCES 14
 

1 Recognizing the Scope of AD 14
 

Prevalence of Dementia 14
 

Links with Other Diseases 14
 

2 Deciphering AD Biology 15
 

Synaptic Dysfunction 16
 

Selective Neuronal Death 16
 

Amyloid and Sleep ............................................. 

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17
 

Cellular Energy Deficits 17
 

What Is Normal Aging? 20
 

3 Discovering New Genetic Mechanisms 21
 

The Search for New Genes 21
 

Epigenetics: Nature Meets Nurture 24
 

4 Preventing AD and Promoting 

Healthy Brain Aging 25
 

Potential AD Risk Factors 25
 

Lifestyle and Successful Cognitive Aging 27
 

5 Detecting Disease Earlier 30
 

Cognitive Testing ............................................... 

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30
 

Other Early Signs and Symptoms 32
 

Biomarkers and ADNI 33
 

6 Developing Novel 


Therapeutic Approaches 35
 

Drug Discovery and Preclinical Development 36
 

New Therapeutic Targets 37
 

7 Testing Therapies for 


Prevention and Treatment 38
 

AD Clinical Trials 38
 

Clinical Trials to Maintain or 


Improve Cognitive Function with Age 46
 

8 Supporting AD Caregivers 51
 

AdVAnCInG thE futuRE of
 

Ad RESEARCh: RESouRCES And
 

CollABoRAtIon........................................... 

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2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 5 ’

52
 

REfEREnCES 57
 
 

 

 

 

 

 

 

A

Introduction 

lzheimer’s disease (AD) is an age-related brain 

 disorder that develops over many years. Its 

 symptoms typically first appear after age 60. 

The course of AD varies from person to person, but in 

most people, the first symptom is memory loss. Memory 

decline becomes more serious as the disease progresses, 

and people often begin having problems with other cognitive functions, such as decision making (including 

financial) and language skills. People with Alzheimer’s 

may also experience behavior and personality changes. 

Eventually, the loss of mental function becomes so 

severe that it impairs daily living and the ability to recognize family and friends. These losses are related to the 

breakdown of the connections between different classes 

of neurons (nerve cells) in the brain and the associated 

death of many of these cells. 

Although AD was first described by Dr. Alois 

Alzheimer more than 100 years ago, scientific study of 

the disease began in earnest only in the early 1970s. 

Since then, a broad and increasingly productive research 

program led by the National Institute on Aging (NIA) 

at the National Institutes of Health (NIH) has revealed 

much about the basic biology of the disease and the 

factors that influence its development and progression. 

This program applies the expertise of many scientific 

disciplines in an attempt to answer complex questions: 

What causes AD? How can it be diagnosed early and 

accurately? How can it be treated? How might it ultimately be prevented? A current focus of research seeks to 

accelerate the pace of “translational research”—the 

transfer of knowledge gained in the laboratory to the 

clinical arena. 

An urgent national health Priority 

The search for more effective ways to treat or prevent 

AD is increasingly urgent. Today, it is estimated that 2.4 

million to 5.1 million people in the United States have 

AD. While estimates vary, depending on how AD is 

measured, scientists agree that without scientific breakthroughs in prevention or early treatment of the disease, 

the number of people with AD will increase significantly 

as society ages. 

Studies suggest that the number of people with the 

disease doubles for every 5-year age interval beyond age 

65. The U.S. Census Bureau estimates that the 65-andolder population will double to about 72 million during 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 6 ’

the next 20 years, starting with the oldest “baby boomers” who turn 65 in 2011. The ranks of the very elderly, 

those 85 years old and older and at the highest risk of 

AD, will increase as well, potentially tripling their numbers by 2050. 

The costs of AD are at the same time deeply personal 

and broadly societal. Families, friends, and caregivers 

experience emotional, physical, and financial stress as 

they watch a loved one become more and more forgetful, 

frustrated, confused, and lost. As the disease runs its 

course and the person with AD loses the ability to live or 

function independently, family members and other caregivers face difficult decisions about long-term care. 

Frequently, they turn to assisted living facilities, then 

nursing homes, for care and support. The number of 

caregivers—and their need for practical and psychological 

support—is expected to escalate rapidly as the population 

ages and the number of people with AD grows. 
 

 

Executive Summary 

The U.S. investment in Alzheimer’s disease (AD) 

research through the National Institutes of 

Health (NIH) has resulted in accelerating progress on several research fronts and has laid the groundwork for future discovery. This report highlights key AD 

research findings and activities in 2009, conducted or 

supported by public funding for the National Institute 

on Aging (NIA) at NIH and other NIH Institutes and 

Centers. NIA leads the Federal Government’s research 

effort to understand and combat this devastating disease 

and is mandated by Congress to prepare this report. 

2009 highlights 

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2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 7 ’

New AD Genes 

International teams studying AD genetics have identified three new genes that are associated with increased 

risk of late-onset AD. Two of these genes contain 

instructions for the synthesis of proteins that may be 

involved in clearing beta-amyloid from the brain and 

preventing its interference with communication among 

brain cells, which is thought to be a major factor in the 

development of AD. These genetic discoveries come at 

a time when researchers are increasingly interested in 

harnessing the brain’s own beta-amyloid clearance mechanisms as a therapeutic strategy. (See the sections New 

human AD genes identified, page 23, and Clearing out 

beta-amyloid, page 37.) 

Earlier AD Diagnosis 

Researchers from the Alzheimer’s Disease Neuroimaging 

Initiative (ADNI) showed that changes in the levels of 

certain proteins in cerebrospinal fluid (CSF) may correlate 

with the risk and progression of AD. These biomarkers 

may be used in the future to identify individuals at risk of 

developing AD. In addition, measuring amyloid in the 

brain may prove promising as a diagnostic tool. A prelim

inary study showed that the presence of high levels of 

brain amyloid in cognitively normal people is linked with 

greater risk of later cognitive decline. (For details, see the 

sections Biomarkers and ADNI, page 33, and Brain 

Amyloid an Early Warning Sign of Possible Cognitive 

Decline in “Normal” Individuals, page 19.) 

Vascular Disease Linked to AD 

AD is typically a disease of old age, which means that 

many people with AD also suffer from other age-related 

diseases and conditions, such as high blood pressure, cerebrovascular disease, or diabetes. Researchers are learning 

that these “co-morbid” conditions may increase the risk of 

AD and speed its clinical progression. For example, there 

is now a growing body of evidence that the cellular 

abnormalities associated with vascular disease feed into 

and exacerbate those associated with AD. Researchers are 

exploring in clinical trials whether the therapeutic interventions known to reduce risk of heart disease and diabetes may also reduce risk of AD. Reports published in 
| Executive Summary 

2009 suggest that the Mediterranean diet, exercise, and 

controlling high blood pressure may be associated with 

reduced risk of AD. (See the sections Links with Other 

Diseases, page 14; Interactions Between AD and Vascular 

Disease, page 28; and AD Clinical Trials, page 38.) 

This Progress Report highlights key 2009 Alzheimer’s disease 


research findings and activities supported by public funding.
 

Cognitive Exercise and 

Successful Cognitive Aging 

The popularly held belief that brain exercise can 

improve cognitive function in older people is now being 

tested. In two different clinical trials, significant cognitive performance gains were seen in people over 65 who 

received training interventions aimed at improving 

either attention or speed and accuracy of verbal information processing. (See Clinical Trials to Maintain or 

Improve Cognitive Function with Age, page 46.) However, 

as in previous trials, there was no evidence that training 

in one dimension improved function in another, so 

questions remain about the overall usefulness of this 

type of training in real-world settings. 

AD Is Not Just a Memory Disorder 

Our view of AD is undergoing a transformation. In the 

past, AD was seen primarily as a memory disorder, and 

intervention focused on memory symptoms. However, 

mood and behavioral problems, such as depression, anxiety, and displays of socially inappropriate behavior, are 

increasingly recognized as co-occurring conditions with 

AD. Mood and behavioral disturbances also appear to 

be associated with more rapid progression from mild 

cognitive impairment (MCI) to dementia, and early 

treatment of these symptoms may help slow that 

progression. For example, treatment with the drug 

donepezil reduced the risk of progression to AD 

among MCI patients with depressive symptoms. 

(See the sections Other Early Signs and Symptoms, page 

32, and Slowing progression to AD in people with MCI 

and depression, page 39.) 

Sleep and AD 

AD may also be linked to sleep problems. Many people 

with AD suffer from sleep disturbances, which can contribute to cognitive impairment through a variety of 

mechanisms. Researchers are starting to study the possibility that therapeutic interventions to improve sleep 

quality may help alleviate some symptoms of AD. (See 

the sections Amyloid and Sleep, page 17, and Treatment 

of sleep apnea may slow cognitive decline, page 39.) 

AD Caregiving 

Two clinical trials, REACH I and REACH II, were previously funded to develop and test strategies for helping 

caregivers manage the stress and emotional burden of 

caring for people with dementia. The REACH OUT 

Program is beginning to implement these strategies 

through local social service agencies. The first such study 

showed a significant improvement in caregivers’ sense of 

burden, social support, depression, and health, as well as 

in care recipients’ behavior problems and mood. (See 

Supporting AD Caregivers, page 51.) 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 8 ’
 

 

 

 

 

 

| Executive Summary 

Recovery Act funds Advance 

Research on Ad and Age-Related 

Cognitive decline 

In 2009, the American Recovery and 

Reinvestment Act (ARRA) provided a 

novel opportunity to spark additional 

Alzheimer’s disease research. NIA targeted promising areas of research in 

awarding more than 100 Alzheimer’s or 

Alzheimer’s-related ARRA research grants, 

totaling $77 million. Projects conducted 

within a short timeframe (2009-2010) included both new 

and ongoing studies to understand the biological mechanisms of the disease, identify additional risk-factor genes 

associated with Alzheimer’s, improve diagnostic tools, find 

biomarkers, develop therapies, conduct clinical trials, and 

explore preventive measures. ARRA funding also provided 

an opportunity to support research on age-related cognitive 

decline, a condition even more prevalent than AD in the 

older population. 

Basic Research 

Basic research to better understand the development and 

progression of AD will lay the foundation for new prevention and treatment interventions. ARRA-supported 

researchers are: 

n Investigating how AD and vascular disease may influence and exacerbate one another. Findings may suggest 

strategies for preventing dementia. 

Investigating how amyloid, a protein implicated in 

AD brain changes, contributes to the formation of clots 

in the brain and blood vessels. 

Examining how energy metabolism influences brain 

aging by looking for correlations among the loss of brain 

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volume, metabolic measures, and dementia status in 

aging and in people with AD. 

Genetic and Other Risk Factors 

The ability to identify people at risk for AD is increasingly important as preventive measures are developed 

and as we learn more about how those at risk may 

reduce their odds of developing the disease. ARRAsupported investigators are: 

n Using genome-wide association studies to compare 

the entire genomes of individuals with and without the 

disease to identify potential genetic risk factors for cognitive decline and AD. 

Investigating whether changes to the brain “histone 

code,” which helps determine the activity of specific 

genes, can mediate the effect of life experiences on the 

development of age-related cognitive decline and AD. 

Exploring the association of AD with vascular risk 

factors (e.g., high blood pressure), markers of inflammation, and pathology pathways in diverse populations. 

Biomarkers for Detection and Diagnosis 

Research suggests that the earliest AD damage begins to 

develop in the brain long before clinical symptoms 

appear. Finding ways to diagnose AD as early as possible 

is critical so that researchers can test interventions and, 

ultimately, treat the disease as early as possible. ARRAsupported investigators are: 

n Building on the highly successful ADNI to determine 

the clinical, cognitive, imaging, genetic, and biochemical 

biomarker characteristics of MCI, often a precursor to AD. 

Identifying best practices for collecting samples of CSF 

and its analysis for proteins that may be associated with 

AD onset and progression, with the goal of identifying 

biomarkers that appear before cognitive symptoms do. 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 9 
 

| Executive Summary 

The American Recovery and Reinvestment Act (ARRA) provided a 

novel opportunity to spark additional Alzheimer’s disease research. 

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Comparing the effectiveness of brain imaging and 

blood biomarkers to diagnose AD. 

Possible Prevention and 

Treatment Strategies 

ARRA-supported investigators are studying a range of 

potential strategies to prevent MCI or AD. This research 

includes: 

n Evaluating the drug levetiracetam in a clinical trial as 

a treatment for MCI, potentially preventing progression 

to AD by reducing the hyperactivity of neurons in the 

hippocampus, a part of the brain important to learning 

and memory. 

Evaluating the effects of exercise in combination with 

two dietary supplements—the omega-3 fatty acid DHA 

and curcumin—on AD biomarkers and cognition in an 

animal model. 

Testing whether blocking a key inflammation 

pathway alleviates the consequences of high cholesterol 

on the brain in mouse models of AD. High cholesterol 

is believed to increase AD risk by triggering inflammation pathways that ultimately damage brain cells. 

Studying how the outer shell, or capsid, of certain 

viruses might be used to carry protective or therapeutic 

molecules into the brains of AD patients. This early 

work is being carried out in a mouse model of AD and, 

if successful, might be used in other neurodegenerative 

diseases as well. 

Studying the drug methylphenidate as a treatment for 

apathy, one of the most common behavioral symptoms 

of AD and one for which there is currently no effective 

treatment. 

Closely following participants who were enrolled in 

the Alzheimer’s Disease Anti-inflammatory Prevention 

Trial (ADAPT) to assess the long-term effects of 

naproxen and celecoxib on cognitive health. 

Understanding Normal Aging and 

Preventing Loss of Cognitive Function 

A growing body of evidence suggests that various interventions may exert a protective effect on the brain in 

older age, but little is known about the underlying 

mechanisms and more intervention testing is needed. 

ARRA-supported researchers are working to: 

n Understand the role that neurotrophic factors (proteins that promote the development of new neurons and 

the repair of damaged ones) play in healthy and 

abnormal brain aging. Animal and human studies have 

shown that circulating levels of neurotrophic factors 

increase with exercise and also with a calorie-restricted 

diet or one rich in fruits and vegetables. 

Elucidate the neural mechanisms that contribute to 

robust age-related decline in prospective memory—the 

act of remembering to carry out an intention such as 

sending a grandchild a birthday card, paying bills on 

time, or taking needed medication. 

Develop automated technologies to map functional 

activity of brain networks, which will help expand our 

understanding of the neural basis of episodic and 

semantic memory and how this function changes with 

normal aging. 

Test a home-technology based cognitive health 

coaching approach to improve function and quality of 

life for older adults. 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 10 ’
 

 

 

 

 

 

 

 

A Brief Primer on 

Alzheimer’s Disease 

and theBrain 

The healthy human brain is made up of tens of billions of neurons that 

are connected through chemical and 

electrical signals. The function of these 

neurons is supported and regulated by 

other brain cells, called glial cells, and by 

the brain’s rich supply of blood vessels. A 

typical neuron has a cell body, an axon, 

and many dendrites. The cell body contains the cell’s nucleus. As in other cell 

types, the nucleus contains the neuron’s 

genetic blueprint and helps regulate 

changes in the neuron’s activity, metabolism, and structure in response to signals 

from outside and inside the cell. The axon 

is a cable-like structure that extends from 

one end of the neuron’s cell body and 

transmits messages to other neurons. 

Dendrites are branch-like structures that 

radiate from the other side of the neuron’s cell body and receive messages 

from the axons of other neurons. 

View a short video 

showing the progression 

of Alzheimer’s disease 

in the brain. 

The function and survival of neurons 

depends on several interdependent 

processes: 

n Communication. When a neuron 

receives enough messages from surrounding cells, an electrical charge is 

generated that travels from the cell body 

to the end of the axon. There, it triggers 

the release of chemicals called neurotransmitters that move across a gap, or 

synapse, to the dendrites of neighboring 

neurons. The neurotransmitters bind to 

specific receptor sites on the dendrites of 

neighboring neurons, triggering chemical 

or electrical changes in those neurons. In 

some cases, neurotransmitter binding 

stimulates a neuron. In others, it inhibits 

the neuron’s activity. Scientists estimate 

that at any one time the average neuron 

makes 7,000 synaptic connections to 

other neurons. 

Metabolism. This process encompasses all the chemical reactions that 

take place in the cell. These reactions 

require chemical energy in the form of 

oxygen and glucose, which is supplied by 

the brain’s blood circulation. The brain 

has an exceptionally high energy demand 

and so has one of the richest blood supplies of any organ. 

Repair. Unlike many short-lived cells 

in the body, neurons have evolved to live a 

long time—more than 100 years in 

humans—so they must constantly maintain and repair themselves. Neurons also 

continuously remodel themselves—for 

example, by breaking down synaptic connections with one neighboring neuron and 

forming new ones with a different neighbor. 

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how does Ad Affect 

the Brain? 

In healthy aging, most types of brain neurons are not lost in large numbers. In AD, 

however, where damage is widespread, 

many neurons stop functioning, lose connections with other neurons, and die 

because communication, metabolism, and 

repair are disrupted. 

At first, AD typically destroys neurons 

and their connections in parts of the brain 

that control memory, including the entorhinal cortex and the hippocampus. It 

later attacks areas in the cerebral cortex 

responsible for language and reasoning. 

Eventually, many other areas of the brain 

are damaged, and a person with AD 

becomes helpless and unresponsive to 

the outside world. 

What Are the Main 

Characteristics of the 

Ad Brain? 

Many changes take place in the brain of 

a person with AD. Some of these changes 

can be observed under the microscope 

after death. The three abnormalities most 

evident in the brains of people who have 

died with AD are: 

n Amyloid plaques. Found in the 

spaces between neurons, plaques consist 

of largely insoluble deposits of a protein 

fragment called beta-amyloid, which is 

generated from a protein called amyloid 

precursor protein (APP). Plaques also 

contain other proteins, remnants of 

degenerating neurons and glia, and other 

cellular material. Scientists used to think 

that amyloid plaques were the primary 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 11 
 

 

 

 

 

 

 

 

 

 

 

 

| A Brief Primer on Alzheimer’s Disease and the Brain 

cause of the damage to neurons seen in 

AD. Now, however, many think that more 

soluble forms of beta-amyloid, seen earlier in the plaque formation process, may 

be the major culprits. 

n Neurofibrillary tangles. Found 

inside neurons, neurofibrillary tangles 

are abnormal aggregates of a protein 

called tau. Healthy neurons are internally 

supported in part by structures called 

microtubules, which help guide nutrients 

and molecules from the cell body to the 

end of the axon. Normally, tau binds to 

microtubules and helps stabilize them. In 

AD, tau undergoes abnormal chemical 

changes that cause it to disengage from 

microtubules and come together with 

other threads of tau, eventually forming 

neurofibrillary tangles. The microtubules 

disintegrate, and the neuron’s transport 

system collapses. As with beta-amyloid, 

some scientists think that early soluble 

forms of abnormal tau may cause the 

most damage to neurons. 

Loss of neuronal connections and 

cell death. In AD, the synaptic connections between certain groups of neurons 

stop functioning and begin to degenerate. 

This feature of AD likely results from the 

accumulation of beta-amyloid and 

abnormal tau. When neurons lose their 

connections, they cannot function properly 

and eventually die. As neuronal injury and 

death spreads through the brain, connections between neurons break down, and 

affected regions begin to shrink in a process called brain atrophy. By the final 

stage of AD, damage is widespread, and 

brain tissue has shrunk significantly. 

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Healthy neuron Dying neuron 

What Causes Ad? 

In some rare cases, people develop AD in 

their 40s or 50s. This form of the disease, 

called “early-onset” AD, often runs in families and is caused by a mutation in one of 

three genes that a person has inherited 

from a parent. The causes of other earlyonset cases are not yet understood. 

More than 90 percent of AD cases 

occur in people older than 60. The development and pathology of this “late-onset” 

form of the disease are very similar to 

those of early-onset AD. The causes of 

late-onset AD are not yet completely 

understood, but they probably include a 

combination of genetic, environmental, 

and lifestyle factors. The importance of 

any one of these factors in increasing or 

decreasing the risk of developing AD may 

differ from person to person. 

Much basic research in AD has 

focused on the genes that cause earlyonset AD, and how mutations in these 

genes disrupt cellular function and lead to 

disease. Scientists hope that what they 

learn about early-onset AD can be applied 

to the late-onset form of the disease. 

Perhaps the greatest mystery is why 

AD largely strikes people of advanced 

age. Why does it take 60 to 80 years or 

more for people to develop signs of the 

disease? Research on how the brain 

changes normally as people age will 

answer this important question, as will 

studying the disease itself. 

how Is Ad diagnosed? 

Clinicians use a range of tools to diagnose “possible AD” (dementia that could 

be due to another condition) or “probable 

AD” (no other cause of dementia can be 

found). Some people with memory problems have a condition called amnestic 

mild cognitive impairment (MCI) that often 

precedes AD. People with MCI have more 

memory problems than normal for people 

their age, but their symptoms are not as 

severe as those seen in AD. Importantly, 

not all people with MCI develop AD. 

Tools for diagnosing AD include a medical history, a physical exam and tests— 

preferably over time—that measure 

memory, language skills, and other abilities 

related to brain functioning. The physician 

may also perform a brain scan. Information 

provided by family members or other caregivers about changes in a person’s day-today function and behavior also help in 

diagnosis. At this time, AD can be diagnosed conclusively only by an autopsy of 

the brain after death. However, in specialized research facilities such as the NIAfunded Alzheimer’s Disease Centers, 

clinicians can diagnose AD in a living 

person with up to 90 percent accuracy. 

Early, accurate diagnosis is crucial 

because it tells people whether they have 

Alzheimer’s or whether their symptoms are 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 12 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

| A Brief Primer on Alzheimer’s Disease and the Brain 

caused by something else. Stroke, tumor, 

Parkinson’s disease, sleep disturbances, or 

side effects of medications are all known 

to affect cognitive function and memory, 

and some of these conditions are reversible. When AD is diagnosed, knowing early 

on can help families plan for the future 

while the person with AD can still participate in making decisions. Researchers are 

developing increasingly accurate diagnostic tests for telltale biomarkers that may 

one day be used in general medical practice to detect the disease before memory 

loss or cognitive impairment is evident. 

how Is Ad treated? 

Only a few medications have been 

approved by the U.S. Food and Drug 

Administration (FDA) to help control the 

cognitive loss that characterizes AD. 

Donepezil (Aricept®), rivastigmine 

(Exelon®), and galantamine (Razadyne®, 

formerly known as Reminyl® and now 

available as a generic drug) are prescribed 

to treat mild to moderate AD symptoms. 

Donepezil also is approved to treat severe 

AD. These drugs act by stopping or slowing the action of acetylcholinesterase, an 

enzyme that breaks down acetylcholine (a 

neurotransmitter that helps in memory 

formation). The drugs maintain some 

patients’ abilities to carry out everyday 

activities and may slow down symptoms 

related to thinking, memory, or speaking 

skills. They also may help with certain 

behavioral symptoms. However, they do 

not stop or reverse AD and appear to help 

patients only for months to a few years. 

Another type of medication, memantine (Namenda®), is prescribed to treat 

moderate to severe AD symptoms. 

This drug appears to work by blocking 

receptors for glutamate, another 

neurotransmitter involved in memory 

function. Studies in animals suggest that 

memantine may have disease-modifying 

effects, although this has not yet been 

demonstrated in humans. 

In addition to these medications, physicians may use other drugs and nondrug 

approaches to treat behavioral and psychiatric problems associated with AD. 

These problems include agitation, verbal 

and physical aggression, wandering, 

depression, sleep disturbances, and delusions. (It is important to note, however, 

that since no drugs are specifically 

approved by the FDA to treat behavioral 

or psychiatric symptoms in dementia, this 

practice constitutes “off-label” usage.) 

nIA’s AdEAR Center offers free Ad Information and Resources 

Efforts to educate and inform people with AD, their families, the public, providers, and others 

interested in the disease complement NIH’s research initiatives. 

The NIA Alzheimer’s Disease Education and Referral (ADEAR) Center provides free information and publications for families, caregivers, and professionals on research, diagnosis, treatment, 

patient care, caregiver needs, long-term care, and education and training related to AD. For example, 

the publication Alzheimer’s Disease: Unraveling the Mystery explains the disease, highlights ongoing 

research, and describes efforts to support caregivers of people with AD. An animated companion video brings to life the latest 

knowledge about AD and the brain. 

Other ADEAR Center publications include Can Alzheimer’s Disease be Prevented?, which summarizes the latest research 

findings on AD risk factors and potential prevention strategies, and Caring for a Person with Alzheimer’s Disease: Your Easyto-Use Guide from the National Institute on Aging, which provides caregiving information and advice. ADEAR fact sheets cover 

a variety of topics, including basic information, AD genetics, and participating in AD clinical trials and studies. Many ADEAR 

publications also are available in Spanish. 

ADEAR staff members answer telephone, email, and written requests and can suggest local and national resources. In 

addition, the ADEAR Center website offers email alerts, the online Connections newsletter, an AD clinical trials database, and 

the AD Library database. 

To read and order these publications, view the AD video, and take advantage of many other resources, visit the ADEAR 

Center at www.nia.nih.gov/Alzheimers or call the Center toll-free at 800-438-4380. 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 13 ’
 

 

 

 

 

Research Advances
 

The NIH scientific portfolio for AD covers a wide 

range of disciplines and research programs. In 

2009, NIH-supported researchers forged new 

understanding of the disease that could lead to future 

breakthroughs in how to prevent, treat, and cope with its 

impact. The following pages highlight important findings 

and explore their potential relevance to the field. 

1 Recognizing the 

Scope of Ad 

A first step toward curing or preventing a disease is to 

get a clear picture of how the disease appears in individuals and across large populations. Critical questions for 

physicians, research scientists, and public policy makers 

involved in AD treatment and prevention include: How 

widespread (or prevalent) is the disease? Is it more or less 

common in certain populations? What is the relationship of AD to other chronic or age-related diseases? 

How is it different from normal cognitive aging? 

Prevalence of Dementia 

As the average age of the U.S. population rises, developing 

a reliable estimate of the current and future prevalence 

of AD becomes increasingly urgent. Knowing how many 

people have or are likely to develop AD can help manage 

private and public health resources in the coming years. 

For example, the number of people living to 100 or 

beyond is expected to be 15 times greater in 50 years 

than it is today. Since the risk of AD increases with age, 

pertinent questions are: What proportion of centenarians will be affected by AD? How many more relatives 

will be impacted? 

Data are available on the current prevalence of AD 

in a number of communities and on a national level, 

but specific data are lacking for the over-97 age group, 

or “oldest old,” living in rural communities. Compared 

with those living in and near cities, people living in rural 

communities are relatively isolated and may have different lifestyles, decreased access to some resources, and 

potentially different rates of dementia. Researchers at 

Oregon Health & Science University in Portland assessed 

dementia prevalence in a sample of people aged 97 or 

older living in the Klamath Basin, a large rural region in 

southern Oregon (Kaye et al., 2009). The study showed 

this population to be within the typical range for people 

of advanced age. Sixty-one percent of the sample had 

dementia, 29 percent suffered from MCI, and 10 percent 

were still cognitively intact. Better understanding of factors that enable nearly 40 percent of people age 97 and 

older to remain dementia-free could help identify strategies for preventing progress to dementia in younger elders. 

Additional advance in estimating prevalence: 

n Wilson et al. (2009a) Biracial population study of mortality in 

mild cognitive impairment and Alzheimer disease. Rush 

Alzheimer’s Disease Center. Supported by NIA and NIEHS. 

Links with Other Diseases 

Plaques and tangles are usually the most obvious disease 

features seen under the microscope in brain tissue from 

deceased AD patients. However, individuals diagnosed 

with AD also often suffer from other diseases affecting 

the brain, such as vascular disease. In a postmortem 

study of 349 people who had been diagnosed before 

death with either AD or MCI, neuropathologists at the 

Rush University Alzheimer’s Disease Center in Chicago, 

IL, found evidence of other disease processes in almost 

half of the AD brains and 20 percent of the MCI brains 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 14 
| Research Advances 

n

n

n

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 15 ’

(Schneider JA et al., 2009). Most common were microinfarcts—small spaces in brain tissue where cells have 

died due to blockage of blood vessels that once nourished them—which are associated with cerebrovascular 

disease.The next most common disease signature was 

Lewy bodies in the cortex. Lewy bodies are abnormal 

clumps of protein often found in the brains of older 

people that differ in structure and composition from 

plaques and tangles. They are associated with dementia 

with Lewy bodies, and are also found in the brains of 

people with Parkinson’s disease. 

A key finding was that people whose brains showed 

“mixed” disease (plaques and tangles plus microinfarcts, 

for example) were more cognitively impaired when they 

died than those whose brains contained only comparable 

levels of plaques and tangles. Microinfarcts and Lewy 

bodies may compound the negative effects of plaques 

and tangles on neural function, so that fewer plaques 

and tangles are required to produce noticeable cognitive 

decline. This study highlights the need to understand 

how other disease processes contribute to brain dysfunction in people diagnosed with AD. In addition, the 

finding that microinfarcts seem to exacerbate the negative impact of plaques and tangles on neural function is 

consistent with increasing evidence of overlap between 

risk factors for AD and vascular disease (see Interactions 

Between AD and Vascular Disease, page 28). 

Diabetes is another disease that often coexists with 

AD in older adults. Neuropathologists at the University 

of Washington in Seattle found that the brains of people 

who had died with diabetes and dementia had more 

neuroinflammation and more microinfarcts than those 

with dementia alone (Sonnen et al., 2009). This finding 

is not surprising, given that diabetes is a risk factor for 

cerebral atherosclerosis (accumulation of fatty deposits 

inside brain blood vessels that restrict or block blood 

flow). Interestingly, the people who had diabetes in 

addition to dementia actually carried less amyloid on 

average at the time of their deaths than did nondiabetics 

with dementia. The brains of nondiabetics with dementia also had higher levels of free radical damage. These 

different patterns of injury suggest different underlying 

mechanisms of pathology and may have implications 

both for mechanisms of disease development and 

possible therapies. 

Is AD more or less common in certain populations? 


What is the relationship of AD to other chronic or age-related diseases?
 

2 deciphering 

Ad Biology 

Scientists believe that the accumulation of beta-amyloid 

fragments around neurons and blood vessels interferes 

with communications between cells. This communication breakdown is followed by loss of synapses and 

death of neurons (see A Brief Primer on Alzheimer’s 

Disease and the Brain, page 11). Much research has 

focused on exactly how beta-amyloid disrupts intercellular communication. Key questions to be answered 

include: 

n With which molecules does beta-amyloid interact at 

the synapse? 

With which specific cellular processes does betaamyloid interfere? 

Which brain “circuits” (systems of interconnected 

neurons) are most affected by beta-amyloid and why? 

What mechanisms support normal cognitive function 

in older individuals who also display substantial levels of 

brain amyloid? 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

| Research Advances 

There is also increasing research interest in apparent 

points of overlap between cellular and molecular 

changes occurring in AD and in “normal” brain aging. 

Synaptic Dysfunction 

How beta-amyloid interferes with 

memory formation 

One mechanism the brain uses to store memories is a process called “long-term potentiation” (LTP). LTP is a 

strengthening of the synaptic connection between two neurons that allows the second neuron to fire more readily. This 

process is thought to contribute to memory formation. 

Beta-amyloid has been shown to interfere with this 

process. Understanding how it does might reveal potential 

molecular targets for AD drug development. In particular, 

researchers would like to identify the proteins involved in 

LTP-beta-amyloid interactions. Reports from the 

University of Southern California Alzheimer’s Disease 

Research Center, State University of New York at Buffalo, 

and Harvard University identified three different synaptic 

proteins interacting with beta-amyloid (Williams et al., 

2009; Gu et al., 2009; Li et al., 2009). All three are 

involved in signaling by the neurotransmitter glutamate. 

Another study suggests an alternative or additional 

beta-amyloid “receptor”: cellular prion protein (PrPc). 

Prion protein in its abnormal form causes mad cow disease 

in cattle and Creutzfeldt-Jacob disease in humans. Scientists 

at Yale University in New Haven, CT, supported by NIA 

and NINDS found that beta-amyloid binds to hippocampal nerve-cell membranes at or near sites where PrPc is 

found. Moreover, binding to PrPc appears to be necessary 

for beta-amyloid to disrupt LTP (Laurén et al., 2009). If it 

is ultimately shown that PrPc is the receptor through which 

beta-amyloid binds to nerve cells and disrupts LTP, then 

drugs that block beta-amyloid binding to PrPc could be 

pursued aggressively as potential AD therapeutics. 

Beta-amyloid and synapse loss 

Beta-amyloid appears not only to disrupt LTP, but to cause 

the collapse of dendritic spines (specialized protrusions on 

the surfaces of dendrites that receive input from other neurons). Loss of dendritic spines is evident around amyloid 

plaques in both human AD and transgenic mouse models 

of AD. Scientists at the Massachusetts General Hospital 

Alzheimer’s Disease Research Center in Boston sought to 

discover whether this loss is caused by the plaque itself or 

by soluble beta-amyloid shed from the plaque. Using a new 

microscopic imaging technique, the researchers were able to 

see amyloid plaques and nearby dendritic spines in greater 

detail than had previously been possible. They discovered 

that plaques are surrounded by halos of soluble betaamyloid, and that spines first begin to collapse upon contact with these halos (Koffie et al., 2009). Thus, plaques 

may serve as a reservoir for soluble beta-amyloid, which in 

turn triggers collapse of spines and loss of synaptic contacts. 

Other advances related to synaptic dysfunction: 

n López-Hernández et al. (2009) Positive modulation of alpha 7 

n AChR responses in rat hippocampal neurons. University of 

Florida. Supported by NIA and NIGMS. 

n Polydoro et al. (2009) Age-dependent impairment of cognitive 

and synaptic function in the htau mouse model of tau pathology. 

Albert Einstein College of Medicine. Supported by NINDS. 

n Sun et al. (2009) Imbalance between GABAergic and glutamatergic transmission impairs adult neurogenesis in an animal 

model of Alzheimer’s disease. University of California, San 

Francisco. Supported by NIA, NINDS, and NCRR. 

Selective Neuronal Death 

AD affects neurons sooner and more severely in certain 

brain regions than in others. Particularly vulnerable are 

neurons in the entorhinal cortex, hippocampus, and certain other cortical regions. A key question is, Why are 

neurons in certain regions especially vulnerable to AD? 

In some cases, it may be because these neurons experience higher-than-average levels of functional activity (see 

Cortical “Hubs” and Amyloid, page 17). 

Neurons may also be more affected in AD because 

they synthesize certain proteins that render them vulnerable. An example is neurons in the basal forebrain, a 

brain region severely affected in AD. These neurons synthesize high levels of a receptor for nerve growth factor, 

which usually helps ensure their survival. However, 

investigators at the Buck Institute for Age Research in 

Novato, California, supported by NIA and NINDS, 

showed that when the receptor is bound by APP, two 

toxic events take place: the APP is cleaved into betaamyloid, and neurons die (Fombonne et al., 2009). 

Additional advance related to selective neuronal death: 

n Robertson et al. (2009) Amyloid-beta expression in retrosplenial 

cortex of triple transgenic mice: relationship to cholinergic axonal 

afferents from medial septum. University of California, Irvine. 

Supported by NIA and NINDS. 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 16 
| Research Advances 

Cortical “hubs” and Amyloid 

I

f there were a map of the neural con

nections within the brain’s cortex, it 

would look something like an airline 

route map, with airport “hubs” such as 

Atlanta, Chicago, and Dallas serving many 

different routes and showing much higher 

activity levels than other points in the sys

tem. Human brain hubs include hot spots in 

several regions of the cortex. They can be 

observed using functional magnetic reso

nance imaging (fMRI), an imaging technique 

that monitors levels of nerve-cell activity in 

different brain regions. Some cortical hubs 

are busier when a person is at rest, others 

when a specific task is being performed. 

Researchers at Harvard University 

compared patterns of this activity to patterns of amyloid deposition in people with 

­

­

­

AD. They found that the regions of highest 

amyloid accumulation coincided with the 

locations of highly active cortical hubs 

(Buckner et al., 2009). The study suggests that these amyloid-associated hubs 

are active both at rest and during task 

performance, consistent with mounting 

evidence that the presence and deposition of amyloid is associated with high 

neuronal activity levels. 

Like airline route maps, the human brain has “hubs” in several regions of the cortex. 

Amyloid and Sleep 

The idea that amyloid deposition is correlated with high 

levels of neuronal activity has received further support 

from a study showing increased beta-amyloid deposition 

after sleep deprivation. Active neurons are known to 

secrete beta-amyloid into the fluid surrounding them. 

Investigators at Washington University in St. Louis, supported by NIA, NINDS, and NIMH, measured betaamyloid levels in AD model mice at different points in 

the sleep-wake cycle. They found levels to be highest at 

the end of the wakeful period and decreased during 

sleep (Kang et al., 2009). A similar pattern was seen for 

beta-amyloid levels in the CSF of human volunteers (10 

young healthy males). Additional studies in AD model 

mice showed that beta-amyloid levels and plaque deposition were increased by chronic sleep deprivation and by 

orexin, a neurohormone that promotes wakefulness. 

Treating mice with a drug that blocks orexin receptors 

blocked the daily rise in beta-amyloid. 

The possibility that chronic sleep deprivation exacerbates amyloid deposition is especially interesting given 

evidence that sleep disturbances, such as sleep apnea, are 

common in the elderly and cause damage to certain 

brain regions. This study provides further impetus for 

testing whether measures that promote healthy sleep also 

reduce risk of brain dysfunction and AD. (Read about a 

sleep apnea treatment study, page 39.) 

Additional advance related to amyloid and sleep: 

n O’Hara et al. (2009) Sleep apnea, apolipoprotein epsilon 4 

allele, and TBI: mechanism for cognitive dysfunction and development of dementia. Sierra-Pacific Mental Illness Research, 

Education, and Clinical Center (MIRECC), Stanford University. 

Supported by NIMH. 

Cellular Energy Deficits 

Neurons need exceptionally high levels of energy to 

support their signaling. Indeed, although the brain 

represents only about 2 percent of the body weight of 

an average adult human, it uses about 20 percent of the 

body’s energy. Neurons are also especially sensitive to 

energy deficits. Failures in energy-generating mechanisms that occur as neurons age may contribute to the 

development of AD. 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 17 ’
| Research Advances 

Mitochondrial fission and fusion 

Often called the cellular “powerhouses,” mitochondria 

are responsible for energy production. Mitochondria are 

highly dynamic—they move around inside cells and can 

fuse with one another or break apart into smaller pieces 

(fission). If the balance between mitochondrial fusion 

and fission tips too much toward fission, the result is 

abnormally small, malformed mitochondria that may 

not function properly. Such abnormal mitochondria 

have been observed in the brains of people with AD. 

Researchers at Case Western Reserve University in 

Cleveland, OH, found that the proteins responsible for 

mitochondrial fission and fusion are abnormally regulated in the AD brain. They also found that applying 

beta-amyloid to rat hippocampal neurons caused the 

mitochondria in the neurons’ dendrites to break apart 

(Wang X. et al., 2009). Thus, abnormal mitochondrial 

dynamics may be a link between beta-amyloid and synaptic degeneration. 

In related work, a research team at the Burnham 

Institute for Medical Research in La Jolla, California, 

supported by NICHD, NEI, NIEHS, and NINDS, 

showed that nitric oxide (NO), thought to be a key 

mediator of beta-amyloid’s neurotoxic effects, stimulates 

the activity of an enzyme that accelerates mitochondrial 

fission (Cho et al., 2009). Drugs that inhibit activity of 

this fission-accelerating enzyme might therefore be useful to explore as a possible therapeutic for AD. 

Changes in brain metabolism in 

normal aging and AD 

Since age is the best known risk factor for AD, it seems 

likely that some of the cellular changes that occur with 

aging contribute to the development of AD. One such 

change, depressed mitochondrial function, was examined by scientists at the University of Southern 

California in Los Angeles, supported by NIA and 

NIMH. The researchers investigated the possible link 

between mitochondrial dysfunction and events in the 

AD disease pathway using a mouse model of AD. They 

found an age-dependent decline in mitochondrial function in both normal and AD model mice, which preceded the onset of amyloid plaque formation (Yao et al., 

2009). Thus, mitochondrial dysfunction might contribute to amyloid deposition, as well as vice versa. 

Another finding also points to the impact of normal 

aging and AD on cellular energy production. While 

nerve cells usually use glucose as their main energy 

source, researchers at the University of Kentucky in 

Lexington, studying the brains of aging rats, observed a 

shift to other fuel sources, such as fats and amino acids. 

This metabolic shift was accompanied by the breakdown 

of myelin, the fat- and protein-rich sheath that insulates 

axons. The earliest stages of cognitive impairment in rats 

coincided with the changes in myelin metabolism. The 

investigators hypothesize that these processes damage 

neuron structure and deplete energy needed for cell-tocell signaling (Kadish et al., 2009). 

Insulin-like growth factor-1 (IGF-1) is a hormone 

that promotes cell growth. The brain IGF signaling 

pathway also appears to be involved in aging, as blocking this pathway prolongs lifespan in organisms ranging 

from worms to mammals. The pathway may also contribute to AD. Investigators at the Salk Institute for 

Biological Studies in La Jolla, CA, discovered that reducing IGF signaling in AD model mice prevented the 

development of AD-like disease symptoms, including 

brain inflammation, behavioral impairment, and neuronal death. Of great interest, the beta-amyloid plaques in 

the brains of these mice differed from those normally 

seen in AD: the fibrils making up the plaques were more 

orderly and tightly packed than usual. These more 

tightly packed beta-amyloid aggregates are less likely to 

shed the soluble form of beta-amyloid, and are therefore 

less likely to be toxic to neurons (Cohen E. et al., 2009). 

Additional advances in brain metabolism, normal aging, 

and AD: 

n Bishop et al. (2009) Review: Neural mechanisms of ageing and 

cognitive decline. Harvard University. 

n Cohen AD et al. (2009b) Basal cerebral metabolism may modulate 

the cognitive effects of Abeta in mild cognitive impairment: an example of brain reserve. University of Pittsburgh. Supported by NIA. 

n Salthouse, TA. (2009) Review: When does age-related cognitive 

decline begin? University of Virginia. 

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| Research Advances 

Brain Amyloid an Early Warning Sign of Possible 

Cognitive decline in “normal” Individuals 

The year 2009 saw intense investiga

tion of the relationship between 

brain amyloid deposits and cognitive 

function. It has been known for many years 

that some cognitively normal individuals had 

high levels of brain amyloid at autopsy. More 

recently, methods became available for imag

ing amyloid in the brains of living people using 

positron emission tomography (PET) and 

radioactive Pittsburgh Compound B (PiB) as an 

amyloid marker. Subsequent imaging studies 

supported by NIA and NIMH funding at the 

University of Pittsburgh, Mayo Clinic, and 

Banner Alzheimer’s Institute produced an 

important result: Amyloid deposits were found 

in the brains not only of people with MCI and 

AD, but also in some older people who were 

cognitively normal (Aizenstein et al., 2008; 

Jack et al., 2009; Reiman et al., 2009). In fact, 

the percentage of nondemented older adults 

with significant levels of brain amyloid ranged 

from 20 to 50 percent in different studies. 

Questions to Explore 

These findings opened the door to explor

ing the future implications of differences 

in amyloid levels among cognitively nor

mal people. Could some older people who 

have high brain amyloid nonetheless 

maintain good cognitive function for 

decades to come? Or, if one scrutinized 

these apparently normal people more rig

orously, would they show the very earliest 

signs of cognitive loss and eventually 

develop AD? The weight of evidence from 

studies supports the second scenario. 

Many cognitively normal people with high 

brain amyloid levels exhibit other abnor

malities associated with cognitive decline. 

Further longitudinal studies will be needed 

to distinguish between those who will 

progress and those who will not. 

Imaging of neuronal activity patterns 

in individuals with high levels of brain 

amyloid in three studies at Washington 

University, Harvard University, and 

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­

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­

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­

Massachusetts General Hospital indicated 

abnormalities in the brain’s “default net

work,” a system of brain regions that is 

most active when a person is not perform

ing a task, but rather focused inward (e.g., 

during daydreaming, envisioning or plan

ning the future, or recollecting the past) 

(Sheline et al., 2010; Sperling et al., 2009; 

Hedden et al., 2009). The pattern of net

work disruption seen in these cognitively 

normal, high amyloid load-bearing individ

uals is similar to that seen in people with 

clinical AD. It involves cortical “hubs” that 

participate in memory formation (see 

Cortical “Hubs” and Amyloid, page 17). 

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­

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PiB-PET Scans Key 

Most importantly, several studies in 2009 

found that cognitively normal people with 

high amyloid loads were more likely to 

suffer eventual cognitive decline than 

peers with low amyloid levels. For exam

ple, one research team at the Washington 

University Alzheimer’s Disease Research 

Center (ADRC) in St. Louis, MO, longitudi

nally studied 135 cognitively normal 

people who had annual cognitive testing 

starting in 1985 and PiB-PET scans start

ing in 2004. All of these individuals scored 

within the normal range on cognitive tests 

when they first entered the study. PiB-PET 

scans showed that 29 participants had 

high brain amyloid loads. This group also 

showed shrinkage of brain areas typically 

affected by AD, as seen in MRI scans, and 

declining performance on visuospatial, 

episodic, and working memory tasks over 

time (Storandt et al., 2009). 

In a related study, the Washington 

University ADRC showed that positive PiBPET scans at baseline were predictive of 

developing very mild AD but not of other 

causes of dementia up to 5.5 years later 

(Morris et al., 2009). This study was limit

ed by the small number of people who 

developed AD and the short followup time. 

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Together, the studies suggest the following sequence of disease events in AD: 

n Amyloid deposition occurs first, and in 

its earliest stages is not associated with 

cognitive impairment. 

n Loss of synapses, neurons, and brain 

volume occurs next, and is accompanied or 

shortly followed by loss of cognitive func

tion (see AD Progression figure, page 30). 

More studies are needed to determine 

the best ways of accurately predicting 

who will go on to develop AD and who 

will not before clinical symptoms emerge. 

This scenario may seem discouraging 

but in fact offers hope. Because significant amyloid deposition seems to occur 

years before clinical diagnosis of AD, 

there may be a window of time in which 

therapeutic intervention might prevent 

disease progression. Accumulation of 

brain amyloid could serve as a warning 

sign that additional testing is necessary 

and therapeutic intervention should be 

considered. Thus, just as people are now 

routinely checked for high cholesterol and 

counseled about lifestyle changes and 

medications to reduce their risk of heart 

disease and stroke, in the future they 

may also be checked for brain amyloid 

and counseled about AD prevention. 

Another encouraging finding is that it is 

possible for a person to have a lot of amyloid 

in his or her brain without significant cogni

tive decline. Thus, in some people the brain 

somehow compensates for the presence of 

beta-amyloid, at least for some period of 

time. The brain’s capacity to compensate for 

AD pathology, called “cognitive reserve,” is 

also being intensively studied. 

Additional advance: 

n Mormino et al. (2009) Episodic memory 

loss is related to hippocampal-mediated 

beta amyloid deposition in elderly subjects. 

University of California, Berkeley. (ADNI) 

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| Research Advances 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 20 ’

Is there any such thing 

as “normal” cognitive aging and, 

if so, what does it look like? 

What Is Normal Aging? 

The close association between age and risk of AD raises 

the question of whether AD is an inevitable consequence 

of aging, especially since many older people with normal 

cognition have substantial levels of brain beta-amyloid. 

Is there any such thing as “normal” cognitive aging and, 

if so, what does it look like? 

Understanding what constitutes normal brain aging 

and age-related cognitive decline is an important focus of 

research. Cognitive decline associated with aging can 

compromise quality of life for older people and looking at 

brain aging in this way may help promote healthy cognitive outcomes. It is anticipated that such research, both in 

animal models and in humans, can provide critically 

important insight into effects of normal aging, distinct 

from AD, as well as providing a biological context for the 

abnormal brain changes in AD. More detailed descriptions of normal aging will also help in developing early 

and sensitive AD diagnostic tools. 

Investigators at NIA’s intramural Laboratory of 

Personality and Cognition in Baltimore, MD, carried 

out an exceptionally detailed analysis of brain changes 

over time in 138 people who were 64 to 86 years of age 

and nondemented at the beginning of the study. Brain 

scans were conducted every year for up to 10 years, and 

cognitive status was evaluated. Some participants developed MCI over the course of the study, while others 

remained cognitively normal. Both groups experienced 

atrophy (shrinkage) of certain brain areas over time, but 

the specific patterns of atrophy differed. For example, 

the group who remained cognitively normal showed 

more atrophy in certain areas of the frontal cortex (the 

portion of the cortex closest to the forehead), whereas 

the group who developed MCI had more prominent 

atrophy in temporal areas (the regions on the sides of 

the brain, closer to the ears) (Driscoll et al., 2009). 

These results suggest that there is a specific trajectory of brain changes that occurs during normal aging, 

distinct from that occurring in AD. Brain changes in 

cellular mitochondria and energy production also occur 

during normal aging (see Changes in brain metabolism in 

normal aging and AD, page 18). Moreover, a review 

from the University of Virginia in Charlottesville suggests that declines in certain aspects of cognitive function, such as memory and speed of processing, may 

begin as early as a person’s 20s or 30s (Salthouse, 2009). 

These observations appear to be dependent on the type 

of study conducted, cross-sectional or longitudinal, and 

debate continues as to the point at which measurable 

and meaningful change occurs. 

Additional advance in understanding normal aging: 

n Bishop et al. (2010) Neural mechanisms of ageing and cognitive decline. Harvard University. 
 

 

 

3 discovering new 


Genetic Mechanisms
 

In the early days of AD research, scientists realized that 

some cases of the disease ran in families. When it did, it 

appeared quite early, in the 40s or early 50s. By analyzing the patterns of inheritance of these early-onset cases 

of AD, researchers proved that these particular forms of 

the disease had a genetic basis. Those findings opened 

an entire area of AD research that continues to be highly 

productive today. Research into the genetics of earlyonset AD has revealed much about the biological basis 

of the disease, the interrelationship of genetic and environmental factors in causing it, and molecular pathways 

that might be targeted to prevent or treat both earlyand late-onset AD. As medical science moves toward 

individualized medicine based on a person’s unique 

genetic makeup, identification of other genes contributing to the development and progression of AD—including those that may be involved in sporadic, late-onset 

disease, the most common form of AD—may help 

determine which preventive and treatment strategies are 

best suited to particular individuals. 

The Search for New Genes 

Four genes affecting the development of AD have been 

known for many years. Mutations in three of them—the 

APP gene found on chromosome 21, the presenilin 1 gene 

on chromosome 14, and the presenilin 2 gene on chromosome 1—cause the rare early-onset forms of familial AD. 

The AD-associated mutations in each of these genes promote the breakdown of the large APP protein along a pathway that generates more harmful forms of beta-amyloid. 

The fourth gene, apolipoprotein E (APOE), found 

on chromosome 19, is linked to late-onset AD. Late-onset 

AD is not “inherited” in the same sense that the earlyonset mutations actually cause AD, but genes involved in 

late-onset AD can affect the risk of developing it. APOE 

was the first gene to be identified as influencing late-onset 

AD. APOE has three forms, or alleles: ε2, ε3, and ε4. 

The ε2 form may provide some protection against AD, 

and ε3 is thought to play a neutral role. The ε4 form can 

increase a person’s risk of developing AD. 

Research shows that additional genes likely influence 

the development of late-onset AD, either as risk factors 

or protective factors. Geneticists worldwide are searching 

for these genes. 

Ad Gene discovery timeline 

APOEε4 

APP 

PS1 

PS2 

First 

Transgenic 

mouse 

models 

First 

published 

GWAS 

PICALM 

CLU 

CR1 

confirmed 

by GWAS 

Five 

additional 

genes 

discovered 

by GWAS 


to be 


confirmed
 

 

| Research Advances 

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 21 ’
| Research Advances 

“normal” functions of Ad Genes 

I

f the genes involved in AD are so troublesome, then why do 

humans have them in the first place? Usually, genes remain 

in human or animal populations only if they have a useful 

biological function and confer a survival advantage. For example, 

there is evidence that the presenilins, particularly PS1, play a 

role in the earliest stages of the development of the nervous 

system. Better understanding the normal or “good” biological 

functions of the proteins encoded by AD genes could shed light 

on how mutations or variations in these genes lead to disease. 

n Several findings, including those from investigators at 

Georgetown University in Washington, DC, supported by NIA and 

NINDS, and Baylor College in Houston, TX, supported by NIA and 

NICHD, indicate a role for APP in the development of synaptic 

connections between nerve cells (Hoe et al., 2009a; Wang Z. et 

al., 2009). In particular, APP appears to promote the growth of 

dendrites, the branch-like structures through which neurons 

receive input from the axons of other neurons. APP is also nec

essary for neurons to form orderly synaptic contacts with other 

neurons or muscle cells. In both cases, APP seems to act in part 

by promoting cell-to-cell adhesion, a process in which certain 

proteins on the membrane of one cell bind to proteins on a 

neighboring cell and help “glue” the two cells together. 

n The presenilins have long been recognized as important to 

the development of neurons. New evidence suggests they also 

regulate the strength and flexibility of synaptic connections in 

the hippocampus. Researchers at Harvard University supported 

by NINDS found that inactivating the presenilin genes in mice 

reduced the process of hippocampal long-term potentiation (LTP) 

(Zhang C. et al., 2009). Another research group at NIA’s 

Laboratory of Neurosciences in Baltimore, MD, found that, 

instead of PS1s enhancing the use of an important chemical 

­

neurotransmitter acetylcholine on hippocampal LTP, the PS1 

mutation impaired synaptic connections. (Wang Y. et al., 2009). 

n Recent work from the Nathan S. Kline Institute in 

Orangeburg, NY, indicates yet another role for normal PS1 in 

neuronal function. It seems to participate in a process called 

“macroautophagy,” in which cells dispose of internal debris. 

Many cellular proteins and structures wear out with time and 

cease to function properly. Most cells have the capacity to target 

their worn-out components and break them down into smaller 

pieces, which are either reused or discarded. This process 

involves lysosomes, parts of cells containing enzymes that 

digest cellular debris. Mutations in PS1 that cause early-onset 

AD disrupt metabolism in the lysosomes, so that they can no 

longer digest cellular debris. This debris then accumulates and 

may contribute to neuronal death (Lee et al., 2010). 

n Like APP, the ApoE protein promotes the growth of dendrites 

and their spines. However, a genetic study in human ApoE model 

mice from Georgetown University in Washington, DC, suggests 

that the ε4 form of APOE, which is associated with higher AD 

risk in humans, is less effective in promoting dendrite and spine 

growth than the other forms of APOE (Dumanis et al., 2009). 

This finding may help explain how the APOE ε4 allele increases 

risk of AD. 

Additional advances in understanding AD genes: 

n Hoe et al. (2009b) The effects of amyloid precursor protein on 

postsynaptic composition and activity. Georgetown University. 

Supported by NIA and NINDS. 

n Maji et al. (2009) Functional amyloids as natural storage of 

peptide hormones in pituitary secretory granules. Zurich, 

Switzerland. Supported by NIDDK. 

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New human AD genes identified 

Genetics research has helped to reveal much about the 

basis of AD, the interrelationship of genetic and environmental factors in causing AD, and pathways amenable to prevention or treatment. Complicating the study 

of AD genetics is the fact that the risk of late-onset AD 

is probably influenced by many genetic risk factors, each 

likely contributing a small risk distributed across different genes affecting a variety of biochemical pathways. 

These genetic factors may influence the age at onset, the 

risk of getting the disease, or disease progression. 

Technological developments in genetic analysis over 

the last few years have played a huge role in pushing this 

area of research forward. Genome-wide association study 

(GWAS) technologies let scientists use sophisticated 

software and hours of computing time to find links 

between individual gene variations and observable traits, 

such as the presence of AD. For just a few hundred dollars, scientists can now rapidly test 500,000 to a million 

sites in an individual’s DNA using a gene chip the size 

of a postage stamp. 

This year, a large GWAS search “struck gold” with 

the discovery of two new late-onset AD genes, CLU and 

PICALM. Variants of these genes that correlated with 

the development of late-onset AD were identified in a 

collaborative study led by researchers at Cardiff 

University, Wales (Harold et al., 2009). The group analyzed more than 16,000 samples collected by dozens of 

laboratories across Europe and the United States, including several funded by NIA and other NIH Institutes. 

Sometimes newly discovered disease genes are mysterious entities of unknown biological function. 

Fortunately, a substantial body of knowledge is already 

available about CLU and PICALM because the proteins 

encoded by these genes have roles in well-studied cellular pathways. CLU (ApoJ/clusterin) is another apolipoprotein and, like ApoE, may play a role in clearing 

beta-amyloid out of the brain and into the blood (see 

Clearing out beta-amyloid, page 37). PICALM (phosphatidylinositol-binding clathrin assembly protein) appears 

to be involved in recycling of cell membrane proteins at 

synapses. Identification of these two new genes should 

help researchers home in on novel specific biological 

processes that are disrupted in AD. 

A third gene, CR1 (complement receptor 1), identifed by the Cardiff University investigators, was confirmed as a “hit” in a smaller collaborative GWAS led by 

French investigators (Lambert et al., 2009). CR1 is an 

immune system protein involved in inflammation 

responses and like CLU, may be involved in clearing 

beta-amyloid from the brain. The French study also 

identified CLU, confirming its potential role in AD. 

A recently published analysis in an independent data 

set has confirmed that CR1, CLU, and PICALM are 

AD susceptibility genes in another population of 

European ancestry (Jun et al., 2010). 

Investigators at Massachusetts General Hospital supported by NIMH identified a fourth potential AD gene, 

ADAM10. They discovered two rare mutations in this 

gene in individuals from seven different late-onset AD 

families. ADAM10 is an alpha-secretase, an enzyme that 

cleaves APP in a way that eliminates its potential to 

form beta-amyloid. A mutation could disrupt this cleavage and add to AD risk (Kim M. et al., 2009). 

Research in animal models as well as humans can 

suggest potential human AD genes. An international 

team of researchers, supported by NIA and NINDS and 

led by the Burnham Institute in La Jolla, CA, and 

Xiamen University, China, identified a new gene in 

mice—Rps23r1—that reduces levels of both betaamyloid and phosphorylated tau (another major 

hallmark of AD) when it is turned on either in AD 

model mice or in human cells in tissue culture (Zhang 

Y.W. et al., 2009). This gene may protect mice against 

the development of AD-like changes in the brain. If this 

gene or one like it is present in humans, therapeutics 

might be designed to mimic its protective effects. 

How are people affected by 

knowing their risk for AD? 

As new genetic risk factors for AD are discovered, 

measures to assess individual risk will be developed. 

Currently, APOE ε4 is the most robust risk marker 

available for late-onset AD, and requests for APOE 

genotyping are increasingly common. The REVEAL 

study group led by researchers at Boston University with 

support from NHGRI and NIA studied the psychological consequences of disclosure of APOE genotype test 

results in a group of 162 symptom-free adults who had a 

parent with AD. This study found that people who had 

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| Research Advances 

the highest genetic risk for AD and were told their test 

results did not suffer significantly greater anxiety or 

depression during the weeks or months after the test 

than did people who either tested negative or who did 

not learn their test results (Green et al., 2009). 

Additional advance in effects of genetic susceptibility testing: 

n Ashida et al. (2009) Disclosing the disclosure: factors associated 

with communicating the results of genetic susceptibility testing 

for Alzheimer’s disease. NHGRI Intramural Program. 

Epigenetics: Nature Meets Nurture 

Until recently, scientists believed that genes and environmental factors acted independently to influence an individual’s biological makeup, including a person’s predisposition 

to different diseases. Now we realize that “nature and nurture” are not so easily untangled. Genes can be affected by 

environmental factors, such as diet or smoking, which a 

person may be exposed to, even in the womb. 

The study of these interactions is called epigenetics, 

and it is emerging as a new frontier of science. Diet and 

exposure to environmental chemicals, among other factors, throughout all stages of human development can 

cause epigenetic changes that may turn on or turn off 

certain genes. Changes in the regulation of genes could 

make people more or less susceptible to developing a 

disease, such as AD, later in life. 

Unlike gene mutations, epigenetic modifications of 

genes do not involve changes to the genetic code. They 

involve chemical alterations that make genes more or 

less accessible to interactions with enzymes responsible 

for “reading” each gene’s code and cranking out the protein for which it codes. Environmental factors leave their 

mark on the genome by altering the epigenetic signature 

of genes. Like gene mutations, epigenetic changes can be 

passed from one cell to its daughter cells during cell 

division, and so can persist for an individual’s lifetime. If 

the cells involved are egg or sperm cells, the changes can 

also be passed to the next generation. (The old phrase 

“You are what you eat” now could be revised to say, 

“You are what you eat and what your mother ate.”) 

METHYL GROUP 

CHROMOSOME 

DNA 

CHEMICAL 

TAG 

HISTONE 

GENE HISTONE TAIL 

DNA hidden, gene turned off 

HISTONE TAIL 

DNA hidden, gene turned on 

The epigenome can mark DNA in two ways, both of which play a 

role in turning genes off or on. The first occurs when certain 

chemical tags called methyl groups attach to the backbone of a 

DNA molecule. The second occurs when a variety of chemical 

tags attach to the tails of histones, which are spool-like proteins 

that package DNA neatly into chromosomes. This action affects 

how tightly DNA is wound around the histones. (Source: NHGRI, 

www.genome.gov) 

There is some evidence that epigenetic mechanisms 

contribute to AD. That may help explain why one individual in a family develops AD while another does not. 

One study, by scientists at the Sun Health Research 

Institute in Sun City, AZ, looked at certain chemical 

modifications in brain tissue samples from deceased identical twins. The comparison examined levels of DNA 

methylation, a chemical modification that can reduce the 

level at which a gene is expressed. One twin had developed AD at age 60 and deteriorated until his death at age 

76; the other died cognitively intact at age 79. Methylated 

DNA levels were significantly lower in the brain tissue 

from the twin who had AD than in that of his brother 

(Mastroeni et al., 2009). The twin with AD had experienced extensive pesticide exposure during his lifetime as 

result of his profession. Pesticides are one environmental 

factor believed to cause epigenetic changes, although it is 

not known if they were a causative factor in this case. 

Recent scientific evidence also points to the involvement of epigenetic mechanisms in memory formation 

and maintenance. One such mechanism involves 

enzymes that chemically modify histones (proteins 

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| Research Advances 

around which DNA is wrapped inside chromosomes) 

and results in the remodeling of chromosomes, the individual coils of DNA and protein storing genetic information inside cells. Two papers from the Massachusetts 

Institute of Technology in Boston and Columbia 

University in New York, NY, supported by NINDS, 

suggest an involvement of histone-modifying enzymes in 

memory formation and AD and point to these enzymes 

as possible targets for therapeutic development (Guan et 

al., 2009; Francis et al., 2009). 

Additional 2009 advance in epigenetics: 

n Debette et al. (2009) Association of parental dementia with 

cognitive and brain MRI measures in middle-aged adults. Boston 

University. Supported by NIA, NINDS, NHLBI. 

looking to the future: 

Epigenetics 

I

n 2008, NIH announced funding for a new Roadmap 

Epigenomics Program (http://commonfund.nih.gov/ 

epigenomics/index.asp), committing more than 

$190 million during the next 5 years to accelerate this 

emerging field of biomedical research. The rationale 

behind this trans-NIH program is to promote understanding of how and when epigenetic processes control genes 

during different stages of development and throughout 

life. Scientists hope the effort will lead to more effective 

ways to prevent and treat disease. 

NIA has played a very active role in the development 

and implementation of the Roadmap Epigenomics Program. 

In 2009, the Program funded 22 projects focused on exploring the epigenomic basis of various aspects of human 

health and disease. Four of these projects focus on establishing the epigenomic landscape of AD and testing 

whether epigenetic dysregulation is related to the 

initiation and progression of AD. 

In 2010, NIA held a workshop “An Integrated GeneticEpigenetic Approach to Alzheimer’s Disease,” which reviewed emerging epigenetic approaches to AD, explored 

synergies between genetic and epigenetic approaches, 

and spurred interactions between leading experts in AD 

genetics and epigenetics. 

4 Preventing Ad and Promoting 

healthy Brain Aging 

Genetic factors cannot fully account for why some people develop AD and others do not. There is mounting 

evidence that a number of nongenetic factors, such as 

diet, lifestyle, and exposure to certain environmental 

agents, may increase or reduce one’s risk of developing 

AD. Understanding these nongenetic risk factors will 

point the way to potential therapies or lifestyle changes 

that can help prevent AD. 

Potential AD Risk Factors 

Advancing age and serious head injury are well-established risk factors for developing AD. Scientists are 

exploring a wide range of other possible factors. 

Estrogen 

The hormone estrogen has important effects on the 

brain, many of which are potentially relevant to cognitive aging and AD. For example, animal studies have 

shown that estrogen protects neurons against a wide 

spectrum of toxic insults, some of which are linked to 

AD. Estrogen can also reduce formation of beta-amyloid 

and can counteract some of the effects of normal aging 

on cognition when administered to nonhuman primates. 

In humans, some large observational studies have suggested a possible protective effect of estrogen for women. 

Clinical trials and studies have attempted to assess whether 

estrogen therapy can protect women against age-associated 

cognitive decline. In the largest trial to date, reported in 

2003, data from the Women’s Health Initiative Memory 

Study (WHIMS) showed that prolonged treatment with a 

common type of hormone therapy (conjugated equine 

estrogens) increased the risk of dementia and adversely 

affected cognition in women age 65 and older. 

However, in the WHI trial, postmenopausal hormone 

therapy was usually started many years after normal reproductive cycles had stopped and involved synthetic hormones. Further, hormone treatment also increased the risk 

of stroke, suggesting that impaired cerebrovascular function 

may have been a factor in participants’ cognitive decline. 

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To try to understand why hormone therapy impaired 

cognitive function in the WHIMS study, researchers at 

Wake Forest University and NIA’s Laboratory of 

Personality and Cognition in Baltimore, MD, used MRI 

to look for brain degeneration in a group of women, ages 

79 to 89, who had participated in the 2003 WHI trial. 

The women who had received hormone therapy showed 

more shrinkage of the hippocampus and frontal cortex 

than those who did not. (These brain regions are important for memory and planning, and also show shrinkage 

in AD.) Many of the women who received hormone 

therapy also showed evidence of varying degrees of brain 

damage due to cerebrovascular disease, but the extent of 

that damage was not significantly higher compared with 

women who had received a placebo (Coker et al., 2009). 

This finding suggests that the adverse effects of hormone 

therapy on cognition were not due to an increase in cerebrovascular disease (Resnick et al., 2009). 

The human clinical data highlight the substantial 

gaps in our understanding of ovarian hormone influences on neurocognitive aging, as recently summarized 

from an NIA-sponsored workshop convened to address 

these issues (Asthana et al., 2009). One of these questions is about timing. Animal studies have shown that 

estrogen has positive effects on the brain, but only if 

administered during or immediately after withdrawal of 

ovarian steroids. Thus, estrogen may protect cognition 

in humans only if administered at a particular age or for 

a specific amount of time after menopause. Two NIAfunded clinical trials in progress will compare the effects 

of early and late hormone therapy on cognition, and 

other endpoints: the Kronos Early Estrogen Prevention– 

Cognitive and Affective Study (KEEPS–CA) and the 

Early versus Late Intervention Trial with Estrogen 

(ELITE) (see AD Clinical Trials, page 38). 

A number of nongenetic factors, such as diet, 


lifestyle, and exposure to certain environmental agents, may increase 


or reduce one’s risk of developing AD.
 

General anesthetics 

An estimated 200 million patients worldwide have surgery with anesthesia each year. Several studies have linked 

general anesthesia in surgery with an increased risk of AD 

later in life. Researchers at Massachusetts General 

Hospital and Harvard University in Boston, supported by 

NIGMS, NIA, and NINDS, looked at the most commonly used inhalation anesthetic (sevoflurane) and found 

increases in beta-amyloid levels and cell death when it was 

applied to a glial tumor cell line in culture. In addition, 

mice anesthetized for 2 hours showed increased betaamyloid deposition in the frontal cortex (Dong et al., 2009). 

It is important to note that no evidence to date with this 

or any other inhalation anesthetic shows similar results in 

humans, but further study of effects of anesthetics on 

development of brain pathology may be warranted. 

Lead 

A pilot study of 47 healthy subjects, 55 to 67 years old, 

provided additional support for previous research suggesting a link between lead exposure and memory impairment. 

Investigators at the University of Rochester, NY, supported 

by NIEHS, found that higher lead levels in bone, which 

indicate accumulated lead exposure over time, were associated with impaired performance on two memory tests used 

to detect MCI (van Wijngaarden et al., 2009). 

Additional advance related to AD risk factors: 

n de la Monte et al. (2009) Mechanisms of nitrosamine-mediated 

neurodegeneration: potential relevance to sporadic Alzheimer’s disease. 

Rhode Island Hospital/Brown University. Supported by NIAAA. 
 

 

 

 

 

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Lifestyle and Successful Cognitive Aging 

Many individuals stay mentally sharp to age 90 and 

beyond, and there has been increasing research emphasis 

on finding out why. Epidemiological–observational– 

studies such as those described below are important to 

identify associations between certain lifestyle factors and 

the risk of developing AD. However, even if substantial 

evidence is found for a potential association, observational studies alone cannot establish a cause-and-effect 

relationship. To be useful in the clinic, associations 

between some factor and AD risk must be able to yield 

an intervention that can be randomly assigned to individuals in a clinical trial, as randomized trials remain the 

gold standard for identifying successful treatments (see 

AD Clinical Trials, page 38). 

Researchers for the Health ABC Study at the 

University of California, San Francisco, and the NIA 

Intramural Research Program identified several factors 

associated with continued cognitive health. In a group 

of 2,509 older people who were functioning well when 

they entered the study (at ages 70 to 79), factors contributing to enhanced or intact cognitive function 

included at least a high school level of education, not 

smoking, and engaging in moderate to vigorous exercise 

on a weekly basis (Yaffe et al., 2009). Similar associations have been found in a variety of studies. 

Social interaction 

A number of studies have found that social interaction, 

whether through work, volunteering, or living with 

someone, is associated with maintaining cognitive 

health. It has not been clear, though, whether this correlation is due to the increased intellectual stimulation and 

physical activity that generally accompany social interaction or whether it was the social interaction itself that 

was beneficial. Researchers at the Rush University 

Alzheimer’s Disease Center in Chicago, IL, addressed 

this question in a large study of nondemented older 

people (average age, 80). Consistent with previous studies, they found that 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. This correlation was significant even after accounting for higher levels of intellectual and physical activity (Krueger et al., 2009). 

Exercise 

Building evidence from epidemiological studies and several small clinical trials in healthy adults have shown that 

aerobic exercise may help prevent age-associated cognitive decline, at least in the short term. Studies in animals 

suggest that exercise may strengthen cognition in part by 

supporting the hippocampus, a brain structure critical for 

learning and memory that is one of the first to deteriorate during both normal brain aging and in AD. A report 

from investigators at the University of Pittsburgh, PA, 

and the University of Illinois, Urbana-Champaign, suggests that exercise supports hippocampal function in 

humans as well. They assessed cardiorespiratory fitness in 

165 older adults using a treadmill test, and found that 

higher fitness levels were associated not only with better 

performance on a spatial memory test but also with 

greater hippocampal volumes (Erickson et al., 2009). 

Work by researchers at Washington University, St. 

Louis, MO, supported by NIA and NIMH, suggests 

some forms of exercise are more beneficial than others, at 

least in one animal model. In AD model mice, voluntary 

exercise was superior to forced exercise in reducing plaque 

deposition and improving memory (Yuede et al., 2009). 

Another study, supported by NIA and NIAMS, from the 

University of California, Irvine, on AD model mice bearing different forms of the APOE gene suggested that exercise is especially beneficial for cognitive function in mice 

with the APOE ε4 form (Nichol et al., 2009). 

Additional advance related to exercise and AD risk: 

n McAuley et al. (2009) Trajectory of declines in physical activity 

in community-dwelling older women: social cognitive influences. 

University of Illinois, Urbana-Champaign. Supported by NIA. 

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Interactions Between Ad and Vascular disease 

The brain has one of the richest supplies of blood vessels of any organ. Cognitive health depends very much on the health of the brain’s blood vessels. Aging is often 

accompanied by problems in cardiovascular and/or cerebrovascular function. Two of the most common are high blood pressure and 

clogging of blood vessels that supply the brain, which can cause 

stroke. Vascular disease, in turn, can cause cognitive impairment. 

It has become clear in recent years that AD and vascular 

disease-associated cognitive impairment are closely intertwined. 

For example, a large proportion of people diagnosed with AD 

also have brain damage due to vascular disease (see Links with 

Other Diseases, page 14). In addition, two analyses of data from 

NIA’s Baltimore Longitudinal Study of Aging and the Honolulu-Asia 

Aging Study found that many of the major risk factors for vascular 

disease may also be risk factors for AD. These findings suggest 

common cellular mechanisms for the two diseases (Wendell et 

al., 2009; Stewart et al., 2009) 

The overlap between vascular disease and AD may be important because drugs and lifestyle modifications known to be 

effective in preventing vascular disease may also help prevent 

AD. In 2009, the following epidemiological and animal studies 

found that some factors known to reduce vascular disease are 

also associated with reduced risk of AD. 

Controlling high blood pressure. A postmortem study of 

brains of people who had hypertension while living, from Mount Sinai 

School of Medicine, New York, NY, found significantly fewer plaques 

and tangles in those who had taken medication to control their blood 

pressure than in those who had not (Hoffman et al., 2009). 

Mediterranean diet. A large study by Columbia University 

researchers in a multiethnic New York community showed that 

people who maintained a Mediterranean diet had a 28 percent 

lower risk of developing MCI and a 48 percent lower risk of pro

gressing from MCI to AD. A Mediterranean diet includes vegetables, 

legumes, fruits, cereals, fish, monounsaturated fats such as olive 

oil, mild to moderate amounts of alcohol, and low intake of saturat

ed fats, dairy products, meat, and poultry (Scarmeas et al., 2009a). 

­

­

Physical activity. Another Columbia University study in the 

same multiethnic New York population showed that people who 

reported regular engagement in “some” physical activity had a 

29 to 41 percent lower risk of developing AD, compared to participants who said they were not physically active. Engaging in 

“much” physical activity was associated with a 37 to 50 percent 

lower risk (Scarmeas et al., 2009b). 

Cholesterol-reducing drugs. Investigators at the University 

of Alabama, Birmingham, supported by NIA and NHLBI, treated AD 

model mice with a drug that mimics apolipoprotein A-1 (the major 

protein in high density lipoprotein, or HDL, the “good” form of cholesterol) together with a statin for controlling cholesterol. The mice 

treated with this combination of drugs showed improved cognitive 

function, reduced amyloid, and reduced inflammation compared 

with untreated AD model mice (Handattu et al., 2009). 

Additional 2009 advance related to vascular disease and AD: 

n Schuff et al. (2009a) Cerebral blood flow in ischemic vascular 

dementia and Alzheimer’s disease, measured by arterial spinlabeling magnetic resonance imaging. University of California, 

San Francisco/VA Medical Center. Supported by NIA. 

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looking to the future: Preventing Ad and 

Age-Related Cognitive decline 

Mounting epidemiological and 

animal-study findings point to 

interesting possibilities for pre

venting AD and cognitive decline. What can 

scientists say definitively now about what 

works to prevent Alzheimer’s and agerelated cognitive decline? To examine this 

critical question, the NIH Office of Medical 

Applications of Research and NIA convened 

a State-of-the-Science Conference, held 

April 26-28, 2010, with co-sponsorship 

from NICHD, NCCAM, NIMH, NINDS, NINR, 

and the Office of Dietary Supplements. 

An independent, 15-member panel 

was convened to review questions and 

evidence. Panel members were not cur

rently involved in Alzheimer’s research 

and represented the fields of preventive 

medicine, geriatrics, internal medicine, 

neurology, neurological surgery, psychiatry, mental health, human nutrition, 

pharmacology, genetic medicine, nursing, 

health economics, health services 

research, and family caregiving. 

Experts from pertinent fields were 

invited to present data to the panel and 

conference audience. The panel also 

received a systematic evidence review 

from the Evidence-based Practice Center 

at Duke University’s Clinical Research 

Institute, prepared under contract with 

the Agency for Healthcare Research and 

Quality. Conference participants also provided oral and written comments in 

response to the conference questions. 

The panel considered all of this evidence 

­

­

when preparing its consensus statement. 

The panel concluded that cognitive 

decline and AD are major causes of mor

bidity and mortality worldwide and are 

substantially burdensome to the people 

affected, their caregivers, and society in 

general. Extensive research during the 

past 20 years has provided important 

insights on the nature and extent of AD 

and cognitive decline. Currently, however, 

firm conclusions cannot be drawn about 

the association of any modifiable risk 

factor with cognitive decline or AD. 

Further, evidence is insufficient to sup

port the use of any pharmaceutical agent 

or dietary supplement to prevent cogni

tive decline or AD. 

However, promising research is underway, the panel noted. These efforts need 

to be increased and added to by new 

insights and innovations. For example, the 

panel indicated that ongoing studies, 

including those of antihypertensive medications, omega-3 fatty acids, physical 

activity, and cognitive engagement, may 

provide new avenues for the prevention or 

delay of cognitive decline or AD. 

NIA’s ongoing research programs are 

actively investigating and testing a variety of strategies to prevent or delay AD 

and cognitive decline. Research includes 

clinical trials investigating exercise, 

statins and blood pressure and diabetes 

medications, hormones, antioxidants, 

cognitive training, and other interventions (see AD Clinical Trials, page 38). 

­

­

­

Further large-scale population-based 

studies and randomized clinical trials are 

needed to investigate strategies to 

maintain cognitive function in individuals 

at risk for decline, to identify factors that 

may delay the onset of AD in people at 

risk, and to identify factors that may 

slow the progression of AD in people 

already diagnosed. 

As this research continues, there are 

very good reasons for adults to adopt or 

maintain lifestyle choices and treatments 

known to promote healthy aging and 

reduce the risk of diseases like diabetes 

or cardiovascular disease. 

For more information on the State-ofthe-Science Conference and consensus 

statement, go to http://consensus.nih. 

gov/2010/alz.htm. 

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5 detecting 

disease Earlier 

Many researchers believe that therapeutic interventions for 

AD are more likely to be effective if initiated early in the 

disease process. Since we now know that the brain damage 

caused by AD can begin long before cognitive impairment 

becomes evident, intensive effort has been aimed at developing methods to detect this damage at its earliest stages. 

This diagram illustrates current thinking about how 

Alzheimer’s changes in the brain contribute to disease 

progression, from a presymptomatic stage through early 

and late mild cognitive impairment to Alzheimer’s 

dementia. The curves on the diagram represent specific 

markers as they appear sequentially over time as the 

disease progresses. 

Scientists are currently exploring three main 

approaches to early diagnosis: cognitive testing, brain 

imaging, and measurement of biomarkers in CSF. In addition, there is a growing body of research on other early 

symptoms and changes that may signal the onset of AD. 

Cognitive Testing 

Extensive cognitive testing has been a key diagnostic tool 

in AD, refined over many years. Many existing tests were 

designed to diagnose relatively later stages of the disease—for example, in people who come to the doctor’s 

office already complaining of memory problems. What is 

currently lacking are tests that can detect and track the 

earliest, most subtle stages of the disease and tests that 

can identify who is at risk of eventually developing the 

disease. Research efforts now concentrate on the development of a new generation of cognitive tests that are more 

sensitive to changes in cognition and more reliably discriminate between normal aging, early stages of AD, and 

cognitive impairment due to other diseases, such as cerebrovascular disease or Lewy body disease. Progress toward 

establishing a detailed account of normal neurocognitive 

aging will importantly inform this effort. 

n MCI is often a transitional stage between normal 

aging and AD. Sensitive, accurate diagnostic tests for 

MCI are critical to identify people at risk of developing 

AD and to predict the likely progression of symptoms. 

There has been considerable variability in assessing how 

common MCI is in the population and the rate at 

which people with MCI progress to AD, due in part to 

the use of different criteria for diagnosing MCI. 

Researchers at the University of California, Los Angeles 

Alzheimer’s Disease Center assessed 115 people with 

amnestic or nonamnestic MCI using a battery of tests 

for different neuropsychological functions, such as 

memory, attention, and visuospatial processing, then followed their progress for 16 months. (In amnestic MCI, 

memory is the dominant problem; in nonamnestic 

MCI, other cognitive impairments dominate, such as 

problems with language, visuospatial processing, and 

attention. People with amnestic MCI are more likely to 

progress to AD than those with nonamnestic MCI.) In 

both the amnestic and nonamnestic groups, the percentage of people who had performance deficits differed 

significantly for different tests. However, the people who 

were most impaired on memory tests at the beginning of 

the study were also the most likely to have persistent 

memory deficits over the long term (Teng et al., 2009). 

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n

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The Mini Mental State Examination (MMSE) was 

designed in 1975 and remains the most widely used 

screening test for dementia. The MMSE is not sensitive 

to mild cognitive changes, nor is it very useful for distinguishing between AD and other forms of dementia. It 

has remained in use in part because it is simple, quick to 

administer, and can be used in any doctor’s office. Most 

clinical trials use MMSE scores to help determine who is 

eligible to participate. A number of new tests are under 

development that retain those virtues but provide more 

sensitive and accurate diagnoses. For example, 

researchers at Mount Sinai Medical Center in Miami, 

FL, reported on the Florida Brief Memory Screen, 

which shows high sensitivity for detection of MCI and 

takes only 3 to 4 minutes to administer. The test is 

available in Spanish and English, an important feature, 

as linguistic issues can compromise test performance 

(Loewenstein et al., 2009). 

n Several computer-based tests have also been developed, 

most of which can be used with a standard personal computer. Most of these tests have to be administered and 

scored by a clinician, as is also true for pen and paperbased tests like the MMSE. University of Pittsburgh 

researchers reported on a new computer-based test, 

Computer Assessment of Mild Cognitive Impairment 

(CAMCI), that is both self-administered and automatically scored. The researchers reported a good sensitivity 

for detection of MCI (Saxton et al., 2009). 

Additional 2009 advance related to cognitive testing: 

n Schneider LS et al. (2009) Characteristics and performance of 

a modified version of the ADCS-CGIC CIBIC+ for mild cognitive impairment trials. University of Southern California. 

Supported by NIA, NCRR. 

Ethnicity and AD diagnosis 

Several reports have suggested racial and ethnic differences in the prevalence of AD. Studies seeking to 

explain these differences have found that cultural factors 

and variations in education quality, for example, can 

affect performance on standardized cognitive tests. 

Another source of diagnostic information, used in conjunction with cognitive tests, is reports from family 

members and other caregivers about how well a person 

is functioning in day-to-day life. However, these informant reports, too, may be affected by ethnic and cultural differences. Investigators from Duke University in 

Durham, NC, found that family member/caregiver 

reports were less likely to predict cognitive impairment 

without dementia in African Americans than in whites 

(Potter et al., 2009). These results are consistent with 

previous studies suggesting that African Americans are 

less likely than whites to report cognitive changes in 

family members. This difference may reflect different 

cultural perceptions of “normal” aging. For example, a 

research team at the University of Michigan and Boston 

University Alzheimer’s Disease Centers studied a group 

of 301 people in the Boston area, most of whom had 

personal experience with AD as a caregiver and/or relative. Significantly more of the African American than 

white participants believed that memory impairment is 

an expected part of aging (Connell et al., 2009). 

looking to the future: 

Cognitive testing 

The AD field is moving toward much earlier 

diagnosis. More sensitive measures that assess 

different cognitive domains in more diverse 

populations are needed. To explore these issues, NIA held 

a workshop in spring 2010, “Assessment of Cognition in 

Early Dementia.” The purpose was to review a range of 

computerized cognitive assessments to determine gaps 

and opportunities for further development, evaluate novel 

assessment methods and cognitive domains (e.g., spatial 

orientation, prospective memory), and determine the best 

ways to assess cognition in diverse populations. 

Information from this meeting will be used in the near 

future to decide which cognitive measures will be incorporated into particular research studies. 
 

 

 

| Research Advances 

Other Early Signs and Symptoms 

The clinical picture of AD is changing considerably. For 

many years since AD was first described in 1906, clinicians believed that it was a rare disease affecting middleaged adults. In the 1960s, at about the same time larger 

numbers of people were living past age 65, it became 

evident that a similar disease occurred in older adults. At 

the time, the clinical description of AD focused on the 

symptom of memory loss, specifically, loss of the ability 

to form and recall memories of recent events. Now there 

is growing recognition that, even in its earliest stages, 

AD can affect other cognitive skills and disrupt mood 

and behavior, sometimes even before memory is 

affected. Scientists are also increasingly aware that the 

symptoms and course of AD can vary considerably from 

person to person, depending in part on whether an individual has other common diseases and conditions of old 

age, such as vascular disease or diabetes. 

Sensory Changes 

Cognitive changes in the early stages of AD may include 

deficits in the ability to process sensory information. 

NIA-supported research published in 2008 showed that 

some people with AD begin losing their sense of smell 

early in the course of the disease (see 2008 Progress 

Report on Alzheimer’s Disease; also additional references 

below). Research reported in 2009 suggests that visuospatial skills also may falter early on. 

looking to the future: 

Sensory and Motor Changes 

These studies and others suggest that examining sensory and motor changes in the context of AD may offer fresh perspectives regarding 

the course, early detection, assessment, and treatment 

of AD. To further explore these new avenues for 

research, NIA held an exploratory workshop in August 

2010, “Sensory and Motor Dysfunctions in Aging and 

Alzheimer’s Disease (AD),” focusing on recent findings 

in sensory and motor changes occurring early in the 

course of AD, gaps in knowledge, and strategies for 

advancing this area of research. Participants included 

experts from the fields of AD as well as leading 

researchers in the relevant sensory and motor fields. 

Visuospatial skills allow us to perceive objects and 

the spatial relationships among them and to judge how 

close or far away we are from objects in our environment. These skills are crucial for navigating city streets, 

our own homes, or an assisted living facility. Researchers 

at the Washington University Alzheimer’s Disease 

Center in St. Louis, MO, studied 444 older people, all 

of whom were cognitively normal at the start of the 

study. About 30 percent of them subsequently developed 

AD. In this group, performance on tests of visuospatial 

skill began to decline 3 years earlier on average than performance on memory tests (Johnson et al., 2009). 

Investigators at the University of Rochester, NY, 

provided further evidence that visuospatial skills can 

decline while memory remains relatively intact (Duffy, 

2009). The team studied navigational problems associated with AD, specifically, the question of why people 

with AD tend to get lost in familiar environments. They 

found that the brain’s electrical responses to navigation 

are reduced in people with early AD, and that this ability can be impaired even in people with no measurable 

memory deficits. 

Another report this year from the University of 

Alabama, Birmingham Alzheimer’s Disease Center 

found that in everyday life, people with MCI have worse 

driving performance than their cognitively normal peers 

(Wadley et al., 2009). The MCI group did not have 

worse visual acuity (sharpness of vision) than the control 

group. Thus, it is possible that the MCI group’s 

impaired driving performance reflected deficits in cortical visuospatial processing, similar to the navigation deficits observed by the Rochester researchers. On the other 

hand, this impaired level of driving performance could 

reflect changes in executive function (e.g., the ability to 

rapidly choose the appropriate action once you have 

detected a potentially dangerous situation), given the 

complexity of driving. 

Additional advances in sensory changes: 

n Murphy et al. (2009) Olfaction in aging and Alzheimer’s disease: event-related potentials to a cross-modal odor-recognition 

memory task discriminate ApoE epsilon4+ and ApoE epsilon 4- 

individuals. San Diego State University. Supported by NIA and 

NIDCD. 

n Wilson et al. (2009b) Olfactory impairment in presymptomatic Alzheimer’s disease. Rush University Alzheimer’s Disease 

Center. Supported by NIA. 

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Behavioral and Mood Problems 

Many people with AD experience behavioral and mood 

disturbances, including depression, irritability, and disinhibition (displays of socially inappropriate behavior). 

Indeed, such “neuropsychiatric” symptoms are the primary reason caregivers consider moving family members 

with AD to nursing homes. 

Behavioral and mood disturbances also appear to be 

associated with more rapid progression from MCI to 

dementia. Researchers at the Instituto Universitario 

CEMIC in Buenos Aires, Argentina, in collaboration 

with Johns Hopkins University Alzheimer’s Disease 

Center scientists, studied 239 people with MCI, of 

whom 36 percent had persistent neuropsychiatric symptoms in addition to cognitive symptoms. They also progressed more rapidly to dementia. During the period of 

the study, 44 percent of the people with both MCI and 

neuropsychiatric symptoms converted to AD, and 18 

percent converted to frontotemporal dementia (FTD), a 

degenerative dementia affecting the frontal and temporal 

lobes of the brain and causing changes in personality, 

behavior, language, and movement. In contrast, only 18 

percent of the people who had MCI without neuropsychiatric symptoms converted to AD, and none to FTD 

(Taragano et al., 2009). 

Biomarkers and ADNI 

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) 

was launched in 2004 to determine which imaging 

methods and fluid biomarkers can best track and predict 

clinical change over time (more information on ADNI, 

page 54). As of fall 2010, ADNI scientists had collected 

3 years of longitudinal data from more than 800 participants (about 200 normal, 400 with MCI, and 200 with 

AD) at 59 U.S. and Canadian sites. In 2009, ADNI 

helped identify a number of precisely measurable, clinically relevant biomarkers that will enable more accurate 

diagnosis and prediction of disease course and also speed 

and cut the cost of clinical trials. 

Structural MRI 

During the course of AD, certain regions of the brain 

shrink due to the degeneration of synapses and death of 

neurons. Researchers have been using brain scans to try 

to detect such changes very early, before people have significant cognitive impairment. A collaborative team of 

investigators from the University of Pennsylvania in 

Philadelphia and NIA’s Laboratory of Personality and 

Cognition in Baltimore, MD, developed a pattern detection program to analyze MRI scans obtained from ADNI 

participants. The program compared patterns of brain 

area loss over time in people with AD with those of cognitively normal people the same age. Based on differences 

in these patterns, the program generated a kind of 

“search image” for AD-like changes, called the “spatial 

patterns of abnormality for recognition of early AD 

(SPARE-AD).” The researchers then used the program to 

analyze people enrolled in NIA’s Baltimore Longitudinal 

Study of Aging neuroimaging study. In that investigation, people who had either MCI or memory decline 

with otherwise normal cognition had the highest 

SPARE-AD scores (Davatzikos et al., 2009). The study 

suggests that sophisticated pattern detection methods 

with MRI imaging may help identify cognitively normal 

individuals who are likely to show cognitive decline. 

A 1-year structural MRI study of 449 participants by 

ADNI investigators at the University of California, San 

Francisco, found that people with AD and MCI lost volume in the hippocampus more quickly than did cognitively normal people The losses were associated with 

deteriorating scores on cognitive assessments. In people 

with AD, higher rates of loss in hippocampal volume also 

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2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 34 ’

correlated with the presence of the ApoE ε4 gene, a risk 

factor for Alzheimer’s. In people with MCI, higher rates of 

hippocampal loss were associated with lower levels of the 

peptide beta-amyloid 1-42 (Aβ1-42) in CSF. The finding 

of accelerating hippocampal loss is important for understanding the natural history of the disease and emphasizes 

the need for early diagnosis and therapeutic intervention, 

the study report noted (Schuff et al., 2009b). 

Other ADNI studies, including one published by 

researchers at the Mayo Clinic in Rochester, MN, have 

shown that PET imaging holds potential for a different 

use: the identification of people with AD pathology who 

have not yet developed dementia. Detection of brain 

beta-amyloid could potentially be used as a risk factor to 

predict future decline to AD (Jack et al., 2009). 

Cerebrospinal fluid 

Researchers took a major step forward in developing a 

test to diagnose early-stage AD by measuring two biomarkers—tau and beta-amyloid proteins—in CSF. 

Previous imaging studies had shown that AD-like 

changes can occur in the brain years before any cognitive symptoms appear. However, CSF testing costs less 

than brain imaging, so researchers have sought CSF biomarker changes correlated with the development and 

progression of AD. A report from the ADNI Biomarker 

Core at the University of Pennsylvania School of 

Medicine in Philadelphia provided strong evidence that 

changes in CSF tau and beta-amyloid signal the onset of 

mild AD. Researchers also established a method for 

standardized testing for these biomarkers (Shaw et al., 

2009). These results may open the door to the discovery 

of an entire panel of CSF biomarkers that will predict 

who is at risk of developing AD and how the disease 

responds to therapies. Like all ADNI results, these findings have been posted to a publicly accessible database 

available to qualified researchers worldwide. 

Additional advances in neuroimaging: 

n Dickerson et al. (2009) The cortical signature of Alzheimer’s disease: regionally specific cortical thinning relates to symptom severity 

in very mild to moderate AD dementia and is detectable in asymptomatic amyloid-positive individuals. Massachusetts General, 

Harvard University. Supported by NIA, NINDS, and NCRR. 

n Fennema-Notestine et al. (2009) Structural MRI biomarkers 

for preclinical and mild Alzheimer’s disease. University of 

California, San Diego (ADNI). 

n McEvoy et al. (2009) Alzheimer disease: quantitative structural 

neuroimaging for detection and prediction of clinical and structural changes in mild cognitive impairment. University of 

California, San Diego. Supported by NIA (ADNI). 

Additional advances in biomarkers: 

n Fagan et al. (2009a) Cerebrospinal fluid tau and ptau(181) 

increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer’s disease. 

Washington University. Supported by NIA, NINDS, and NCRR. 

n Fagan et al. (2009b) Decreased cerebrospinal fluid Abeta(42) 

correlates with brain atrophy in cognitively normal elderly. 

Washington University. Supported by NIA, NINDS, and NCRR. 

n Jagust et al. (2009) Relationships between biomarkers in aging 

and dementia. University of California, Berkeley (ADNI). 

n Okereke et al. (2009) Ten-year change in plasma amyloid beta 

levels and late-life cognitive decline. Harvard University. 

Supported by NIA and NCCAM. 

In 2009, ADNI helped identify a 

number of precisely measurable, clinically relevant biomarkers. 
 

 

 

 

 

 

| Research Advances 

6 developing novel 

therapeutic Approaches 

Translational research is a multidisciplinary effort that 

enables the transfer of information between basic-science 

laboratory studies and clinical research for the purpose 

of developing novel therapies. The discovery and development of new drugs for neurological disorders is 

extremely challenging and very expensive. On average, it 

takes more than 13 years and costs $1.78 billion from 

the discovery of a new therapeutic target to the time a 

new drug receives FDA approval for use in the general 

patient population (Paul et al., 2010). At each step of 

the translational process, there is a very high failure rate. 

In recognition of the difficulties in moving basic scientific knowledge toward drug development, NIA’s Division 

of Neuroscience instituted a series of funding initiatives 

aimed at creating a robust AD translational research program. The aim is to increase the number of investigational 

new drugs that can then be tested in humans. 

nIA’s Alzheimer’s disease translational Research Program 

During the last 5 years, NIA launched a series of funding initiatives 

to support early drug discovery and preclinical therapy development for AD. The funding opportunity PAS 10-151 supports exploratory drug discovery research using the R21 grant mechanism, and 

the funding opportunity PA 10-205 supports the preclinical development of promising candidate therapeutics through a cooperative 

agreement mechanism (U01). In addition, NIA participates in drug 

discovery funding opportunities initiated by other Institutes (PAR 

10-001 and PAR 10-002).The U01 program in conjunction with 

toxicology services provided through an NIA contract enable 

researchers involved in preclinical development of candidate therapeutics to secure an Investigational New Drug (IND) status from the 

FDA. Once a compound has received an IND status, the multiple 

steps of testing in humans (clinical development) can be pursued 

either by the pharmaceutical industry or through NIA’s clinical trial 

funding opportunities or clinical trial consortium (ADCS). 

Target Discovery 

Basic Research 

Drug Discovery 

Preclinical Drug

Development 

AD Pilot Clinical Trials, PAR 08-062 (R01) 

Alzheimer’s Disease Cooperative Study (U01) 

Investigator Initiated Clinical Trials (R01) 

Successful Therapeutic 

Intervention for AD Clinical Development 

Industry 

NIA 

Target Validation 

Assay Development 

Screening, Hits to Leads 

PAS 10-151 (R21) 

PAR 10-001 (R01) 

PAR 10-002 (R21) 

Lead Selection and 

Lead Optimization 

PAR 10-205 (U01) 

IND-enabling Toxicology 

Contract Services IND 

{

{

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| Research Advances 

Drug Discovery and 

Preclinical Development 

NIA support provides critical investments in the riskiest 

early steps of AD drug discovery and preclinical drug 

development, which the pharmaceutical industry is 

unlikely to pursue. The NIA Translational Research 

Program funds a diverse portfolio of more than 60 projects, ranging from early drug discovery to preclinical 

development of novel therapeutic compounds aimed at 

a variety of targets (see Petanceska et al., 2009, for a 

detailed summary). 

To date, this Program includes more than a dozen 

preclinical drug development projects focused on 1) preclinical optimization of novel therapeutic candidates, 

2) repurposing and/or reformulation of drugs currently 

in use to treat other disease conditions, and 3) preclinical development of naturally occurring compounds. 

Following are examples of new candidate therapeutics 

for each of these three areas. 

Novel compounds 

Tau aggregation inhibitors. One of the hallmarks of 

AD is the abnormal clustering of the tau protein into 

neurofibrillary tangles (see A Brief Primer on AD and the 

Brain, page 11). Tau has emerged as an attractive therapeutic target for AD and other neurodegenerative diseases, commonly known as tauopathies. A multidisciplinary team from the University of Pennsylvania in 

Philadelphia reported the discovery in mice of two candidate compounds that are effective inhibitors of tau 

aggregation and can penetrate the blood brain barrier 

after being orally administered (Ballatore et al., 2010). 

The Translational Research Program is supporting the 

further preclinical optimization of these compounds. 

Hsp90 inhibitors. Heat shock protein 90 (Hsp90) is a 

member of a large family of molecules that help regulate 

the transformation of healthy cells to diseased ones. Until 

recently, Hsp90 was mostly known for its involvement in 

malignant transformation in cancer. But several laboratories have now provided evidence that Hsp90 plays a role 

in maintaining the stability of abnormally folded neuronal proteins, allowing the accumulation of toxic aggregates (Luo et al., 2010). Previous research has shown that 

agents that inhibit Hsp90 can protect neurons against 

beta-amyloid toxicity as well as tau aggregation. A drug 

discovery research team from the University of Kansas in 

Lawrence involved in the design of novel Hsp90 inhibitors for AD reported that three new analogues of the 

Hsp90 inhibitor novobiocin provide excellent neuroprotection, with little, if any, toxicity in a cell culture model 

of beta-amyloid (Lu Y et al., 2009). 

Old drug, new purpose 

Memory is governed by long-term changes in nerve cell 

firing patterns, which in turn require changes in the 

expression of certain neuronal genes. Regulation of gene 

expression is the business of proteins called “transcription factors.” The activity of one such factor, CREB 

(which seems to be particularly important in memory 

formation) can be increased using the drug sildenafil 

(Viagra®). When scientists at Columbia University in 

New York, supported by NIA and NINDS, applied 

sildenafil to hippocampal cells from AD model mice in 

tissue culture, they saw immediate and long-lasting 

improvements in synaptic function. In addition, shortterm (2- to 3-week) administration of sildenafil to living 

AD model mice significantly improved their performance in memory tests up to 3 months later. 

Interestingly, the drug also reduced beta-amyloid levels 

in these mice, perhaps through its effects on gene 

expression (Puzzo et al., 2009). 

Nature to the rescue 

Data from epidemiological studies and laboratory experiments suggest that gonadal steroid hormones (sex steroids) and their metabolites can promote neuronal 

health, while their decline or absence is associated with 

higher risk of neurodegenerative disease, including 

Alzheimer’s (see Estrogen, page 25). One of the steroids 

that declines in the aged brain, and in AD brains in particular, is allopregnanolone. Previous experimental evidence demonstrated the ability of this neurosteroid to 

stimulate the production of neuronal progenitor cells 

(cells that ultimately develop into functional neuronal 

cells in the brain) in rodent models. A multidisciplinary 

team from the University of Southern California in Los 

Angeles initiated a translational project focused on the 

preclinical development of allopregnanolone as a regenerative AD therapeutic. The team reported that allopregnanolone can rescue the loss of neurogenic potential in a 

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| Research Advances 

transgenic mouse model of AD and reverse associated 

cognitive decline (Wang JM et al., 2010). The USC 

team is currently identifying a formulation and dosing 

regimen for allopregnanolone that will result in an optimal efficacy and safety profile for testing in future clinical trials in humans. 

Additional advances in drug discovery and preclinical 

drug development: 

n Cohen AD et al. (2009a) Anti-amyloid effects of small molecule Abeta-binding agents in PS1/APP mice. University of 

Pittsburgh. Supported by NIA. 

n Ma QL et al. (2009) Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via 

c-Jun N-terminal kinase signaling: suppression by omega-3 fatty 

acids and curcumin. University of California, Los Angeles. 

Supported by NIA and NCCAM. 

New Therapeutic Targets 

As scientists continue to learn more about the complexity 

of the processes and mechanisms of AD, they are also discovering potential new targets for attacking the disease and 

new approaches for treating it. These basic research findings 

are the stepping stones for translational research efforts that 

ultimately may lead to new, effective drug therapies. 

Nourishing the brain with its own growth factor 

Brain-derived neurotrophic factor (BDNF), a growth factor produced by neurons, is essential for early brain 

development and healthy brain function in adulthood. 

Among other actions, BDNF supports nerve cell growth 

and survival and promotes synaptic outgrowth and plasticity. In people with AD, BDNF levels are abnormally 

low in certain brain regions where neurons are dying. To 

test the possible therapeutic effects of BDNF, researchers 

at the University of California, San Diego used a gene 

therapy approach in several animal models of AD and 

aging. They found that BDNF had beneficial effects in 

all of the models. In AD model mice, it induced recovery 

of synapses and synaptic signaling markers and improved 

spatial memory. In rats, BDNF prevented the death of 

cortical nerve cells that were exposed to beta-amyloid in 

tissue culture. BDNF gene therapy also had positive 

effects on spatial learning and memory in the aged rats, 

as well as in nonhuman primates (Nagahara et al., 2009). 

These findings indicate that BDNF has multiple protective effects on the neuronal systems that deteriorate during AD and suggest that therapeutic delivery of BDNF 

or other means of stimulating BDNF activity holds 

promise as a therapeutic approach for the disease. 

Stem cell therapy for AD 

Neural stem cells—cells present in both embryonic and 

adult neural tissue that have the capacity to develop into 

neurons—have received less consideration as therapy for 

AD than for other neurodegenerative disorders like 

Parkinson’s disease and stroke. Because AD affects a 

wide variety of cell types across widespread regions of 

the brain, it seemed implausible that many different cells 

could be replaced using stem cells. Recently, however, 

scientists have realized that stem cells can improve brain 

function not only by replacing lost cells, but also by 

promoting the survival and function of remaining cells. 

Researchers at the University of California, Irvine, 

supported by NIA and NIAMS, took neural stem cells 

from newborn normal mice and transplanted them into 

the hippocampal regions of aged AD model mice with 

widespread plaques and tangles. The transplanted neural 

stem cells reversed spatial learning and memory deficits in 

the older mice. They did so not by reducing plaques or 

tangles in their brains, but by promoting the growth of 

new synapses in surrounding brain tissue. The beneficial 

effect of these stem cells turned out to be due to their 

secretion of the growth factor BDNF (Blurton-Jones et al., 

2009). This study is important because it suggests the 

potential of neural stem cell therapy in AD and shows its 

beneficial effects in old transgenic mice with substantial 

AD-like pathology in their brains. 

Clearing out beta-amyloid 

A number of potential new therapeutic targets are emerging from studies of the multiple mechanisms by which 

beta-amyloid is removed or cleared from the brain. Betaamyloid clearance is accomplished by proteins on brain 

blood vessels that bind beta-amyloid and transport it out 

of the brain and into the blood. A research team at 

Washington University in St. Louis, supported by NIA 

and the NIH Neuroscience Blueprint, showed that by 

experimentally increasing levels of the beta-amyloid 

transport protein LRP-1 in the mouse brain, it was possible to dramatically enhance beta-amyloid clearance and 

reduce its accumulation (Kim J et al., 2009). 

Work by another team of investigators at the 

University of Rochester, NY, supported by NIA, 
 

 

 

 

 

 

 

 

 

 

 

 

| Research Advances 

NINDS, and NHLBI, raised the possibility that betaamyloid clearance by the same transport protein is disrupted in some forms of AD. They found that LRP-1 

production is suppressed by two gene regulatory proteins (SRF and myocardin) present in abnormally high 

levels in the brain blood vessels of some people with 

AD. Levels of these regulatory proteins in turn are stimulated by low blood oxygen levels, a condition associated 

with AD (Bell et al., 2009). 

Additional advances related to translational research and 

beta-amyloid clearance: 

n Lakshmana et al. (2009) Novel role of RanBP9 in BACE1 

processing of amyloid precursor protein and amyloid beta peptide generation. University of California, San Diego. Supported 

by NIA. 

n Lakshmana et al. (2010) A fragment of the scaffolding protein 

RanBP9 is increased in Alzheimer’s disease brains and strongly 

potentiates beta-amyloid peptide generation. University of 

California, San Diego. Supported by NIA. 

n Oddo et al. (2009) Genetically altering Abeta distribution from 

the brain to the vasculature ameliorates tau pathology. University 

of California, Irvine. Supported by NIA. 

n Persaud-Sawin et al. (2009) Raft aggregation with specific 

receptor recruitment is required for microglial phagocytosis of 

Abeta42. NIEHS Intramural Program. 

looking to the future: 

translational Research 

A

lthough NIA’s AD Translational Research Program 

has built significant momentum, much remains to 

be done. To this end, NIA held an advisory panel 

workshop on “Alzheimer’s Disease Preclinical Therapy 

Development” in October 2010. This meeting convened 

leading therapy development experts from academia, biotechnology and pharmaceutical companies, and diseasefocused foundations to develop recommendations for 

continued improvements in translational research efforts. 

7 testing therapies for 

Prevention and treatment 

AD Clinical Trials 

Clinical trials, which compare a potential new treatment 

with a standard treatment or a placebo (an inactive substance), are the only way to demonstrate whether a drug 

or other type of treatment is safe and effective in 

humans. The first stage of human trials, Phase I, involves 

testing a new treatment in a small group of healthy people to evaluate safety and tolerability. In Phase II, the 

treatment is given to a larger group of people with the 

disease to see if it is effective and to further evaluate 

safety. In Phase III, the last stage before a treatment is 

approved by the FDA, the treatment is given to a large 

group of people with the disease to confirm its effectiveness and monitor safety. Phase III trials are complex and 

expensive, involving hundreds or even thousands of people and often conducted over long periods of time. 

In AD, some clinical trials focus on treatment— 

strategies to preserve cognitive function for as long as 

possible and alleviate behavioral or psychiatric problems. 

Other trials aim to delay progression from MCI to AD 

(secondary prevention). Still others focus on primary 

prevention—strategies to help cognitively healthy people 

reduce the risk of developing AD in the future. 

NIA provides both infrastructure and funding 

opportunities for clinical development of AD therapeutics. The major clinical trial programs are the Alzheimer’s 

Disease Cooperative Study (ADCS) and the AD Pilot 

Clinical Trials Initiative (see additional information, pages 

53 and 56). These programs are in addition to continued 

support of investigator-initiated clinical trials for AD, 

MCI, and age-related cognitive decline. 

Results from completed AD clinical trials 

Two trials published in 2009 support the notion that 

AD progression can be slowed by targeting symptoms 

other than memory loss (for example, depression or 

sleep apnea, in the trials reported here). A third study 

argues against the popular belief that gingko biloba is 

effective in preventing cognitive decline. Eleven additional clinical trials reached completion this year; the 

results are still being analyzed and/or awaiting publication (see Recently Completed Trials, page 40). 

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Two trials found that AD 

progression can be slowed by targeting 

symptoms other than memory loss, 

such as depression or sleep apnea. 

Slowing progression to AD among 

people with MCI and depression 

People with MCI are at higher risk for progressing to 

AD if they also have neuropsychiatric symptoms such as 

depression, apathy, or anxiety. The Alzheimer’s Disease 

Cooperative Study (ADCS) examined the effects of 

depression on progression from amnestic MCI to AD in 

208 people who had depression and 548 who did not. 

Symptoms of depression were assessed as a secondary 

outcome measure as part of the ADCS trial of donepezil 

(Aricept®), vitamin E, and placebo in participants with 

MCI. Study investigators reported that depressed 

patients were more likely to progress from MCI to AD 

than nondepressed patients. Also, the proportion of 

depressed patients progressing to AD was significantly 

lower for the donepezil group than for the combined 

vitamin E/placebo group for a little more than 2 years 

and remained marginally lower for up to 2.7 years. 

Nondepressed MCI patients who received donepezil 

initially exhibited a slower rate of progression compared 

to the vitamin E and placebo groups, but by 2 years 

there was no difference between the groups. These 

findings demonstrate that donepezil can reduce the 

increased risk of progression to AD in MCI patients 

with depressive symptoms (Lu PH et al., 2009). 

Treatment of sleep apnea may slow cognitive decline 

Obstructive sleep apnea is common among people with 

AD. The condition reduces brain oxygen levels and 

disrupts normal sleep patterns and thus may exacerbate 

cognitive and behavioral problems in people with AD. 

Researchers at the University of California, San Diego, 

supported by NIA and NCRR, evaluated the long-term 

effects of continuous positive airway pressure (CPAP) 

treatment in a small sample of 10 people who had participated in a larger 6-week randomized controlled trial of 

CPAP in AD patients with obstructive sleep apnea. Five 

of the participants had continued CPAP use for a little 

more than a year after the larger trial ended, and the other 

five had not. Those who continued CPAP use showed less 

cognitive decline and daytime sleepiness, greater stabilization of depressive symptoms, and better sleep quality than 

those who discontinued CPAP use. Importantly, caregivers of people in the CPAP group reported that their sleep 

was better and that the patients’ behavioral disturbances 

improved (Cooke et al., 2009). The results of this small 

study suggest that long-term CPAP treatment for patients 

with AD and obstructive sleep apnea may slow cognitive 

decline and produce lasting improvements in sleep and 

mood. Larger randomized controlled trials are needed to 

test these findings. (See also Amyloid and Sleep, page 17.) 

Gingko not effective in reducing 

risk of AD or cognitive decline 

Gingko biloba is a widely marketed supplement used by 

people hoping to improve their cognitive health. The largest double-blind, randomized controlled trial to date, the 

Ginkgo Evaluation of Memory (GEM) study, included 

3,069 community-dwelling older adults aged 72 to 96 

years who had either normal cognition or MCI. The study, 

funded by NCCAM, NIA, and NHLBI, was conducted 

in six academic medical centers in the United States 

between 2000 and 2008. The primary analysis demonstrated that gingko was not effective in reducing risk of 

either AD or dementia overall. To learn if ginkgo has more 

subtle effects on cognitive health, GEM investigators analyzed additional data from this trial. They found no significant effect on cognitive decline or on more specific 

measures of memory, attention, visuospatial skill, language, 

and executive functioning (Snitz et al., 2009). 
 

 

 

 

 

 

 

 

 

 

 

 

| Research Advances 

Recently Completed trials 

The following clinical trials supported by NIA were recently completed and are undergoing data analysis: 

n ACCORD–MIND (Action to Control Cardiovascular Risk in 

Diabetes–Memory in Diabetes)—NIA-funded primary 

prevention add-on trial to NHLBI’s ACCORD trial 

Principal Investigator (PI): Lenore Launer, NIA Intramural 

Research Program 

n ESPRIT (Evaluating Simvastatin’s Potential Role in Therapy) 

PI: Cynthia Carlsson, University of Wisconsin 

n RECALL (Rosiglitazone Effects on Cognition for Adults in 

Later Life) 

PI: Suzanne Craft, University of Washington/VA Medical Center 

n SNIFF 120 (Study of Insulin to Fight Forgetfulness, 120 

Days) 

PI: Suzanne Craft, University of Washington/VA Medical Center 

n SHARP-P (Seniors Health and Activity Research 

Program Pilot) 

PI: Mark Espeland, Wake Forest University 

n Transdermal Nicotine Treatment of MCI 

PI: Paul Newhouse, University of Vermont 

Investigators are preparing and submitting results for publication 

from the following completed clinical trials supported by NIA: 

n Huperzine A in Alzheimer’s Disease—ADCS 

PI: Paul Aisen, University of California, San Diego 

n VALID (Valproate in Dementia)—ADCS 

PI: Pierre Tariot, Banner Alzheimer’s Institute 

n CLASP (Cholesterol Lowering Agent to Slow Progression 

of Alzheimer’s Disease Study)—ADCS 

PI: Mary Sano, Mount Sinai 

n Antioxidant Trial (Vitamins E and C, alpha lipoic acid, 

coenzyme Q)—ADCS 

PI: Douglas Galasko, University of California, San Diego 

n PREPARE (Prevention of Postmenopausal Alzheimer 

Disease and Cognitive Loss with Replacement Estrogen) 

PI: Mary Sano, Mount Sinai 

Observational studies on treatments 

There has been increasing interest in combination therapy for AD—simultaneous administration of two or 

more drugs or behavioral interventions. Investigators at 

the University of Pittsburgh Alzheimer’s Disease 

Research Center looked at the effects of combined treatment with drugs from each of the two major classes currently approved to treat AD, cholinesterase inhibitors 

and an NMDA receptor blocker (memantine). They 

studied data from 943 probable AD patients at the 

Center from April 1983 to December 2004 who had 

been treated with a cholinesterase inhibitor alone, a cholinesterase inhibitor plus memantine, or no medication. 

The researchers found that those treated with two drugs 

delayed admission to a nursing home significantly longer 

than those who took just one drug (Lopez et al., 2009). 

Cholinesterase inhibitors may ameliorate some types 

of behavioral symptoms in AD patients, but what happens when those drugs are stopped? Researchers at 

Brown University in Providence, RI, found that discontinuation of cholinesterase medications in nursing home 

residents with dementia who had been treated for 3 to 9 

months was associated with some worsening behavioral 

changes and less time engaged in leisure-related activities 

compared to residents who received longer-term treatment (greater than 9 months) (Daiello et al., 2009). 

Ongoing clinical trials 

Alzheimer’s Disease Cooperative Study 

The ADCS, a large clinical trials consortium with sites 

throughout the United States and Canada, is a major initiative for AD clinical trials in the Federal Government. It 

addresses treatments for cognitive and behavioral symptoms (see additional information on page 53). The ADCS 

mission is to advance research in the development of clinical trial designs, instruments, and interventions that 

might be useful for treating patients with AD, particularly 

interventions that might not be developed by industry. 

The most recent round of new ADCS studies, 

funded in October 2006, explore a variety of approaches: 

n Docosahexaenoic acid (DHA). This completed trial 

examined whether treatment with DHA, an omega-3 fatty 

acid found in fish, would slow cognitive decline in people 

with AD. Observational studies associate high fish consumption with reduced risk of AD in people, and studies 

in mouse models of AD show that dietary DHA reduces 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 40 
 

 

 

 

 

 

 

 

 

| Research Advances 

brain levels of beta-amyloid, oxidative damage associated 

with beta-amyloid, and neurotoxicity. The manuscript of 

the results has been accepted for publication in the Journal 

of the American Medical Association (JAMA). 

n Intravenous immunoglobulin (IVIg). IVIg, a blood 

product that is administered intravenously, contains naturally occurring antibodies against beta-amyloid. Preliminary 

studies have shown that IVIg may improve cognition, and 

research has demonstrated that IVIg increases levels of antibeta-amyloid antibodies in plasma and promotes clearance 

of beta-amyloid from CSF. This ongoing Phase III, doubleblind randomized controlled trial will demonstrate whether 

IVIg is effective in treating AD. 

Home-based assessment. This ongoing study, conducted in people aged 75 and older, will examine the 

development and use of three types of home-based assessments: 1) a low-technology telephone assessment, 2) a 

high-technology automated telephone assessment, and 3) 

a high-technology computer assessment. Cognition, daily 

functioning, mood, and other factors will be evaluated in 

each of the methods. These innovative assessment and 

data collection tools will be compared to traditional 

in-person measures. The findings from this study will 

provide information on how home-based assessments 

might be used in prevention trials. Such methods could 

significantly reduce the cost and increase the feasibility of 

participation in long-term clinical trials. 

Resveratrol. This Phase II, double-blind randomized 

controlled trial, scheduled to begin in 2011, will evaluate the impact of resveratrol treatment on AD biomarkers and clinical outcomes in patients with mild to 

moderate AD. Resveratrol, a compound found in grapes 

and wine, has been shown in animal studies to be neuroprotective, and observational studies have shown that 

moderate consumption of red wine is associated with a 

lower incidence of AD. 

NIH currently supports 37 active clinical trials, 

including pilot and large-scale trials, of a wide range of 

interventions to prevent, slow, or treat AD and/or MCI 

(see Table 1 and Table 2). In particular, the NIA is currently funding seven primary prevention and six secondary prevention trials (Table 1). Of the primary prevention 

n

n

trials, two 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 mmHg to 120 mmHg. The 

add-on study, SPRINT-MIND, funded by NIA and 

NINDS, will assess the effect of lowering systolic blood 

pressure 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. 

A number of the prevention trials are focusing on 

lifestyle interventions, including exercise, cognitive 

training, and a combination of the two. Other prevention trials examine how treatments for diabetes might 

reduce risk of AD. Diabetes is associated with the development of AD, and insulin regulation has been shown 

to be disrupted in AD. Two trials are examining the 

effect of the diabetes medications metformin and pioglitazone on cognition and progression to AD in MCI 

subjects who are also obese. The trial using pioglitazone 

compares the effects of the medication and exercise 

(endurance training) as well as a placebo. 

Another recently completed diabetes-related trial 

(SNIFF-120) examined the effects of intranasal insulin in 

people with MCI or early AD. The idea is that restoring 

normal insulin function in the brain may provide cognitive benefit and slow disease progression. Administering 

insulin through the nose does not result in increased 

peripheral insulin levels, and the drug enters the brain 

within 15 minutes. Data analysis is ongoing for this trial. 

Table 2 summarizes treatment trials to delay the 

progression of AD and to treat the behavioral disturbances typical of the disease. It also summarizes several 

trials that are testing biomarkers and performing feasibility studies. Taken together, the trials test a wide range 

of potential therapies. Several are due to be completed 

in the next 2 years; other longer trials will not finish 

data collection until 2014 or later. It is important to 

note that the year the trial is completed does not include 

the additional time necessary for analysis of data and 

publication of findings. 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 41 
 

 

 

 

 

 

 

| Research Advances 

tABlE 1. ongoing Ad/MCI Prevention Clinical trials funded by nIA 

Trial Name 

Principal 

Investigator/ 

Institution Intervention Population 

Type 

of Trial 

Anticipated 

Completion 

Date 

Antioxidants 

PREADVISE (Prevention 

of Alzheimer’s Disease 

by Vitamin E and 

Selenium)* 

Frederick Schmitt, 

Univ. of Kentucky 

Vitamin E, Selenium,
 

Vitamin E + Selenium
 

Men age 60-90 Primary 

Prevention 

2014 

Vitamin E in Aging 

Persons with Down 

Syndrome 

Arthur Dalton, 

NY State Inst. for Basic 

Research in 

Developmental 

Disabilities 

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)† 

John Paul San Giovanni 

(Study Director), NEI 

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 

Cardiovascular 

ASPREE (Aspirin in 

Reducing Events in 

the Elderly) 

Richard Grimm, 

Berman Center for 

Outcomes & Clinical 

Research; John McNeil, 

Monash Univ. 

Aspirin Healthy adults age 70+ Primary 

Prevention 

2017 

SPRINT-MIND 

(Systolic Blood 

Pressure Intervention 

Trial-MIND)* 

David Reboussin, Wake 

Forest Univ. 

Blood pressure 

lowering to 

<140 mmHg versus 

<120 mmHg 

Adults age 55+ with systolic 

blood pressure of 130 mmHg 

or higher, history of 

cardiovascular disease, 

high risk for heart disease 

Primary 

Prevention 

2017 

Hormones 

ELITE (Early Versus 

Late Intervention with 

Estradiol) 

Howard Hodis, 

Univ. of Southern 

California 

17β-estradiol Healthy early (less than 6 

years) or late (10 years+) 

menopausal women 

Primary 

Prevention 

2014 

SMART 

(Somatotrophics, 

Memory, and Aging 

Research Trial) 

Michael Vitiello, 

Univ. of Washington 

Growth hormone 

releasing hormone 

(GHRH) 

People with MCI and healthy 

older adults age 55-80 

Secondary 

Prevention 

2011 

Testosterone 

Supplementation in 

Men with MCI 

Monique Cherrier, 

Univ. of Washington 

Testosterone Older men with MCI and 

low testosterone 

Secondary 

Prevention 

2011 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 42 
Trial Name 

Principal 

Investigator/ 

Institution Intervention Population 

Type 

of Trial 

Anticipated 

Completion 

Date 

Diabetes 

Metformin in Amnestic 

MCI 

Jose Luchsinger, 

Columbia Univ. 

Metformin Overweight/obese older 

adults with MCI 

Secondary 

Prevention 

2012 

Pioglitazone & Exercise 

Effects on Older Adults 

with MCI and 

Metabolic Syndrome 

Robert Schwartz, Univ. 

of Colorado, Denver 

Pioglitazone Overweight/obese older 

adults with MCI 

Secondary 

Prevention 

2012 

Exercise, Cognitive Training 

Exercise Versus 

Cognitive Interventions 

for Elders at Risk for 

Dementia 

David Loewenstein, 

Mount Sinai Medical 

Center, Miami 

Cognitive training, 

aerobic exercise 

training, cognitive 

training + aerobic 

exercise training 

People with MCI Secondary 

Prevention 

2012 

Lifestyle Interventions 

and Independence for 

Elders (LIFE) 

Marco Pahor, 

Univ. of Florida 

Aerobic exercise, 

resistance, and 

flexibility exercises 

Adults age 70+ Primary 

Prevention 

2015 

Memory Training 

Intervention in Mild 

Cognitive Impairment 

Miriam Mintzer, Johns 

Hopkins Univ. 

Repetition lag training 

procedure (RLTP) 

People with MCI Secondary 

Prevention 

2014 

Note: For information on new and currently recruiting trials, visit: www.nia.nih.gov/Alzheimers/ResearchInformation/ClinicalTrials 

or www.ClinicalTrials.gov. 

* NIA-funded primary prevention add-on trials: PREADVISE (add-on to National Cancer Institute’s SELECT trial); 

SPRINT-MIND (add-on to National Heart, Lung, and Blood Institute’s and National Institute of Diabetes and Digestive 

and Kidney Diseases’ SPRINT trial; co-funded with the National Institute of Neurological Disorders and Stroke). 

† Co-funded primary prevention trial: AREDS2 (National Eye Institute, lead institute). 

| Research Advances 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 43 
tABlE 2. ongoing Ad/MCI treatment, Biomarker, and feasibility 

Clinical trials funded by nIA 

Trial Name 

Principal Investigator/ 

Institution Intervention Population 

Anticipated 

Completion 

Date 

Cardiovascular 

Effects of Simvastatin 

on CSF AD Biomarkers 

in Cognitively Normal 

Subjects 

Gail Li, Univ. of Washington Simvastatin Cognitively normal 

adults age 45-64 

2013 

Statin Effects on 

Beta-Amyloid and 

Cerebral Perfusion in 

Adults at Risk for AD 

Cynthia Carlsson, 

Univ. of Wisconsin, Madison 

Simvastatin Adults at high risk 

of AD (family history, 

APOE4) age 45-65 

2013 

Hormones 

Alzheimer’s Disease: 

Potential Benefit of 

Isoflavones 

Carey Gleason, 

Univ. of Wisconsin, Madison 

Novasoy (soy isoflavones– 

phytoestrogens) 

People with AD 2010 

Estrogen Receptor-beta 

phytoSERMs for 

Management 

Lon Schneider, 

Univ. of Southern California 

ER2-selective 

phytoestrogens 

(phytoSERMs–selective 

estrogen receptor 

modulators) 

Postmenopausal 

women age 50-59 

2014 

Raloxifene for Women 

with Alzheimer’s Disease 

Victor Henderson, 

Stanford Univ. 

Raloxifene Older women 

with AD 

2012 

Exercise, Cognitive Training 

Aerobic Fitness in 

Slowing the Progression 

of AD 

Jeffrey Burns, 

Univ. of Kansas 

Aerobic exercise training People with AD 2014 

Conversational 

Engagement as a Means 

to Delay AD Onset 

Hiroko Dodge, Oregon 

Health & Science Univ. 

Internet-based 

conversational engagement 

Adults age 75+ 2014 

Effects of Standardized 

Aerobic Exercise Training 

on Neurocognition and 

Neurodegeneration 

Thomas Obisesan, 

Howard Univ. 

Aerobic exercise training African Americans 

with AD 

2012 

MCI: Cerebrovascular 

Dysfunction and 

Exercise Training 

Rong Zhang & 

Hanzhang Lu, Univ. of 

Texas Southwestern 

Endurance exercise training People with MCI 2014 

Neural Effects of 

Exercise, Cognitive, or 

Combined Training in 

AD At-Risk Elders 

Stephen Rao, 

Cleveland Clinic 

Cognitive training, 

aerobic exercise training, 

cognitive training + aerobic 

exercise training 

Healthy adults age 

65-85 

2012 

| Research Advances 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 44 
Trial Name 

Principal Investigator/ 

Institution Intervention Population 

Anticipated 

Completion 

Date 

Other Interventions 

AAV-NGF Gene Delivery 

in Alzheimer’s Disease 

Paul Aisen, Univ. of 

California, San Diego 

Nerve growth factor (NGF) 

gene delivery 

People with AD 2014 

ADMIT (Alzheimer’s Disease 

Multiple Intervention Trial) 

Chris Callahan, 

Indiana Univ. 

Home-based 

occupational therapy 

People with AD 2016 

fMRI Activation in Mild 

Cognitive Impairment 

Michela Gallagher, 

Johns Hopkins Univ. 

Levetiracetam People with MCI 2012 

Glucose Regulation and 

Memory in Alzheimer’s 

Disease 

Suzanne Craft, 

Univ. of Washington 

Improved insulin resistance, 

3 studies: diet, triglyceride 

emulsion, rosiglitazone 

People with AD and 

age-matched healthy 

older adults 

2016 

Intravenous Immunoglobulin 

(IVIg) for Treatment of AD 

(passive immunization)* 

Norman Relkin, Weill 

Medical College, Cornell Univ. 

IVIg People with AD 2013 

Lipoic Acid and Omega-3 

Fatty Acids in AD 

Lynne Shinto, Oregon 

Health & Science Univ. 

Lipoic acid and/or omega-3 

fatty acids (DHA and EPA) 

People with AD 2014 

Thalidomide as BACE1 

Inhibitor in AD 

Marwan Sabbagh, Banner 

Sun Health Research Inst. 

Thalidomide People with AD 2012 

Therapeutic Effects of 

Cataract Removal in AD 

Grover Cleveland Gilmore, 

Case Western Reserve Univ. 

Cataract removal surgery People with AD 2014 

Behavioral Disturbance Interventions 

ADMET (Apathy in 

Alzheimer’s Disease 

Methylphenidate Trial) 

Jacobo Mintzer, Medical 

Univ. of South Carolina; 

Krista Lanctot, Sunnybrook 

Health Sciences Center; 

Paul Rosenberg, 

Johns Hopkins Univ. 

Methylphenidate People with AD 2012 

Antipsychotic 

Discontinuation in AD 

Davangere Devanand, 

NYSPI/Columbia Univ. 

Risperidone People with AD 2011 

CITAD (Citalopram 

Treatment for Agitation in 

Alzheimer Dementia) 

Constantine Lyketsos, 

Johns Hopkins Univ. 

Citalopram People with AD 2014 

Light Treatment for Sleep/ 

Wake Disturbances in AD 

Jerome Yesavage, 

Stanford Univ. 

Light treatment People with AD and 

their caregivers 

2010 

Prazosin Treatment for 

Disruptive Agitation in 

Alzheimer’s Disease 

Elaine Peskind, 

Univ. of Washington 

Prazosin People with AD 2013 

TREA (Treatment Routes 

for Exploring Agitation) 

Jiska Cohen-Mansfield, 

Research Inst. on Aging 

TREA-systematic approach 

to individualizing 

nonpharmacological 

interventions for persons 

with dementia 

Nursing home 

residents with 

AD/dementia 

2012 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 45 

| Research Advances 

Note: For information on new and currently recruiting trials, visit: www.nia.nih.gov/Alzheimers/ResearchInformation/ClinicalTrials 

or www.ClinicalTrials.gov. 

*Alzheimer’s Disease Cooperative Study trial 
| Research Advances 

looking to the future: Biomarkers and Ad Clinical trials 

A

D clinical trials have progressed 

 from a focus on symptomatic 

 treatment to disease modifica

tion to halting the progression from MCI 

to AD (secondary prevention) to prevent

ing MCI/AD (primary prevention). Many 

researchers believe that prevention trials 

that are started before AD pathology has 

taken hold have the best chance of a 

positive result. However, the conduct of 

prevention trials needs to become more 

efficient by reducing the time and/or 

number of subjects involved, each of 

which would reduce the cost. It is clear 

from completed AD prevention trials, 

such as ADAPT (AD Anti-Inflammatory 

­

­

­

­

­

Prevention Trial) and GEMS (Ginkgo 

Evaluation of Memory Study), that using 

as endpoints the progression from nor

mal cognition to a clinical diagnosis of 

MCI/AD or changes in cognition takes 8 

to 10 years and costs tens of millions of 

dollars. 

Based on the results of ADNI and 

similar imaging and fluid biomarker stud

ies, the AD clinical trials community is 

starting to consider the use of biomark

ers as potential endpoints in prevention 

trials. Biomarkers such as structural MRI,

amyloid PET imaging, FDG PET, and CSF 

protein concentrations may ultimately 

provide a window into the course of the 

­

­

­

disease in the living brain. Their use in 

clinical trials may show whether a partic

ular intervention affects underlying brain 

pathology more quickly than traditional 

clinical/neuropsychological outcome 

measures would. These biomarkers could 

also be used as selection factors to 

determine which normal subjects, for 

example, have significant beta-amyloid 

loads in their brains and may be at high

er risk of progression to MCI/AD in a clin

ical trial. Discussions about the feasibility 

 and cost of such biomarker prevention 

trials are ongoing, but this is certainly an 

area of research that will be much more 

prominent in the near future. 

Clinical Trials to Maintain or Improve 

Cognitive Function with Age 

As the population ages, there is growing interest not 

only in preventing AD but in maintaining general good 

cognitive function and health throughout life. Although 

modest in comparison with AD, cognitive decline associated with normal aging significantly compromises 

quality of life and independent living. Terms like “use it 

or lose it” refer to mental fitness and perhaps how exercise or diet might keep cognitive decline at bay. NIA is 

testing a number of interventions to see if they might 

directly benefit cognitive health. As these tests move forward, NIH encourages the adoption of healthy lifestyle 

practices, as some, like exercise and social engagement, 

are known to reduce risk of other diseases or are otherwise important as people age. 

Trial results 

There is widespread popular belief that mental fitness 

can be increased with consistent brain exercise (e.g., 

crossword puzzles, Web-based games). To date, clinical 

trials have yielded little clear evidence to support this 

notion. This year, however, two clinical trials reported 

that different cognitive training protocols improved 

certain aspects of cognitive function in older adults. 

The Improvement in Memory with Plasticity-based 

Adaptive Cognitive Training (IMPACT) study tested a 

computer-based training intervention designed to 

improve speed and accuracy of auditory information 

processing in a randomized trial with 487 cognitively 

normal older adults age 65 and older in San Francisco 

and Los Angeles, CA, and Rochester, MN. 

Investigators found that training on one particular 

set of auditory tasks can improve a person’s performance 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 46 ’
 

 

 

 

 

 

| Research Advances 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 47 ’

on other auditory tasks and that participants who 

received training later showed improved performance on 

not only the specific exercises they had been trained 

with, but other auditory memory and attention exercises 

as well. (Smith et al., 2009) 

In another study of 66 cognitively normal adults 

ages 65 to 75 at Wake Forest University in WinstonSalem, NC, supported by NIA, NINDS, and NCRR, 

researchers observed significant benefits of an intervention aimed at improving the brain’s ability to focus on 

one set of visual or auditory signals while resisting distraction by irrelevant ones (Mozolic et al., 2009). These 

trials showed training effects on highly related tasks, but 

leave the question unanswered as to what sort of brain 

exercise, or combination of exercises, could improve 

cognitive performance more broadly. 

The Experience Corps study from Johns Hopkins 

University in Baltimore, MD, supports the concept that 

activities aimed at enriching life experience can lead to 

positive changes in specific brain circuits in older people. 

Employing an “immersion” intervention that combined 

physical, social, and cognitive activity simultaneously 

through participation in a volunteer program for young 

children in Baltimore City public schools, the researchers 

examined cognitive improvements and brain function in 

eight older female study participants who were already in 

the study compared to nine matched controls who were 

on the wait list to participate. The study revealed improved 

executive function—the ability to exercise control over 

cognitive function, such as switching quickly and accurately from task to task or carrying out a sequence of 

tasks appropriately—in the study participants that was 

correlated with increased activity in prefrontal cortex relative to controls (Carlson et al., 2009). The results indicate that an intervention designed to promote better 

cognitive function through everyday activity may 

enhance plasticity in relevant brain regions. Larger studies will be necessary to validate these findings. 

Additional advance in remediating age-related cognitive 

impairment: 

n Hertzog et al. (2009) Enrichment effects on adult cognitive 

development: can the functional capacity of older adults be 

preserved and enhanced? 

NIA is testing a number of different interventions to 

see if they might directly benefit cognitive health. 

Ongoing trials on age-related cognitive function 

NIA currently supports 27 active clinical trials, including pilot and large-scale trials as well as treatment studies, to better understand the mechanisms related to 

cognitive decline and to better target interventions (see 

Table 3). Approaches include cognitive training, exercise, 

nutritional supplementation, hormone therapy, combinations of these, and pharmacological intervention. In 

addition, interventions to control hypertension and to 

regulate kidney dialysis to improve cognitive function 

are underway. Even though the range of interventions is 

wide, the trials share the common focus of trying to 

remediate age-related cognitive decline. 
tABlE 3. ongoing Age-Related Cognitive decline 

Clinical trials funded by nIA 

Trial Name 

Principal Investigator/ 

Institution Intervention Population 

Anticipated 

Completion 

Date 

Cognitive Training 

Active Interventions for 

the Aging Mind 

Denise Park, 

Univ. of Texas, Dallas 

Cognitive enrichment 

through training in digital 

photography or quilting 

Healthy adults 

age 60+ 

2012 

Brain-Based Approach 

to Enhancing Executive 

Control Functions in 

Healthy Aging 

Mark D’Esposito, Univ. of 

California, Berkeley 

Cognitive training Healthy adults 

age 50+ 

2012 

Expanding the 

Implementation of an 

Effective Cognitive 

Aging Intervention 

Helga Noice, 

Elmhurst College 

Cognitive enrichment 

through training in acting 

Healthy adults 

age 65+ 

2010 

Experience Corps Trial: 

Improving Health in Older 

Populations through 

Generativity 

George Rebok, 

Johns Hopkins Univ. 

Health promotion for older 

adults embedded within a 

social engagement program 

(volunteering in schools) 

Healthy adults 

age 60+ 

2011 

Senior Odyssey: A Test 

of the Engagement 

Hypothesis of 

Cognitive Aging 

Elizabeth Stine-Morrow, 

Univ. of Illinois, 

Urbana-Champaign 

Cognitive enhancement 

through participation in the 

Odyssey of the Mind program 

Healthy adults 

age 60+ 

2012 

Speed of Processing Modes 

to Prevent Cognitive Decline 

in Older Adults 

Fredric D. Wolinsky, 

Univ. of Iowa 

Comparison of standard 

versus enhanced visual 

processing training 

Healthy adults 

age 50+ 

2011 

Omega-3 Fatty Acids and Antioxidants 

Omega-3 and Blueberry 

Supplementation in 

Age-Related Cognitive 

Decline 

Robert Krikorian, 

Univ. of Cincinnati 

Omega-3 and blueberry 

supplements 

Healthy adults 

age 62-80 

2012 

Cardiovascular 

Aging and the 

Renin-Angiotensin 

System in Elderly 

Hypertensive Individuals 

Ihab Hajjar, Hebrew 

Rehabilitation Center for Aged 

Angiotensin receptor 

blocker, angiotensin-converting 

enzyme inhibitor, diuretic 

Adults age 60+ 

with uncontrolled 

hypertension and 

cognitive impairment 

2012 

| Research Advances 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 48 
Trial Name 

Principal Investigator/ 

Institution Intervention Population 

Anticipated 

Completion 

Date 

Hormones 

Estrogen Effects on 

Cholinergic Function in 

Older Women 

Paul Newhouse, 

Univ. of Vermont 

Acute or chronic 17β-estradiol 

+ muscarinic and nicotinic 

cholinergic antagonist 

Healthy women 

age 50+ 

2014 

Estrogen Use in Protection 

from Cognitive Decline 

Natalie Rasgon, 

Stanford Univ. 

Continuation of or removal 

from postmenopausal 

estrogen treatment 

Healthy women 

age 50-65 

2011 

Hormones and Cognitive 

Processing in Early 

Postmenopausal Women 

Yolanda Smith, 

Univ. of Michigan 

Estradiol and prometrium 

(progesterone) 

Healthy early 

postmenopausal 

women age 45-55 

2011 

KEEPS-CA (Kronos Early 

Estrogen Prevention Study– 

Cognitive and Affective 

Study) 

Sanjay Asthana, 

Univ. of Wisconsin, Madison 

Oral conjugated equine 

estrogen and transdermal 

17β-estradiol 

Healthy 

postmenopausal 

women age 42-58 

2012 

Mechanisms for Sex 

Steroid Effects on 

Cognition in Aging 

Jeri Janowsky, 

Oregon Health & Science 

Univ. 

Gonadotropin releasing 

hormone agonist, testosterone, 

testosterone + aromatase 

inhibitor 

Healthy adults 

age 60-80 and 

25-35 

2009 

Sex Steroids and 

Cognition in 

Postmenopausal Women 

Elliot Hirshman, 

George Washington Univ. 

Dehydroepiandrosterone 

(DHEA) 

Healthy 

postmenopausal 

women age 55-65 

and 70-80 

2011 

Testosterone Trial Peter Snyder, Univ. of 

Pennsylvania 

Testosterone gel Older men 2015 

Exercise 

Cognitive Benefits of 

Aerobic Exercise 

Across the Lifespan 

Yaakov Stern & 

Richard Sloan, 

Columbia Univ. 

Stretching/toning or 

aerobic conditioning 

Healthy adults 

age 25-65 

2015 

Dose-Response Study of 

Exercise in Older Adults 

Jeffrey Burns, 

Univ. of Kansas 

Aerobic exercise Healthy older adults 2012 

Exercise, Age-Related 

Memory Decline, and 

Hippocampal Function 

Scott Small & 

Richard Sloan, 

Columbia Univ. 

Exercise training or 

maintenance of sedentary 

lifestyle 

Healthy adults 

age 20-65 

2015 

Exercise, Cognitive Training 

Brain and Cognitive 

Changes after Reasoning 

or Physical Training in 

Cognitively Normal Seniors 

Sandra Chapman, 

Univ. of Texas, Dallas 

Cognitive training, 

aerobic exercise 

Adults age 60-75 2011 

Combined Exercise and 

Cognitive Training 

Intervention in Normal Aging 

Yaakov Stern, 

Columbia Univ. 

Aerobic exercise and 

cognitive training 

Healthy adults 

age 65-75 

2012 

| Research Advances 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 49 
Trial Name 

Principal Investigator/ 

Institution Intervention Population 

Anticipated 

Completion 

Date 

Exercise, Cognitive Training (Continued) 

Combining Exercise and 

Cognitive Training to 

Improve Everyday Function 

Ellen Binder & 

Mark McDaniel, 

Washington Univ. 

Aerobic exercise and 

cognitive training 

Healthy adults 

age 55-75 

2012 

Impact of Exercise and 

Engagement on Cognition 

in Older Adults 

Denise Park, 

Univ. of Texas, Dallas 

Walking, exercise regimen 

(aerobic tasks); quilting, 

photography (cognitive tasks) 

Healthy adults 

age 60-85 

2011 

Improvement of Visual 

Processing in Older Adults 

Karlene Ball, Univ. of 

Alabama, Birmingham 

Combination of visual 

processing training 

and exercise 

Healthy adults 

age 65+ 

2011 

Influence of Fitness and 

Cognitive Training on 

Brain and Cognition 

Arthur Kramer, Univ .of 

Illinois, Urbana-Champaign 

Aerobic training (walking), 

combined aerobic training/ 

cognitive training (dancing) 

Adults age 60-75 2015 

Tai Chi and Guided 

Autobiography for 

Remediation of Age-Related 

Cognitive Decline 

Victor Henderson, 

Stanford Univ. 

Low-impact Tai Chi exercise 

and autobiographical writing 

Healthy adults 

age 70+ 

2012 

Other 

Guanfacine Treatment 

for Prefrontal Cognitive 

Dysfunction in Elderly 

Subjects 

Christopher Van Dyck, 

Yale Univ. 

Guanfacine Healthy adults 

age 75+ 

2011 

Mechanisms of Cognitive 

Impairment in Chronic 

Kidney Disease 

Manjula Kurella Tamura, 

Stanford Univ. 

Frequent hemodialysis Adults age 55+ 2012 

| Research Advances 

Note: For information on new and currently recruiting trials, visit: www.nia.nih.gov/Alzheimers/ResearchInformation/ClinicalTrials 

or www.ClinicalTrials.gov. 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 50 
| Research Advances 

8 Supporting 

Ad Caregivers 

­

Family members often bear much of the burden of caring for people with AD. This includes the time and 

energy spent on caretaking, worry about the mental and 

physical decline of a loved one, and frustration in trying 

to communicate with and help them. While caregiving 

can be rewarding, it can also be incredibly stressful and 

contribute to physical and emotional health problems 

for the caregiver. Understanding caregivers’ needs and 

health risks and supporting them are critical for reducing the personal and public health burden of AD. 

Starting in 1995, NIA and NINR funded two clini

cal trials, REACH I and REACH II, to develop and test 

strategies for helping dementia caregivers manage their 

stress and emotional burden. The interventions included 

education on dementia, training in specific caregiving 

skills, and encouragement and techniques for physical 

and emotional self-care. The REACH findings are now 

being put into practice through two Federal agencies, the 

Veterans Administration (VA) and the Administration on 

Aging (AoA). 

The VA successfully used REACH strategies in a 

demonstration project with 19 of its home health care 

services and is now considering the use of REACH 

throughout the VA system. AoA’s REACH OUT 

Program is beginning to implement these strategies 

through local social service agencies. Researchers 

reported on one of the AoA-funded efforts, a partnership between the Alabama Department of Senior 

Services and the University of Alabama. An analysis of 

236 caregivers showed significant improvement in caregivers’ sense of burden, social support, depression, and 

health, as well as care recipient behavior problems and 

mood (Burgio et al., 2009). 

Efforts are underway to develop tests to gauge the 

emotional well-being of caregivers and identify areas 

where they may need support. One of these, the Risk 

Appraisal Measure (RAM), was tested on participants in 

the REACH II trial. The test probes six areas in which 

caregivers are at risk: depression, burden, self-care, 

health behavior, physical safety, and problem behaviors 

in the care recipients. RAM shows promise as a test to 

identify caregivers who might benefit from assistance in 

specific areas, for use in future research on supportive 

measures, and as a guide for clinicians and community 

health agencies (Czaja et al., 2009). 

Occupational therapy 

Participation in meaningful activity is known to promote well-being in older adults, and its potential to 

reduce symptoms of dementia is now receiving more 

attention. The Tailored Activity Program (TAP) is a 

home-based occupational therapy plan that assesses the 

interests and capabilities of individuals with dementia, 

provides a program of customized activities for each 

individual, and trains their families to use those activities as part of their daily care routines. A preliminary 

study of 57 people with dementia and their caregivers, 

conducted by researchers at Thomas Jefferson University 

in Philadelphia, PA, and funded by NIMH, found that 

the TAP program improved overall levels of pleasure and 

engagement in the demented individuals, as assessed by 

their caregivers. It also reduced the extent to which caregivers were upset by the behavioral symptoms of the 

individuals they were caring for, and improved their 

sense of skill and personal control in dealing with 

behavioral problems (Gitlin et al., 2009). 

Additional advances in support for caregivers: 

n Hilgeman et al. (2009) Testing a theoretical model of the stress 

process in Alzheimer’s caregivers with race as a moderator. 

University of Alabama, Tuscaloosa. Supported by NIA and NINR. 

n Mitchell et al. (2009) The clinical course of advanced dementia. Hebrew SeniorLife Institute for Aging Research, Boston. 

Supported by NIA. 

n Norton et al. (2009) Caregiver-recipient closeness and symptom progression in Alzheimer disease. Utah State University. 

Supported by NIA. 

n Skarupski et al. (2009) Race differences in emotional adaptation of family caregivers. Rush University. Supported by NIA. 

n Vitaliano et al. (2009) Depressed mood mediates decline in 

cognitive processing speed in caregivers. University of 

Washington. Supported by NIDDK, NCRR, and NIMH. 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’ 51 
| Advancing the Future of AD Research 

Advancing the Future of AD Research: 

resources and collaboration

A

lzheimer’s researchers are gaining better under­

 standing of AD pathology and using new insights 

 to develop therapies more likely to be successful 

in clinical trials. The outpouring of AD-related applications in response to the 2009 American Recovery and 

Reinvestment Act (ARRA) initiative, many of which 

were successful in review, demonstrated the vitality of 

new ideas in the scientific community. Several of these 

ideas, now supported by ARRA and non-ARRA funds, 

resulted in large collaborative projects designed to 

address the multifaceted nature of aging and AD 

research. However, the profusion of good ideas combined with investment in more expensive collaborative 

grants has its downside, and that is that the overall success rate for grants is very low and may be difficult to 

improve in the current economic climate. 

As planners and stewards of Federally funded science, NIA must both develop and sustain the research 

infrastructure necessary for productive research and at 

the same time phase out approaches that may have outlived their usefulness. In this endeavor, it is critical to 

maintain and encourage lines of research that hold 

promise for new therapies while reducing investment in 

research less crucial to the mission. The Institute keeps 

current and looks to the future in several ways—by convening and collaborating in forward-looking workshops 

in these new areas; by working within NIA to vigorously 

discuss new science and opportunities for new investments; and by partnering with other NIH Institutes and 

Federal agencies, not-for-profit groups, and industry. 

Collaboration has been key for NIA’s coordinating 

mechanisms and initiatives. By pooling and sharing data 

widely, and efficiently using the well-established AD 

research infrastructure, NIA is advancing AD science 

even within the limits of existing resources. 

Research Infrastructure 

NIA Intramural Research Program (IRP). In addition 

to funding a broad portfolio of aging-related and AD 

research at institutions across the country, NIA supports 

its own laboratory and clinical research program based 

in Baltimore, MD. The NIA IRP focuses on understanding age-related changes in physiology and behavior, 

the ability to adapt to biological and environmental 

stresses, and developing insight about the pathophysiology of age-related diseases, including AD. Laboratory 

research ranges from basic science, such as neurogenetics 

and cellular and molecular neurosciences, to personality 

and cognition. The IRP also leads the Baltimore 

Longitudinal Study of Aging, America’s longest-running 

scientific study of human aging, begun in 1958, along 

with other clinical research studies. 

Alzheimer’s Disease Centers. NIA’s Alzheimer’s Disease 

Centers (ADCs) form the backbone of the national AD 

research effort. These multidisciplinary centers, located 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 52 ’
 

 

 

| Advancing the Future of AD Research 

at 30 institutions nationwide, promote research, training 

and education, and technology transfer. With participation by the community, the Centers conduct longitudinal multicenter and collaborative studies of AD 

diagnosis and treatment, age-related neurodegenerative 

diseases, and predictors of future change in people without dementia that may indicate the initial stages of 

development of AD. Complementary studies, such as 

imaging studies and autopsy evaluations, also are conducted at ADCs. All people enrolled in the Centers 

receive a standard annual evaluation. Data from those 

evaluations are collected and stored by the National 

Alzheimer’s Coordinating Center (NACC, see below) as 

the Uniform Data Set. 

The ADCs serve as sites for other major studies, 

such as the ADCS and ADNI (see descriptions below). 

Recently, DNA from 10,000 individuals enrolled in 

the ADCs was collected for use by the Alzheimer’s 

Disease Genetics Consortium (ADGC) for whole 

genome analysis. 

National Alzheimer’s Coordinating Center (NACC). 

NIA established NACC in 1999 with the goal of pooling and sharing data on participants in ADC studies. 

The longitudinal clinical data from living subjects and 

the brain material and pathological data collected at 

autopsy give scientists opportunities to conduct clinicalpathological studies with much larger patient samples 

collected from multiple centers than they could working 

independently. NACC helps coordinate these studies 

and, in some cases, provides limited funding. 

By 2009, NACC had collected information on more 

than 90,000 ADC study participants and neuropathologic data on more than 10,000 brains from autopsied 

participants. Much of these data and autopsy materials 

are available to qualified AD researchers worldwide. 

Since 2000, there have been over 60 publications by 

external researchers using NACC data, 51 publications 

by NACC personnel, and 95 publications from NACCfunded collaborative ADC projects. 

One such study quantitatively assessed pathological 

plaques and neurofibrillary tangles at autopsy in 97 nondemented participants age 60 years or older (average age 

84 years) who had been enrolled in one of seven different ADCs. While all of the research subjects had been 

As planners and stewards 

of Federally funded science, NIA must 

develop and sustain the infrastructure 

necessary for productive research. 

determined not to have dementia before death, some 

did have mild cognitive impairment. The researchers 

concluded that it is likely that neuropathological processes related to AD in persons without dementia are 

associated with this mild cognitive decline. By age 80-85 

years, many nondemented older adults had substantial 

AD pathology. (Price et al., 2009) 

The NACC data are helping to reveal different 

symptom patterns in different subsets of AD patients— 

patterns that would not have become apparent without 

analyzing a dataset of this size. NACC has also been 

involved in coordinating other NIA efforts, such as the 

identification and selection of appropriate postmortem 

material from the individual ADCs to send to the 

National Cell Repository for Alzheimer’s Disease for use 

in the ADGC GWAS studies. 

Alzheimer’s Disease Cooperative Study (ADCS). NIA 

launched the ADCS in 1991 to develop and test new 

interventions and treatments for AD that might not 

otherwise be developed by industry. Operated under a 

cooperative agreement with the University of 

California, San Diego, the large clinical trials consortium, a significant component of NIA’s AD Prevention 

Initiative, comprises more than 75 sites throughout the 

United States and Canada. The ADCS focuses on testing agents that lack patent protection, patented drugs 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 53 ’
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

| Advancing the Future of AD Research 

that are marketed for other indications, and novel compounds developed by individuals, academic institutions, 

and small biotech companies. It also develops new evaluation instruments for clinical trials and innovative 

approaches to clinical trial design. The group also provides infrastructure support to other Federally funded 

clinical efforts, including ADNI and the Dominantly 

Inherited Alzheimer Network (DIAN, a study of familial AD). (See Alzheimer’s Disease Cooperative Study, 

page 40, for a summary of current trials and studies 

conducted by the ADCS.) 

The National Cell Repository for Alzheimer’s Disease 

(NCRAD). This NIA-funded repository, located at 

Indiana University Medical Center in Indianapolis, provides resources that help researchers identify the genes 

that contribute to AD and other types of dementia. 

NCRAD collects and maintains biological specimens 

and associated data on almost 43,000 people from a 

variety of sources, including genetically informative, 

phenotypically well-characterized families with multiple 

individuals affected by AD, as well as people enrolled in 

ADNI, ADGC, and the Ginkgo Evaluation of Memory 

Study. Qualified research scientists may apply to 

NCRAD for samples and data to conduct genetic 

research. Since it was funded, more than 52,000 DNA 

samples have been requested and sent to investigators 

across the U.S., resulting in 204 publications. 

NIA Genetics of Alzheimer’s Disease Data Storage 

Site (NIAGADS). Located at the University of 

Pennsylvania, NIAGADS is a Web-based data warehouse 

for AD genetic data. All genetic data derived from NIAfunded studies on the genetics of late-onset AD are 

deposited at NIAGADS, another NIA-approved site, or 

both. Data from GWAS that are stored at NIAGADS 

are also made available through the database of 

Genotype and Phenotype (dbGaP) at the National 

Library of Medicine’s National Center for Biotechnology 

Information, which was developed to archive and 

distribute the results of large-scale GWAS analyses. 

Through dbGaP, data sets from multiple GWAS done 

on different platforms can be merged, and data from 

thousands of study participants can be analyzed 

together, increasing the probability of gene discovery. 

ADNI has already borne remarkable fruit: more than 170 papers 

using ADNI data have been published from investigators around the world. 

Initiatives 

Alzheimer’s Disease Neuroimaging Initiative (ADNI). 

In 2004, NIA launched this groundbreaking initiative, 

the largest public-private partnership to date in AD 

research. The goal was to find neuroimaging and other 

biological markers that could be used to detect AD 

progression and measure the effectiveness of potential 

therapies. The study recruited 800 participants, a mix of 

cognitively healthy people and those with AD or MCI. 

To speed the pace of analysis and findings, ADNI investigators agreed to make their collected data widely available. MRI and PET scan brain images as well as clinical, 

genetic, and fluid biomarker data are available to qualified 

researchers worldwide through a Web-based database. 

The first phase of ADNI has already borne remarkable fruit: more than 170 papers using ADNI data have 

been published from investigators around the world, and 

many more will come as further data are collected and 

analyzed. These early findings have generated excitement 

about using brain and fluid markers to identify people 

who may be at risk for developing AD or for cataloguing 

their pace of deterioration. Accomplishments include 

new findings about how changes in the structure of the 

hippocampus may help detect disease progression and 

effectiveness of potential treatments, and the establishment of biomarker and imaging measures that predict 

risk for cognitive decline and conversion to dementia in 

this clinical cohort. (See Biomarkers and ADNI, page 33, 

for descriptions of several published studies.) The success 

of ADNI has inspired similar efforts in Europe, Japan, 

and Australia. A follow-on effort, ADNI-GO, was 

launched with ARRA funds in 2009, and ADNI 2 was 

launched in fall 2010. ADNI 2 will enroll a new cohort 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 54 ’
 

| Advancing the Future of AD Research 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE ’

of participants with very early MCI and continue to follow participants in the other ADNI cohorts, with the 

goal of identifying and tracking early changes in the 

brain before the onset of AD symptoms. 

Alzheimer’s Disease Genetics Initiative (ADGI) and 

Alzheimer’s Disease Genetics Consortium (ADGC). 

The study of AD genetics is complicated by the likelihood that the risk of late-onset AD is influenced by 

many genes, each of which confers a relatively small risk. 

Identifying these genes requires analyzing the genomes 

of large numbers of people. ADGI was launched in 

2003 to identify at least 1,000 families containing both 

members who have late-onset AD and members who do 

not. The ADGC was funded in 2009 to support the use 

of large-scale, high-throughput genetics technologies by 

researchers studying late-onset AD. 

The ADGC confirmed the likely role of three newly 

discovered genes in contributing to the risk of LOAD 

(see Discovering New Genetic Mechanisms, page 21) and 

is now working to confirm additional genes in collaboration with research groups in Europe. In addition to providing additional insight into AD pathogenesis and 

suggesting therapeutic targets, these new gene discoveries may also one day help predict who is at risk for AD. 

The ADGC 

confirmed the likely role of 

three newly discovered late-onset 

AD genes and is now working 

to confirm additional genes. 

Revising AD Diagnostic Criteria. NIA and the 

Alzheimer’s Association organized two meetings in 

spring 2009 to discuss new data and technologies for 

improving the clinical diagnosis of AD and a research 

agenda for diagnosis at earlier stages of the disease. The 

current system of AD classification has deficiencies that 

limit its utility for drug development, research, and 

practice. Existing standards for diagnosis of the dementia stage of AD, the NINCDS-ADRDA clinical criteria, 

are more than 25 years old and do not address very early 

and presymptomatic AD. They were developed without 

the knowledge available from more recent studies on the 

epidemiology of AD, clinical-pathologic correlations, 

and diagnostic imaging and fluid biomarkers. 

Following discussion at the meetings, three working 

groups were set up, one to revise the NINCDSADRDA criteria for Alzheimer’s dementia; a second to 

better define the stage(s) between normal and 

Alzheimer’s dementia, often termed MCI; and a third 

to examine factors in older individuals with no symptoms or very minor symptoms that may predict MCI 

and Alzheimer’s dementia. 

The overall goals of this project are to better define 

the natural history of AD, from its asymptomatic stages 

to clinically diagnosed dementia, and to attempt to 

relate clinical symptoms as they emerge to underlying 

pathophysiology. An overarching goal is to stimulate 

research on how imaging and fluid biomarkers can contribute to the identification of people at risk for cognitive dysfunction and to better diagnose them after 

symptoms appear. 

The groups presented their preliminary proposals at 

the International Conference on Alzheimer’s Disease 

(ICAD) in July 2010. The three committees are reviewing public comments and will publish proposed guidelines in a scientific journal in 2011. The guidelines, 

primarily for use in research studies, will likely be revisited and revised periodically as new data emerge from 

imaging and biomarker research studies. 

AD Translational Initiative. Launched in 2004, the 

AD Translational Initiative supports early drug discovery 

and drug development research by academic scientists 

and small biotechnology companies, with the goal of 

55 
 

 

 

 

 

 

| Advancing the Future of AD Research 

2OO9 PROGRESS REPORT on ALZHEIMER S DISEASE 56 ’

finding ways to treat and prevent AD, MCI, and agerelated cognitive decline. This effort is broadening the 

range of potential treatments and therapeutic targets by 

supporting critical steps of translational research that are 

traditionally not supported by the pharmaceutical industry. In 2009, the NIA committed $5 million to continue 

two funding initiatives for early drug discovery and preclinical drug development through 2012. (See more 

about translational research, page 35.) 

AD Pilot Clinical Trials Initiative. This initiative, 

begun in 1999, is aimed at increasing the number and 

quality of preliminary clinical evaluation of interventions 

for AD, MCI, and age-associated cognitive decline. The 

goal is not to duplicate or compete with pharmaceutical 

companies but to encourage, complement, and accelerate 

the process of testing new, innovative, and effective treatments. Initially focused on drug interventions, the program has been broadened to nonpharmacologic as well as 

pharmacologic interventions. NCCAM and NINR also 

participate in this initiative. (See AD Clinical Trials, 

page 38, for summaries of pilot clinical trials.) 

Research Partnership on Cognitive Aging. Through 

the Foundation for NIH, NIA and the McKnight Brain 

Research Foundation convened a Cognitive Aging 

Summit in 2007 focused on healthy brain aging and 

function. This summit helped galvanize the field and 

served as a catalyst for two subsequent research initiatives. The first, “Remediation of Age-Related Cognitive 

Decline,” is funding research on pilot interventions to 

reverse age-related decline or maintain successful function. The second, “Neural and Behavioral Profiles of 

Cognitive Aging,” is funding studies to understand 

neural and behavioral mechanisms involved the maintenance of cognitive health and to identify characteristics 

that distinguish normal age-related change from pathological decline. A second Summit, held in October 

2010, shared progress from funded studies and identified future research directions. 

NIH Toolbox for Assessment of Neurological and 

Behavioral Function. Awarded in 2006, this contract is 

supported by the NIH Blueprint for Neuroscience 

Research and the NIH Opportunity Network for Basic 

Behavioral and Social Science Research. The goal is to 

develop a set of brief tests to assess cognitive, sensory, 

motor, and emotional function, particularly in studies 

with many people (such as epidemiological studies and 

clinical trials). The tests will be available in English and 

Spanish and applicable for use in individuals age 3 to 

85, enabling direct comparison of cognitive and other 

abilities at different ages across the lifespan. 

NIH Blueprint for Neuroscience Research Initiative 

on the Human Connectome Project. The Human 

Connectome Project was started in 2010 to develop and 

share knowledge about the structural and functional 

connectivity of the healthy human brain. This collaborative effort will use state-of-the-art imaging instruments, 

analysis tools, and informatics technologies to map the 

neural pathways underlying human brain function. The 

project will map the connectomes in 1,200 healthy 

adults—twin pairs and their siblings—and will study 

anatomical and functional connections between regions 

of the brain, which will be related to behavioral test 

data. The goal is to reveal the contributions of genes and 

environment in shaping brain circuitry and the variability in such connectivity. The human connectome map of 

the healthy adult brain will serve as a foundation to further understand how brain networks change with age 

and neurological diseases like Alzheimer’s. 

The AD Translational Initiative is broadening the 

range of potential treatments and therapeutic targets by supporting critical 

research steps not traditionally supported by industry. 
 

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U.S. Department of Health and Human Services 

National Institutes of Health 

National Institute on Aging 

NIH Publication Number: 10-7500 

November 2010