U.S. Department of 

Health and Human Services

Alzheimer’s

Disease

Progress Report on

2OO8

Moving Discovery Forward Moving Discovery Forward

National Institute on Aging

National Institutes of Health

U.S. Department of Health and Human Services

Alzheimer’s

Disease

Progress Report on

2OO8

Moving Discovery Forward
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) as well as research aimed at finding ways to prevent and treat AD. 

The Institute’s AD research program is integral to one of its main goals, 

which is to enhance the quality of life of older people by expanding 

knowledge about the aging brain and nervous system. This 2008 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 (page 32)

 National Heart, Lung, and Blood Institute (pages 23, 26, 32, 35)

 National Human Genome Research Institute (page 22)

 National Institute of Diabetes and Digestive 

and Kidney Diseases (page 23)

 National Institute of Environmental Health Sciences (pages 19, 28)

 National Institute of Mental Health 

(pages 17, 18, 21, 22, 31, 37, 38, 39)

 National Institute of Neurological Disorders 

and Stroke (pages 17, 18, 19, 21, 29)

 National Institute of Nursing Research (pages 37, 39)

AD research efforts also are supported by the Eunice Kennedy Shriver 

National Institute of Child Health and Human Development, 

National Cancer Institute, National Center for Research Resources, 

National Eye Institute, National Institute of Biomedical Imaging 

and Bioengineering, and John E. Fogarty International Center. 

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4 INTRODUCTION 

5 An Urgent National Health Priority

5 About This Report 

6 A Brief Primer on Alzheimer’s Disease

8 AD RESEARCH HAS COME A 

LONG WAY 

 9 Basic Science Tools and 

Techniques and AD Animal Models

 9 Genetics 

 10 Epidemiology 

 11 Neuroimaging 

 12 Translational Research 

14 THE RAPID PACE OF DISCOVERY 

IN RESEARCH CONTINUES 

 15 Epidemiology of AD and 

Related Dementias 

 16 Improving Our Basic 

Understanding of AD 

 20 Normal Cognitive Aging, 

Cognitive Decline, and AD: 

What’s the Difference? 

Table ofContents

 21 Accelerating the Search for 

Genetic Causes and Risk Factors 

 23 Understanding Nongenetic Risk 

and Protective Factors 

 26 Exploring All Possibilities to 

Improve AD Diagnosis 

 28 Boosting the Search for 

Effective AD Therapies 

 30 Supporting the Gold Standard: 

AD Clinical Trials 

 37 Helping People Cope with AD 

40 OUTLOOK FOR THE FUTURE 

 40 Nurturing the AD Research 

Infrastructure 

 43 AD Research Advances: 

A Look to the Future 

43 CONCLUSION 

44 REFERENCES 
Alzheimer’s disease is an age-related, currently 

 irreversible brain disorder that develops over 

many years. In the very early stage, people experience some memory loss, which may be mistaken 

for memory changes that happen to many people 

in normal aging. As the disease progresses, these 

symptoms gradually lead to marked memory loss 

and a decline in other cognitive abilities, such as 

decision making and language skills. Eventually, 

Alzheimer’s leads to behavior and personality 

changes, a severe loss of mental function that 

impairs daily living, and an inability 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 eventual death of many of these cells.

Though the features of AD were first 

described by Dr. Alois Alzheimer more than 100 

years ago, the scientific study of the disease intensified about 30 years ago. The course of AD varies 

from person to person. In most people, symptoms 

first appear after age 60. While AD and other 

dementias are caused by diseases that affect the 

brain, other age-related changes in the brain 

and body may play a role in their development. 

An increasingly productive research program 

has revealed much about the basic biology of 

the disease and the factors that influence its 

development. It is hoped that these findings will 

ultimately lead to effective treatment approaches 

and preventive strategies. 

Introduction
An Urgent National 

Health Priority

AD research today is taking place against the 

backdrop of an urgent demographic reality. We 

know that aging is the major risk factor for AD. 

Estimates vary, but experts suggest that as many as 

5.1 million Americans may have Alzheimer’s disease. In 2000, 35 million people were older than 

65, and one Census projection estimates that that 

number will double by 2050. The large “baby 

boom” generation will begin to reach its 65th 

birthday in 2011. The ranks of the very elderly, 

those people 85 years old and older and at the 

highest risk of AD, will increase as well. Studies 

suggest that the prevalence of AD (the number of 

people with the disease at any one time) doubles 

for every 5-year age group beyond age 65.

The costs of AD are, of course, both societal 

and deeply personal. Caregivers and friends experience emotional, physical, and financial stress 

as they watch a loved one become more and more 

forgetful, frustrated, and confused. As the disease 

runs its course and the abilities of people with 

AD steadily decline, family members who have 

cared for a person with AD at home 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 needs—can be expected 

to escalate rapidly as the population ages and 

the number of people with AD grows. 

The National Institutes of Health has 

responded to this urgent public health problem 

with a broad program of AD research led by 

the National Institute on Aging. This program 

applies the expertise of many scientific disciplines 

in an attempt to answer difficult questions about 

what causes AD, how it can be diagnosed early 

and accurately, how it can be treated, and how 

it might ultimately be prevented. AD research is 

now increasingly focused on transferring knowledge gained in the laboratory to the clinical arena 

as quickly as possible.

About This Report

The 2008 Progress Report on Alzheimer’s Disease

describes this important, multi-faceted AD 

research program. It begins with a brief primer 

that reviews the main features of the disease, discusses the causes, and describes how AD currently 

is diagnosed and treated. The next section, “AD 

Research Has Come a Long Way,” looks at the 

remarkable achievements of the past few years and 

the accelerating pace of discovery. The following 

section, “The Rapid Pace of Discovery in Research 

Continues,” highlights recent advances in nine 

major areas of investigation. The Progress Report 

concludes with an outline of the diverse ways in 

which NIH is building on the momentum of 

prior groundbreaking AD research. 

2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE 5
The healthy human brain is made 

up of billions of different kinds of 

neurons that are connected through 

chemical and electrical signals. A typical 

neuron has a nucleus in a cell body, 

an axon, and many dendrites. Neuronal 

function is supported by other kinds of 

cells called glial cells. As with all cells, 

the nucleus of a neuron contains the 

cell’s genetic blueprint and helps regulate the cell’s activities in response to 

signals from outside and inside the cell. 

The axon transmits messages to other 

neurons. Dendrites receive messages 

from axons of other nerve cells or from 

specialized sense organs. The survival 

of neurons depends on the healthy 

functioning of three interdependent 

processes: 

Communication. When a neuron 

receives enough messages from surrounding cells, an electrical charge is 

generated that travels to the end of the 

axon. Here, it triggers the release of 

chemicals called neurotransmitters that 

move across a gap, or synapse, to 

the dendrites of neighboring neurons. 

Scientists estimate that the typical 

neuron has up to 15,000 synapses. 

The neurotransmitters bind to specific 

receptor sites on the dendrites of 

neighboring neurons, triggering 

chemical changes and building up 

new electrical charges. 

Metabolism. This process encompasses all the chemical reactions that 

take place in the cell. Efficient metabolism requires adequate blood circulation 

to supply the cells with oxygen and 

glucose (the brain’s primary fuel). 

Repair. Neurons are programmed to 

live a long time—even more than 100 

years—so they must constantly maintain, repair, and remodel themselves.

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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, many neurons stop functioning, 

lose connections with other neurons, and 

die because communication, metabolism, 

and repair are disrupted.

At first, AD typically destroys neurons 

in parts of the brain that control memory, 

including the entorhinal cortex, the hippocampus, and related structures. It later 

attacks areas responsible for language 

and reasoning. Eventually, many other 

areas of the brain are damaged, and the 

person 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. The three major characteristics that reflect the pathology, or 

damage, caused by the disease are:

Amyloid plaques. Found in the spaces 

between neurons, plaques consist of 

largely insoluble deposits of aggregated 

protein fragments called beta-amyloid 

peptides, other proteins, remnants of 

neurons, degenerating dendrites and 

axons, glia, and other cellular material. 

Scientists used to think that plaques 

caused most 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. 

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 

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microtubules, which help guide nutrients 

and molecules from the cell body to the 

end of the axon. Tau, which normally has 

a certain number of phosphate molecules 

attached to it, binds to microtubules and 

stabilizes them. In AD, an abnormally high 

number of additional phosphate molecules 

attach to tau. As a result, tau disengages 

from the microtubules and begins to clump 

together with other threads of tau, eventually forming neurofibrillary tangles. When 

this happens, 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 damage 

to neurons.

Loss of connections between 

cells and cell death. 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 death spreads through 

the brain, 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.

What Causes AD?

Very rarely, people develop AD in their 

40s or 50s. In many of these cases, the 

disease runs in families and is caused 

by a mutation in one of three genes that 

a person has inherited from a parent. 

This form of the disease is called “earlyonset” AD. Not all early-onset cases are 

caused by such mutations. 

More than 90 percent of AD cases 

develop in people older than 60, however. The development and pathology of 

this form of AD, called “late-onset” Alzheimer’s disease, are very similar to 

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Alzheimer’s Disease A Brief Primer on

6 2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE
those of early-onset AD. We don’t yet 

completely understand the causes of lateonset AD, but they probably include genetic, 

environmental, and lifestyle factors. The 

importance of these factors in increasing 

or decreasing the risk of developing 

AD differs from person to person. Scientists 

hope that what they learn about earlyonset AD also 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 30 to 50 years or 

more for people to develop signs of the 

disease? Research on how the brain 

changes normally as people age will help 

provide answers to this important question.

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). These tools include a medical history, a physical exam, brain scans, and 

tests that measure memory, language 

skills, and other abilities related to brain 

functioning. Knowledge about the clinical 

and behavioral changes from the disease 

also helps in diagnosing AD. At this time, 

AD can be diagnosed conclusively only by 

studying the brain after death. However, 

in specialized research facilities, 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 their symptoms 

are 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. Early diagnosis also 

helps families plan for the future while 

the person with AD can still participate 

in making decisions. Researchers are 

developing increasingly accurate diagnostic tests and techniques that may 

one day be used in general medical 

practice to detect the disease early—

ideally before serious symptoms emerge. 

How Is AD Treated?

A variety of treatments address 

behavioral and psychiatric problems 

that occur as AD progresses. 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 people’s abilities to 

carry out activities of daily living and 

may maintain some 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 only for months 

to a few years.

Another type of AD medication, 

memantine (Namenda®), is prescribed 

to treat moderate to severe AD symptoms. This drug appears to work by 

regulating levels of glutamate, another 

neurotransmitter involved in memory 

function. Like the cholinesterase 

inhibitors, memantine does not stop 

or reverse AD.

In addition to these medications, 

physicians use 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. 

Visit the NIA Alzheimer’s Disease Education and Referral (ADEAR) 

Center website at www.nia.nih.gov/Alzheimers/ADvideo to view a 

short animated video about AD and the brain.

Healthy neuron

Dying neuron

2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE 7
I

n 1906, Dr. Alois Alzheimer, a German psychiatrist and neuropathologist, first described the 

features of what we now know as AD when he 

reported the case of 51-year-old Auguste D. At 

the time, few took notice, and for 50 years 

afterwards, knowledge about the disease grew 

slowly. One reason AD was overlooked was because relatively few people lived long enough to 

develop it in old age. Forgetfulness and symptoms of senility in those who did reach their 

older years were accepted as a normal part of 

aging and due to “hardening of the arteries.”

However, steady improvements in scientific 

methods and instruments allowed scientists to 

study the abnormal structures that Dr. Alzheimer 

described. In the 1960s and 1970s, scientists 

began to realize that the plaques and tangles they 

saw in younger people diagnosed with “Alzheimer’s 

disease” were actually the same as the structures 

often found in the brains of older people who 

had died with dementia. Slowly, AD became 

recognized as a distinct disease state associated 

with aging (Katzman, 1976). Since then, 

Alzheimer’s research has accelerated rapidly, 

resulting in an explosion of knowledge about 

AD, other neurodegenerative diseases of aging, 

and even normal aging itself. 

Advances in many scientific areas have made 

significant advances in knowledge possible. 

Several of these advances, described below, have 

been particularly valuable in helping scientists 

study this complex disease. 

ad Research

Has Come a Long Way

Research 

has accelerated rapidly, 

resulting in an explosion of 

knowledge about AD, other 

neurodegenerative diseases, 

and normal aging.

8 2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE
Basic Science Tools and 

Techniques and AD Animal Models 

Scientists cannot conduct research without the right 

tools and methods. In AD research, these tools and 

methods have developed rapidly, allowing scientists to 

probe the where, why, and how of AD at the cellular, 

molecular, and genetic levels. At the same time, new 

technology has allowed scientists to process and 

analyze vast quantities of data at impressive speeds.

Animal models, such as rodents, often are used 

for basic research to study human diseases because 

they are biologically similar to humans. These animals 

have a shorter lifespan than humans and therefore 

allow scientists to study disease development over 

brief time periods—a critically important advantage 

in AD research because the disease takes decades to 

develop in the human brain. In addition, scientists 

can control the animals’ environment, which allows 

them to focus on particular aspects of the disease.

Advances in basic science and animal models 

have given scientists considerable knowledge about 

AD’s three defining characteristics: beta-amyloid 

plaques, tau tangles, and loss of connections between 

neurons. Scientists have detailed the steps by which 

beta-amyloid plaques and tau tangles are formed 

and have improved their understanding of the roles 

that various enzymes and other proteins play in 

these processes. In the past 5 years, scientists also 

have come to recognize that early, soluble forms 

of plaques and possibly tangles may actually be 

more damaging to neurons than full-blown plaques 

and tangles. They are learning more about how 

these early forms actually do their damage.

These advances also have helped scientists 

correlate what they know about damaging changes 

inside the brain with outward changes they see in a 

person, such as memory loss, losses in other cognitive abilities, and behavior and personality changes. 

These “clinicopathologic” correlations provide clues 

about biological pathways that lead to AD and 

generate insights into potential therapeutic targets.

Genetics 

In the early days of AD research, investigators realized 

that some cases of the disease ran in families. They 

found that in these families, the disease occurred 

at an early age, when people were in their 40s or 

early 50s, indicating that AD had some genetic 

basis. These findings opened an entire area of AD 

research that continues to be highly productive 

today. Genetics research has helped to reveal much 

about the biological basis of the disease, the interrelationship of genetic and environmental factors in 

causing AD, and pathways amenable to prevention 

or treatment. As medical science progresses into 

individualized medicine based on a person’s unique 

genetic makeup, this knowledge may help to identify 

which risk factors and preventive and treatment 

strategies are best suited to particular individuals.

Four genes affecting the development of earlyand late-onset AD have been defined. Mutations in 

three genes—the amyloid precursor protein (APP) 

2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE 9
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. Mutations in each of these genes 

promote the breakdown of the large APP protein in 

a way that leads to increased production of harmful 

beta-amyloid fragments.

The fourth gene, APOE, found on chromosome 

19, is linked to the far more common late-onset AD. 

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

These alleles do not cause AD. Rather, they influence 

the risk of developing the disease. The ε2 form 

may provide some protection against AD, and ε3 is 

thought to play a neutral role. The ε4 form increases a 

person’s risk of developing AD. 

Most experts believe that additional genes may 

influence the development of late-onset AD in some 

way. Geneticists around the world are searching for 

these genes. Genome-wide association studies (GWAS), 

which use methods that can rapidly test up to a million 

sites in one person’s genes, will help find those elusive 

genetic variations. Since 2007, several international 

research groups conducting GWAS have identified 

variants of the SORL1, CLU, PICALM, and CR1 

genes that may play a role in risk of late-onset 

Alzheimer’s.

Epidemiology 

Epidemiology is the study of disease in a population 

setting. Epidemiologic research may lead to estimates 

of the number of individuals living with the disease 

(prevalence) or the number of individuals who develop 

the disease during a particular period of time 

(incidence). 

Epidemiologic research also focuses on identifying 

personal characteristics or attributes, such as lifestyles 

or behaviors, that relate to developing the disease. 

Once scientists realized that AD was a distinct disease 

and not an inevitable consequence of aging, they 

began to search for factors that caused or were related 

to its development. Scientists turned to epidemiology 

to relate AD to lifestyle and environmental factors as 

well as to basic personal characteristics and other factors 

hypothesized to change the likelihood of developing 

the disease. Such studies have paved the way for 

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—Inside the Brain: 

NIA’s ADEAR Center Offers Free AD Information and Resources

Unraveling the Mystery of Alzheimer’s 

Disease—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 Easy-to-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, the 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 toll-free at 

800-438-4380. 

10 2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE
additional research in test tube and animal studies and 

in clinical trials.

If one theme in AD research predominates today, it 

is the pathological and clinical complexity of the disease. 

It is likely that AD has no single cause but develops 

from multiple processes that interact over many years. 

Epidemiologic studies have helped to make that fact 

abundantly clear, and they also have provided many 

valuable clues about specific factors that may affect the 

development of the disease. These clues, in turn, have 

opened up entire new areas of productive research. 

A growing body of epidemiologic research, for 

example, suggests that the metabolic changes that occur 

in a variety of age-related chronic diseases, such as heart 

disease, stroke, high blood pressure, and type 2 diabetes, 

may contribute to the development and affect the severity 

of AD or cause vascular dementia. (Vascular dementia 

occurs when a series of strokes or changes in the brain’s 

blood supply leads to the death of brain tissue.) 

Epidemiologic studies also suggest that several lifestyle 

factors—a healthful diet and physical activity, not 

smoking, and having strong social networks—may 

reduce AD risk. Scientists are conducting animal studies 

and clinical trials to determine whether changing lifestyle factors can alter a person’s chances of developing 

AD—and how this might happen.

Neuroimaging 

Until recently, scientists could “see” the characteristics 

of AD in the brain only at autopsy, after a person with 

the disease had died. However, autopsies present a 

static picture, usually revealing only the very advanced 

stage of the disease. Scientists had no way to observe 

the disease in the living brain at early stages or to 

see how the disease affected the brain over time. The 

Three neuroimaging tests are 

commonly used in AD research:

Magnetic Resonance 

Imaging (MRI). This 

type of scan uses 

magnetic fields to generate computer images 

of body structures. 

In AD research, MRI 

is used to create 

detailed maps of the brain, showing 

the size and anatomy of brain regions 

and structures. As AD progresses and 

neurons die in large numbers, regions of 

the brain shrink and fluid-filled spaces 

called ventricles enlarge. MRI has been 

used extensively to track this process.

Functional Magnetic Resonance 

Imaging (fMRI). An fMRI is a type of 

MRI that allows scientists to measure 

brain activity during a cognitive task, 

such as remembering or learning. These 

scans are providing many insights 

into how AD affects the brain’s ability 

to function and how the brain tries to 

compensate for damage caused by the 

disease.

Positron 

Emission 

Tomography 

(PET). In a 

PET scan, a 

small amount 

of a short-lived 

radioactive substance is attached to another molecule 

and injected into the body. The radioactive molecule travels through the blood 

and becomes concentrated in the organs 

and tissues where it is normally found. 

The PET machine measures the energy 

given off by the radioactive material 

and translates that information into pictures that can be viewed on a computer 

screen. PET scans frequently are used 

in brain research because they allow 

researchers to observe and measure 

activity in different parts of the brain by 

monitoring blood flow and the concentrations of the radioactive material in 

different areas of the brain. 

In a PET scan breakthrough, 

researchers reported in 2004 on their 

development of a radioactive substance, 

Pittsburgh Compound B (PiB), that binds 

to beta-amyloid in the brain (Klunk et 

al., 2004). Investigators can use radioactive PiB in PET scans to measure the 

concentration of beta-amyloid in brain 

regions that are particularly vulnerable 

to AD. These concentrations can then 

be compared to outward changes in 

memory or other cognitive abilities. 

Neuroimaging: Opening New Windows on the Brain

FDG and PIB in Aging and AD

AD -FDG

AD-PIB

Normal

Control -

PIB

2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE 11
development of neuroimaging techniques, including 

magnetic resonance imaging (MRI), functional MRI 

(fMRI), and positron emission tomography (PET), 

and their application to AD radically changed all that. 

Researchers can now observe and measure the size 

and structure of specific brain regions in people who 

are healthy or have symptoms of AD. They also can 

measure the accumulation of beta-amyloid plaques in 

brain tissue. In addition, neuroimaging technologies 

allow scientists to observe brain function in people 

performing cognitive tasks. Importantly, these technologies allow researchers to track changes in these 

dimensions over time. 

Developments in neuroimaging techniques have 

greatly increased our knowledge about how AD progresses. They have helped us understand that damage 

in the brain begins long before any clinical symptoms 

are evident and that this process develops slowly over 

many years. By the time a person is diagnosed, the 

disease is well-established, with current treatment 

options limited or effective for only a short time. In 

combination with results of the traditional battery of 

tests given to people suspected of having dementia, 

neuroimaging has been essential in helping researchers 

understand and chart brain changes that occur during 

the evolution from healthy aging to mild cognitive 

impairment to Alzheimer’s. (Mild cognitive impairment, 

or MCI, is a condition of memory loss but without 

the other cognitive problems of AD. People with MCI 

are an important group for researchers because many 

of them go on to develop AD.) Understanding these 

changes opens the door to earlier and more accurate 

diagnosis, new intervention points for therapies, and 

improved methods for tracking responses to treatment.

Translational Research

Translational research is a multidisciplinary effort that 

creates a two-way loop between basic science laboratory 

studies and clinical research. It allows valuable knowledge from the laboratory to be applied to potential new 

tests or interventions in clinical trials, and findings from 

clinical trials to be taken back to the lab and investigated 

in basic science studies to refine the nature of future 

clinical trials. Translational research also serves as a 

crucial means for collaboration among scientists who 

focus on understanding the cellular, molecular, and 

pathologic dimensions of disease and clinicians who 

focus on treating people. 

Translational research serves as a crucial means for collaboration 

among scientists who focus on understanding the cellular, molecular, and 

pathologic dimensions of disease and clinicians who focus on treating people.

12 2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE
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n May 2009, HBO Documentary Films 

launched a multimedia initiative highlighting the groundbreaking discoveries 

of leading AD researchers and poignantly 

depicting the effects of the disease on 

those with AD and their families. The 

Alzheimer’s Project was co-presented 

by HBO Documentary Films and NIA, in 

association with the Alzheimer’s Association, Fidelity® Charitable Gift Fund, 

and Geoffrey Beene Gives Back®

Alzheimer’s Initiative. 

The Alzheimer’s Project features a 

four-part documentary series, 15 short 

supplemental films, a companion book 

published by Public Affairs Books, a 

dedicated website, and a nationwide 

community-based information and 

outreach campaign. HBO and other 

participating television service providers 

offered the documentary series for free 

to viewers when the series debuted May 

10–12, 2009. The documentary series 

and the 15 supplemental films can now 

HBO’s The Alzheimer’s Project Showcases 

Recent AD Research Progress

be viewed free on the HBO and NIA 

websites, as well as on YouTube, Facebook, 

and iTunes. An additional 18 films, geared 

toward the scientific community, are 

hosted on the Alzheimer’s Research 

Forum website. 

The documentary films include THE 

MEMORY LOSS TAPES, which enters the 

lives of seven individuals living with AD 

and shows the full spectrum of the progression of the disease; MOMENTUM IN 

SCIENCE, a two-part, state-of-the-science 

film, which takes viewers inside the 

laboratories and clinics of 25 leading 

scientists and physicians, revealing some 

of the most cutting-edge research 

advances; ‘GRANDPA, DO YOU KNOW 

WHO I AM?’ WITH MARIA SHRIVER,

which captures what it means to be a 

child or grandchild of a person with 

Alzheimer’s; and CAREGIVERS, which 

highlights the sacrifices and successes 

of people who ex-perience their loved 

ones’ descent into dementia. 

THE MEMORY LOSS TAPES has 

received an Emmy for Exceptional Merit 

in Nonfiction Filmmaking, ‘GRANDPA, DO 

YOU KNOW WHO I AM?’ WITH MARIA 

SHRIVER won an Emmy for Outstanding 

Children’s Nonfiction Program, and 

MOMENTUM IN SCIENCE garnered an 

Emmy nomination. The Alzheimer’s 

Project also has received the Television 

Critics Association award for Outstanding 

Achievement in News and Information. 

For more information on The Alzheimer’s 

Project, visit www.nia.nih.gov/

Alzheimers/HBO. 

2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE 13
I

n 2008, scientists supported by NIH made 

advances in a number of areas important to AD: 

 Epidemiology

 Basic research

 The interface between healthy 

cognitive aging and AD

 Genetic causes and risk factors

 Nongenetic risk and protective factors

 Diagnosis

 The search for effective therapies

 Clinical trials

 Coping and caregiver support

These areas of investigation focus on the 

central issues of AD—what occurs during the 

disease process, what we can do to promote 

healthy cognitive aging and prevent AD, and what 

we can do once the disease has taken hold. The 

following sections describe new knowledge that 

may hold the key to future prevention, treatment, 

and coping and caregiving strategies. 

n

n

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n

n

n

n

n

AD research 

focuses on central issues—

what occurs during the 

disease process, what we 

can do to promote brain 

health and prevent AD, 

and what we can do 

once the disease has 

taken hold.

The Rapid Pace of Discovery 

inResearch

14 2OO8 PROGRESS REPORT PROGRESS REPORT on ALZHEIMER ALZHEIMER’

S DISEASE S DISEASE
Epidemiology of AD and 

Related Dementias

The ability to tackle a major public health problem 

depends in part on understanding the dimensions of 

the problem. For example, how many people have the 

condition in question? How many people develop it 

each year? How many people have a precursor to the 

condition, or some variant of the condition? Having 

an accurate-as-possible picture of the scope of AD, 

related dementias, and age-related cognitive impairment helps scientists, policy makers, health care providers, and health care insurers determine the costs of 

caring for people with these conditions and develop 

appropriate services and resources. 

This information also helps investigators reliably 

track trends in prevalence and incidence and correlate 

those trends with changes in environmental and biological factors. These correlations may provide insights 

into potential risk and protective factors and inform 

the design of prevention and treatment interventions.

The prevalence of Alzheimer’s and related dementias, such as vascular dementia, dementia with Lewy 

bodies, Parkinson’s disease dementia, and frontotemporal lobar degeneration, increases exponentially with 

age. Of people with late-onset dementia, about half 

have Alzheimer’s, 16 percent have vascular dementia, 

and 30 percent have other forms of dementia (Kester 

and Scheltens, 2009). The prevalence of AD in the 

United States has been variously estimated, ranging 

from as high as 5.1 million among people 65 or older 

to about half that many, depending on how the condition was defined and what methods were used to find 

people with AD. The public health problem presented 

by AD is large and, with age the best known risk 

factor for AD, the numbers will likely increase as the 

elderly segment of the population grows, at least until 

effective interventions to prevent the disease or halt its 

progress are found.

In 2007, 2008, and 2009, several groups of researchers 

reported what they learned from studies examining 

the prevalence of AD and related dementias and the 

prevalence of age-associated cognitive impairment. 

A research team analyzed the prevalence of cognitive impairment that does not meet the threshold for a 

diagnosis of dementia (Plassman et al., 2008). Knowing 

how many people have cognitive impairment has important health care policy implications because that 

condition is associated with an increased risk of disability, increased health care costs, and progression to 

dementia. The investigators determined that 5.4 million people, or 22.2 percent of Americans age 71 and 

older, had cognitive impairment without dementia. 

This first-ever population-based national study also 

identified 12 subtypes of cognitive impairment without dementia and found that the subtypes varied in 

prevalence and outcomes. 

Investigators at the Rush Alzheimer’s Disease 

Center in Chicago focused on the spectrum of neuropathological abnormalities found in several major 

dementing disorders, such as AD, Parkinson’s disease 

dementia, Lewy body disease, and stroke (Schneider et 

al., 2007). An examination of brain tissue from 

deceased participants in the Rush Memory and Aging 

Project showed some differences in the occurrence of 

neuropathological abnormalities observed in those 

who died with dementia and those who died without 

dementia. More specifically, the study found that the 

majority of community-dwelling older people had 

some brain pathology; those with dementia most often 

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2OO8 PROGRESS REPORT PROGRESS REPORT on ALZHEIMER ALZHEIMER’

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had multiple brain pathologies. The presence of 

multiple pathologies greatly increased the odds of 

dementia.

Investigators at the University of Michigan assessed 

the influence of recent medical, demographic, and 

social trends on the cognitive health of older adults 

(Langa et al., 2008). Using data from the nationally 

representative longitudinal Health and Retirement 

Study (HRS), they compared the prevalence of “cognitive impairment consistent with dementia” among 

survey participants in 1993 and 2002. Results showed 

that fewer older Americans reached the threshold of 

significant cognitive impairment in 2002 compared 

with 1993, although those who reached that threshold, 

on average, died earlier than the others. These findings 

suggest that rates of very severe cognitive impairment 

may be decreasing. One major difference between the 

1993 and 2002 groups was the higher education, on 

average, of the latter group. It may be that, compared 

to people with less education, individuals with more 

education are able to sustain greater damage from AD 

or other dementia-related pathology before clinical 

signs of impairment appear. Other factors, such as 

improvements in treatment and prevention for stroke, 

heart disease, and vascular conditions from 1993 to 

2002, also may have influenced these results. The 

study authors suggest that building and maintaining 

cognitive reserve through formal education in childhood and continued cognitive stimulation through 

work and leisure in adulthood could limit the burden 

of cognitive impairment consistent with dementia 

among the growing number of older adults. 

The Indianapolis-Ibadan Dementia Project, established in 1991, continues to search for risk factors and 

protective factors for AD and other cognitive impairment by comparing two groups of community-dwelling 

elderly who live in vastly different environments: a 

group of African Americans in Indianapolis, Indiana, 

and a group of Yoruba in Ibadan, Nigeria. The study 

periodically conducts assessments of the two groups, 

employing the same research design, methods, and 

investigators. One study from this project compared 

prevalence rates for African Americans in the 1992 

community-based sample to a newly enrolled sample 

in 2001 (Hall et al., 2009). The overall age-adjusted 

prevalence rate for AD at age 70 years and older in 

n

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2001 was 6.8 percent, and in the 1992 cohort, the 

prevalence rate was 5.5 percent. These rates, however, 

were not significantly different despite differences in 

risk factors between the two cohorts. The 2001 cohort 

had higher mean years of education, and fewer lived 

in rural areas during childhood. However, this later 

cohort also had higher rates of hypertension and history of depression, and more cohort members were 

taking antihypertensive medications, anti-diabetic 

medications, and statins. 

Both the HRS and Indianapolis-Ibadan studies 

suggest that prevalence rates of dementia are not increasing in the United States, at least for individuals 

who live in the community. The latter study, from 

Indianapolis, was restricted to African Americans and 

also showed no significant increase over time in the 

prevalence rate of AD. More studies from U.S. populations, over longer periods of time, are needed to get 

a clearer picture of changes in incidence and prevalence 

rates for dementia and AD. If prevalence and incidence 

rates remain constant over time and the U.S. population 

of older people continues to increase, then there will be 

more and more cases of dementia and AD in the future.

Improving Our Basic 

Understanding of AD

AD-related studies at the cellular and molecular levels 

historically have focused on understanding the wide 

range of processes that interfere with, or enhance, the 

function and survival of neurons and their connections. 

The overarching aim of these studies is to identify 

molecular targets that can be translated and developed 

into AD therapies. Many investigators are continuing 

to study basic mechanisms and to examine the potential roles of different forms of beta-amyloid and other 

factors that contribute to neuronal damage and death. 

Beta-amyloid

It has long been accepted that beta-amyloid plaques 

are a major feature of AD and their mere physical 

presence distorts the architecture of the brain. The 

effects of this structural distortion on the function and 

activity of neuronal networks are only now beginning 

to be measured. Scientists also understand the basic 

steps by which beta-amyloid fragments are produced 

and have begun to understand how the fragments 

clump together in aggregates to form insoluble 

16 2OO8 PROGRESS REPORT on ALZHEIMER’

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plaques. More recent data point to small, soluble 

aggregates of beta-amyloid peptides, not the insoluble 

late-stage plaques, as the main culprits in neuronal 

damage. These small beta-amyloid aggregates, called 

oligomers, consist of two or three and sometimes up 

to a dozen such small fragments excised from amyloid 

precursor protein (APP), the parent protein. Several 

reports published in 2008 revealed new evidence 

about the toxic effects of oligomers.

A research team from Brigham and Women’s Hospital 

and Harvard Medical School compared forms of soluble beta-amyloid oligomers—those with only one peptide (monomer), two peptides (dimer), and three 

peptides (trimer)—to see whether their toxic effects 

on neurons were different (Shankar et al., 2008). The 

researchers extracted beta-amyloid from autopsied 

human brains of people with and without confirmed 

AD and processed it to isolate soluble beta-amyloid 

monomer, dimer, or trimer oligomers. They then 

examined the effects of the different oligomers on 

various types of brain functioning in rats. Only the 

beta-amyloid dimers significantly impaired these functions. The researchers also chemically synthesized a 

pure beta-amyloid dimer and found that it produced 

the same harmful effects on neuronal function. In 

contrast, the large extracellular beta-amyloid plaques 

did not show these toxic effects unless they were treated 

to release dimers. These data strongly support a new 

view of the role of beta-amyloid in the AD disease 

process—as soluble toxic dimers. These results point 

to the need to focus on therapeutic approaches that 

interrupt the transition of the beta-amyloid molecules 

from single beta-amyloid monomers to dimers. 

Investigators from the Scripps Research Institute in 

La Jolla, California, studied the biochemical process by 

which synthetic and naturally occurring beta-amyloid 

fragments form aggregates and fibrils (an intermediate 

stage of beta-amyloid aggregation between soluble 

oligomers and insoluble plaques) (Bieschke et al., 2008). 

They found that beta-amyloid monomers were not 

toxic but became toxic as they aggregated into spherical 

or incompletely aggregated fibrils. These findings support the hypothesis that an intermediate oligomeric 

configuration of beta-amyloid is toxic to neurons in AD. 

An implication from this research is that other toxic 

oligomeric proteins or peptides—tau, synuclein, and 

prion proteins, for example—might behave similarly.

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Researchers from Massachusetts General Hospital 

and Harvard Medical School traced the formation of 

beta-amyloid plaques in living transgenic mice (MeyerLuehmann et al., 2008). A highly sophisticated microscopic technology (in vivo multiphoton microscopy, 

which allows visualization of structures within the brain) 

enabled scientists to visualize the formation of amyloid 

plaques in real time. The amyloid plaques grew very 

quickly—from small microplaques to their final size—

within 24 hours and stayed that final size for at least 

the remainder of the 1-week period of observation. 

The researchers also observed that in the days following 

their formation (the extent of this study), microplaques 

could rapidly damage the axons and dendrites of nearby 

nerve cells. They could not determine the underlying 

processes that resulted in the development of amyloid 

plaques. These results have led to speculation that betaamyloid oligomers may be precursors to this sudden 

growth, that the plaques act as a local source of soluble 

beta-amyloid, and that the soluble beta-amyloid may 

be inducing alterations in neighboring dendrites and 

axons. This published report, the first to describe the 

rapid and progressive development of amyloid plaques 

in living animals, differs from the traditional view that 

had evolved from studies in autopsy material. In the 

traditional view, amyloid plaques develop through a 

slow and extended process.

In the mid-1970s, scientists discovered that levels of 

the neurotransmitter acetylcholine fell sharply in people 

with AD. Acetylcholine is used by neurons in the hippocampus and cerebral cortex, areas of the brain involved 

in memory formation. Three of the drugs currently 

approved to treat AD act by stopping or slowing the 

action of an enzyme that degrades the acetylcholine 

neurotransmitter. However, these drugs have adverse 

side effects, and investigators continue to study this 

neurotransmitter in hopes of identifying more effective agents with fewer side effects.

A scientific team at Vanderbilt University, supported 

largely by the National Institute of Mental Health (NIMH), 

the National Institute of Neurological Disorders and 

Stroke (NINDS), the Alzheimer’s Association, and the 

NIH Roadmap Molecular Libraries Screening Centers 

Network, found a novel small molecule in rat brain cells 

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(Jones et al., 2008). This molecule, TBPB, selectively 

bound one of the two types of acetylcholine receptors 

in neurons and increased the use of a non-amyloidogenic 

pathway through which APP was processed. As a result, 

the production of toxic beta-amyloid was reduced. 

Further, TBPB enhanced the efficiency of acetylcholinemediated communication in the hippocampus. TBPB’s 

binding and its fidelity for one subtype of acetylcholine 

receptor also suggested that molecules based on its 

structure may have fewer adverse side effects than the 

earlier compounds used in AD treatment. Additional 

studies in AD animal models are needed to determine 

whether TBPB can decrease beta-amyloid production 

and lessen cognitive decline in living brains with fewer 

side effects. Successful studies in animals one day may 

lead to human clinical trials of a new drug candidate. 

Other 2008 advances in beta-amyloid research include:

Banwait S et al. C-terminal cleavage of the amyloid-beta 

protein precursor at Asp664: A switch associated with 

Alzheimer’s disease. Buck Institute for Age Research, 

Novato, California. Research supported by NIA. 

www.ncbi.nlm.nih.gov/pubmed/18334752

Cenini G et al. Elevated levels of pro-apoptotic p53 and its 

oxidative modification by the lipid peroxidation product, 

HNE, in brain from subjects with amnestic mild cognitive 

impairment and Alzheimer’s disease. University of Kentucky 

Lexington. Research supported by NIA. www.ncbi.nlm.nih.

gov/pubmed/18494939

Chen K et al. Cooperation between NOD2 and Toll-like 

receptor 2 ligands in the up-regulation of mouse mFPR2, a 

G-protein-coupled Abeta42 peptide receptor, in microglial cells. 

Research supported by NCI. www.ncbi.nlm.nih.gov/

pubmed/18299458

Jin JJ et al. Toll-like receptor 4-dependent signaling in animal 

model of Alzheimer’s Disease. University of Illinois, Chicago. 

Research supported by NEI. www.ncbi.nlm.nih.gov/

pubmed/18510752

Kuchibhotla KV et al. Abeta plaques lead to aberrant 

regulation of calcium homeostasis in vivo resulting in 

structural and functional disruption of neuronal networks. 

Massachusetts General Hospital. Research supported by 

NIA. www.ncbi.nlm.nih.gov/pubmed/18667150

Parikh V et al. Cholinergic mediation of attention: 

Contributions of phasic and tonic increases in prefrontal 

cholinergic activity. University of Michigan. Research 

supported by NIMH and NINDS. www.ncbi.nlm.nih.gov/

pubmed/18591483

Zheng J et al. Annular structures as intermediates in fibril 

formation of Alzheimer Aβ17−42. University of Akron. 

Research supported by NCI. www.ncbi.nlm.nih.gov/

pubmed/18457440

See the References section for complete citations.

Other Basic Science Advances

Although beta-amyloid remains a major focus of AD 

basic science research, investigators recognize that other 

factors also likely play a role in the pathogenesis of the 

disease. During 2008, scientists reported on studies demonstrating progress in several areas unrelated to amyloid.

Researchers at the University of California Irvine 

investigated the effects of exercise on inflammation and 

the immune system in AD transgenic mice (Nichol et 

al., 2008). Chronic stimulation of the immune response 

by beta-amyloid appears to activate special cells in the 

brain, called microglia, that release the inflammatory 

cytokines (a type of protein) IL-1b and TNF-a in toxic 

concentrations. These inflammatory proteins could be 

contributing to the neurodegeneration and progression 

of AD-like pathology rather than the removal of betaamyloid (as might be expected of an adaptive immune 

response evolved to protect an organism from foreign 

material). The researchers found that levels of IL-1b 

and TNF-a were higher in sedentary 18-month-old AD 

transgenic mice than in sedentary 18-month-old nonAD mice. After the aged sedentary AD transgenic mice 

were allowed 3 weeks of exercise in running wheels, the 

researchers found the mice had significantly lowered 

levels of IL-1b and TNF-a. In fact, the levels were no 

different from the non-AD aged sedentary control 

mice. The lowered levels of cytokines also correlated 

with improved learning. Exercise decreased the levels of 

pro-inflammatory markers in these older AD transgenic 

mice, and increased the markers of the adaptive 

immune response. The overall impact of this was to 

remove beta-amyloid from the brain. The research 

suggests that in mice even in the later stages of AD, 

exercise can help clear toxic beta-amyloid through 

stimulation of anti-inflammatory mechanisms.

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In a series of experiments involving phospholipase 

A2 (PLA2), a protein involved in the production of 

fatty acids, researchers at the Gladstone Institute of 

Neurological Disease in San Francisco and the 

University of California San Francisco observed that 

many of the changes in the brain tissue of people with 

AD may involve changes in membrane excitability at 

the synapse, induced by the breakdown products of 

fatty acids (Sanchez-Mejia et al., 2008). These scientists, who were funded by NINDS and NIA, asked 

whether modifying fatty acid metabolism could affect 

AD progression and identified a subset of fatty acids 

that are present at higher levels in AD mouse models 

and in people with AD compared to their healthy 

counterparts. The investigators crossbred genetically 

engineered mice—mutant human APP mice and mice 

with one or two copies of PLA2—to generate AD 

transgenic mice in which PLA2 was lower than 

n normal. This latter group of mice showed improvements in cognitive and behavioral tests and lived 

longer than the short-lived AD transgenic mice. These 

results suggest that inhibition of PLA2 may offer an 

opportunity to intervene therapeutically in AD. 

Other 2008 advances in AD basic sciences include:

Greco SJ et al. Leptin reduces Alzheimer’s disease-related 

tau phosphorylation in neuronal cells. Neurotez Inc., 

Bridgewater, New Jersey. Research supported by NIA. 

www.ncbi.nlm.nih.gov/pubmed/18801339

Lim J et al. Pin1 has opposite effects on wild-type and 

P301L tau stability and tauopathy. Beth Israel Deaconess 

Medical Center and Harvard Medical School. Research supported by NIA. www.ncbi.nlm.nih.gov/pubmed/18431510

See the References section for complete citations.

Scientists generally agree that AD 

develops over many years as a 

result of genetic and environmental factors. However, much is still unknown 

about the exact nature of these factors, 

how they interact, and how the interactions may differ from person to person. 

Two studies, the first funded by National 

Institute of Environmental Health Sciences 

(NIEHS) and NIA, the second by NIEHS 

alone, have taken a close look at the 

possible effects of early-life environmental exposures on risk of AD. 

Rodent studies have shown that 

exposure to lead during early-life brain 

development predetermined the expression and regulation in old age of amyloid 

precursor protein, or APP, and its betaamyloid product. Researchers at the 

n

Studies Look at Early-Life Environmental Exposures and Risk of AD

University of Rhode Island, Kingston, 

looked at whether the same events 

occurred in female monkeys (Wu et al., 

2008). They added lead acetate to the 

diet of a group of monkeys during their 

first year of life, and 23 years later found 

extensive evidence of AD-like pathology 

in their brains after death. This change 

was not evident in the brains of monkeys 

whose diets had not been supplemented 

with lead acetate. These findings implicate 

an environmental agent—lead—in AD 

pathogenesis and suggest that infancy 

is an important period of vulnerability in 

the brain to agents that could increase 

future susceptibility to neurodegeneration 

and AD pathology. 

In another environmental-exposures 

study, scientists at University of Montana, 

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Missoula, studied whether living in cities 

with high levels of air pollution was associated with brain inflammation and neurodegeneration in a group of healthy children 

and young adults who had died suddenly 

(Calderón-Garcidueñas et al., 2008). 

Examination of the children’s brain tissue 

revealed indicators of neuroinflammation, 

an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of beta-amyloid and alphasynuclein 

(a protein found in an abnormal form in 

Parkinson’s disease). The researchers 

suggest that exposure to air pollution 

should be considered a risk factor for 

AD and Parkinson’s disease, and that 

carriers of the APOE ε4 allele who live 

in polluted environments could have an 

increased risk of developing AD. 

2OO8 PROGRESS REPORT on ALZHEIMER’

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Normal Cognitive Aging, 

Cognitive Decline, and AD: 

What’s the Difference?

Improvements in public health, medical care, nutrition, and living standards have resulted in our now 

living longer than ever before. Many older adults enjoy 

active, productive lives, but they also face the risk of 

memory and other cognitive problems. This challenge 

has provided a major impetus for research into healthy 

cognitive aging. Scientists—and the public—want to 

know how and why some people remain cognitively 

healthy all their lives while others do not. Answers to 

these questions also can help researchers understand 

what goes wrong in AD or other neurodegenerative 

diseases and can point the way to interventions that 

might maintain successful brain and cognitive aging. 

As knowledge about the spectrum of stages from 

healthy cognitive aging to AD grows, it has become 

increasingly evident that no clear distinctions separate 

a healthy brain and a diseased brain. Most people 

develop some plaques and tangles in their brains as 

they get older, but not everyone develops cognitive 

problems, MCI, or AD. At what point does an agerelated process become a disease-causing process? 

Several studies published in 2008 and 2009 explored 

this question.

Researchers at the University of Pittsburgh School 

of Medicine conducted PiB PET scans to image 

amyloid deposits in the brains of 43 adults, 65 to 

88 years old, who did not have clinical AD or MCI 

(Aizenstein et al., 2008). The 9 participants with 

beta-amyloid deposits in at least one brain region performed as well on cognitive tests as the 29 participants 

who had no amyloid deposits and the 5 participants 

with “intermediate” evidence of amyloid deposits. The 

finding that an older person with “significant amyloid 

burden” can be cognitively normal suggests either that 

some people may have a high level of cognitive reserve 

or that beta-amyloid deposition alone does not explain 

cognitive impairment. (See page 25 for more information about cognitive reserve.) Another possibility is 

n

that some of these individuals will go on to develop 

AD, even though they are cognitively normal to start. 

In that case, PiB PET may be useful in identifying 

AD before clinical symptoms appear. These findings 

mirror those previously found in post-mortem studies, 

where the brains of some people with normal cognition were found to have significant amyloid deposits. 

A team of scientists at the Banner Alzheimer’s 

Institute in Phoenix, Arizona, conducted PiB PET 

scans in 28 cognitively normal older people, correlating 

the results with the presence of the APOE ε4 gene 

(Reiman et al., 2009). The researchers found higher 

levels of beta-amyloid deposits in people with one 

and two copies of the APOE ε4 gene than in those 

without this version of the gene. These results echo 

earlier findings showing that APOE ε4 carriers have 

higher levels of amyloid in their brains at death than 

do people without this risk factor. Findings from these 

two studies suggest the possible usefulness of PiB PET 

scans to detect AD before clinical signs and symptoms 

appear. This will be crucial for testing promising 

prevention therapies. 

Longitudinal studies also are being conducted to 

determine the long-term consequences of beta-amyloid 

deposits in brain and whether they invariably lead to AD. 

University of California Berkeley scientists looked 

at the relationship between extent of brain amyloid 

deposits (measured using PiB PET scans), hippocampal volume (measured using MRI), and episodic 

memory (for example, memory of times or places) in 

three groups: cognitively healthy participants in the 

Berkeley Aging Cohort, cognitively healthy participants in the AD Neuroimaging Initiative (ADNI), and 

ADNI participants with MCI (Mormino et al., 2009) 

(see page 41 for information about ADNI). In the 

Berkeley Aging Cohort participants and ADNI participants with MCI, brain amyloid deposits were associated with smaller hippocampal volumes and worse 

episodic memory. In the healthy ADNI participants, 

brain amyloid deposits were associated with smaller 

hippocampal volumes but normal episodic memory. 

The researchers conducted analyses suggesting that 

beta-amyloid deposition, hippocampal atrophy, 

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and declines in episodic memory occur sequentially 

in elderly subjects, with beta-amyloid deposition 

being the triggering event. In other words, declining 

episodic memory in older individuals may be caused 

by hippocampal atrophy induced by beta-amyloid.

Other 2008 advances in normal cognitive aging, cognitive 

decline, and AD include:

Geda YE et al. Prevalence of neuropsychiatric symptoms in 

mild cognitive impairment and normal cognitive aging: 

Population-based study. Mayo Clinic, Rochester, MN. Research 

supported by NIMH, NIA, NINDS, and the Agency for 

Healthcare Quality and Research. www.ncbi.nlm.nih.gov/

pubmed/18838636

Iacono D et al. Neuronal hypertrophy in asymptomatic 

Alzheimer disease. Johns Hopkins University. Research supported 

by NIA and the Burroughs Wellcome Fund for Translational 

Research. www.ncbi.nlm.nih.gov/pubmed/18520776

Sojkova J et al. Longitudinal cerebral blood flow and amyloid 

deposition: An emerging pattern? NIA Intramural Research 

Program. www.ncbi.nlm.nih.gov/pubmed/18703614

See the References section for complete citations.

Accelerating the Search for 

Genetic Causes and Risk Factors

It is clear that AD has genetic links. Finding those 

links and learning how they play out over time is an 

enormous job, however, given the complexity of the 

human genome. Further complicating the study of 

AD genetics is the fact that late-onset AD is probably 

influenced by many risk and protective factor genes, 

each conferring a small measure of harm or safety 

and affecting a variety of biochemical pathways. 

These pathways may influence the age at onset and 

the risk of getting the disease or its progression. 

In recent years, computer and other technology 

advances have made an astounding contribution 

to progress in genetics research. Developments in 

these technologies now permit scientists to conduct 

studies, such as genome-wide association studies, 

that involve rapid processing of vast amounts of 

genetic data. A GWAS is a study of genetic variations 

across the entire human genome that is designed to 

identify genetic associations with observable traits 

(such as blood pressure or weight) or the presence or 

People with early-onset AD and their 

families have contributed enormously 

to our overall knowledge of the disease. 

A new NIA-funded research network is 

now asking adult children of people with 

early-onset AD to join the Dominantly 

Inherited Alzheimer’s Disease Network 

(DIAN) study, a 6-year, multimillion dollar 

effort that aims to identify the sequence 

of brain changes in early-onset AD, even 

before symptoms appear. 

Until now, research into inherited earlyonset AD was hindered by the rarity of 

the condition and geographic distances 

between patients and research centers. 

DIAN is designed to overcome those 

challenges. Study participants will undergo 

genetic analyses, cognitive testing, and 

neuroimaging scans and will provide blood 

and cerebrospinal fluid samples. These 

assessments, images, and samples should 

enable researchers to determine the type 

and sequence of changes in the brain in 

early-onset inherited AD. By understanding 

this process, scientists hope to learn 

about the more common late-onset form 

of the disease. Knowledge gained also 

may eventually lead to targets for therapies 

that can delay or even prevent progress 

of the disease. 

This collaborative, international effort 

will link a network of research sites in 

the United States, England, and Australia 

to family members of people with these 

rare forms of AD. The study is being led 

by scientists at Washington University 

School of Medicine in St. Louis. Collaborators 

include Massachusetts General Hospital; 

Brigham and Women’s Hospital; Brown 

University; Columbia University; Indiana 

University; the University of California Los 

Angeles; University College, London Institute 

of Neurology at Queen’s Square; and a 

consortium of the Universities of Melbourne 

and New South Wales and Edith Cowan 

University in Australia. 

For more information about DIAN, visit 

www.dian-info.org. 

New International Early-Onset Network Helps Scientists 

Search for Biological Clues to AD

2OO8 PROGRESS REPORT on ALZHEIMER’

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absence of a disease or condition. This technology 

associates single nucleotide polymorphisms (SNPs), 

which are single changes in nucleotides (the building 

blocks of DNA), in specific locations on a strand of 

DNA when compared to the same location in other 

DNA strands from other individuals. Used to study 

human genetic variation, SNPs are a powerful way 

to investigate genetic predispositions to health or 

disease. GWAS, as well as other sophisticated analytic 

techniques, are being used to look for associations 

between genes and late-onset AD and are highlighted 

in recent advances in this area of AD research. 

Using several familial collections of DNA and 

clinical data collected as part of the NIMH Genetics 

Initiative Study, the NIA National Cell Repository 

on Alzheimer’s Disease, and the Consortium on 

Alzheimer’s Genetics, (supported by the Cure Alzheimer 

Fund), investigators at Massachusetts General Hospital 

conducted a GWAS to identify SNPs that might be 

linked to AD (Bertram et al., 2008). In addition 

to confirming the well-established APOE risk factor 

gene on chromosome 19, the researchers identified 

a new SNP on chromosome 14 that showed a strong 

association with AD as well as several other possible 

candidates. None of these new markers had previously 

been associated with AD. Additional whole genome 

analyses in larger sample sets will be needed to 

confirm these loci. 

A research team from the Taub Institute for 

Research on Alzheimer’s Disease and the Aging Brain 

at Columbia University studied well-characterized 

clinical and genetic data from people with AD and 

age-matched healthy individuals participating in 

the NIA Late-Onset Alzheimer’s Disease Family 

Study (Lee et al., 2008). The scientists used several 

approaches to analyze the data to identify genetic 

locations associated with increased risk of late-onset 

AD. In addition to confirming the strong connection 

to the APOE gene, the researchers found several 

promising genes on chromosomes 7, 16, 17, 20, and 

22. As with the previous study, these findings must 

be replicated using other genetic analyses before candidate genes for follow-up analysis are identified, and 

the functions of these genes are elucidated. Recently, 

researchers conducting GWAS have identified variants 

of the SORL1, CLU, PICALM, and CR1 genes that 

may play a role in risk for late-onset Alzheimer’s.

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n

These two studies demonstrate that AD is a complex disease that involves the interaction of a number 

of genes that influence risk of the disease and its manifestations. Sample sets including several thousand cases 

and controls, and the use of large independent confirmatory sample sets will be necessary to identify risk 

genes with low effect size. A number of such collaborative GWAS studies are underway. 

As knowledge grows about genetic links to AD, 

scientists are hoping to use this knowledge to help 

predict future risk of developing the disease. 

The APOE gene directs the formation of the ApoE 

protein, which is involved in transporting cholesterol 

in the blood and the central nervous system. A study 

conducted at the Banner Alzheimer’s Institute and 

Banner Good Samaritan PET Center (Reiman et al., 

2008) looked at the relationship between an aggregated 

cholesterol-related genetic risk score (CREGS, based on 

seven cholesterol-related genes associated with AD risk) 

and regional brain glucose metabolism measured with 

FDG PET in 141 cognitively normal, late middle-aged 

individuals. The scientists found a significant inverse 

correlation between the CREGS score and regional glucose metabolism in brain regions known to be involved 

in AD. This relationship held even after factoring out 

the effects of the APOE ε4 gene. These findings further 

suggest that cholesterol metabolism has a role in the risk 

of developing AD and support the role of cholesterollowering approaches in AD prevention.

The ability to discern possible genetic links to diseases means that scientists also need to develop genetic 

risk assessment and risk communication strategies to 

help people understand what these risks may mean in 

their own lives. The REVEAL (Risk Evaluation and 

Education for Alzheimer’s Disease) Study is a multicenter series of clinical trials supported by the National 

Human Genome Research Institute (NHGRI) and 

NIA that aims to examine the psychosocial and behavioral effect of providing close relatives of people with 

AD with genetic susceptibility testing and information 

about their chances of developing the disease. 

The REVEAL study assessed the ethical issues involved 

in genetic testing of African Americans and the ways in 

which this group interpreted and responded to genetic 

information (Christensen et al., 2008). Using data from 

the long-term, NIA-funded Multi-Institutional Research 

in Alzheimer’s Genetic Epidemiology (MIRAGE) study, 

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22 2OO8 PROGRESS REPORT on ALZHEIMER’

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the research team found that African Americans responded 

well to having genetic risk susceptibility information 

available to them when culturally appropriate education 

strategies were employed. This study is among the first 

to include ethnicity in a genetic risk assessment for AD 

and suggests protocols that can be used to develop 

culturally appropriate risk communication strategies. 

Other 2008 advances in AD genetics include:

Bekris LM et al. Multiple SNPs within and surrounding the 

apolipoprotein E gene influence cerebrospinal fluid apolipoprotein E protein levels. Geriatric Research, Education, and 

Clinical Center, VA Puget Sound Health Care System, Seattle. 

Research supported by NIA. www.ncbi.nlm.nih.gov/pubmed/

18430993

Berchtold NC et al. Gene expression changes in the course of 

normal brain aging are sexually dimorphic. University of 

California Irvine. Research supported by NIA. www.ncbi.nlm.

nih.gov/pubmed/18832152

Kauwe JS et al. Variation in MAPT is associated with 

cerebrospinal fluid tau levels in the presence of amyloid-beta 

deposition. Washington University School of Medicine, St. Louis. 

Research supported by NIA. www.ncbi.nlm.nih.gov/pubmed/

18541914

See the References section for complete citations.

Understanding Nongenetic Risk 

and Protective Factors 

Genetic studies have shed considerable light on genes 

involved in the development of the familial forms 

of early-onset AD and on genetic risk factors for 

late-onset AD. It is apparent, however, that genetic 

risk factors cannot fully explain the initiation and 

Type 2 diabetes has emerged as a 

major focus of interest for AD 

researchers, and the following studies 

illustrate the diverse avenues of investigation being conducted to understand 

the relationship between the two diseases. 

All of these avenues—from test tube studies 

to studies in laboratory animals to epidemiologic studies in groups of people—

lay the groundwork for clinical trials that 

can test possible therapeutic or prevention strategies in humans. 

Scientists at the Salk Institute for 

Biological Studies in La Jolla, California, 

induced diabetes in a strain of young AD 

transgenic mice (Burdo et al., 2009). The 

diabetic mice displayed a significant loss 

in both learning and memory compared 

to control animals. Furthermore, the 

mice were found to have damaged blood 

vessels well before pathologic signs of 

AD appeared. The findings of this study, 

which was supported by the National 

Institute of Diabetes and Digestive and 

Kidney Diseases, suggest that damage 

n

to the brain’s blood vessels caused by 

uncontrolled diabetes, in concert with 

increasing beta-amyloid accumulation, 

appears to contribute to brain pathology 

and cognitive defects.

People with type 2 diabetes are 

known to be at increased risk of cognitive decline, but less is known about 

which cognitive abilities are affected and 

how undiagnosed diabetes and impaired 

fasting glucose relate to cognitive performance. A study by researchers at the 

University of Massachusetts Medical 

School analyzed data from the intramural NIA Age, Gene/Environment 

Susceptibility-Reykjavík Study (AGESReykjavík) (Saczynski et al., 2008). This 

study was designed to examine risk factors, including genetic susceptibility and 

gene/environment interaction, in relation 

to disease and disability in old age. The 

research team found that study participants with type 2 diabetes had poorer 

cognitive performance than did healthy 

people, particularly with respect to the 

n

speed at which they were able to process information. Participants with undiagnosed diabetes had the lowest 

cognitive performance compared to all 

other participants in the study. 

Researchers supported by the National 

Heart, Lung, and Blood Institute (NHLBI) 

and NIA analyzed data from the ongoing 

Cardiovascular Health Study Cognition 

Study to examine the combined effect of 

type 2 diabetes and the APOE ε4 gene 

on the risk of AD, AD with vascular 

dementia, and vascular dementia without 

AD (Irie et al., 2008). Compared with 

those who had neither type 2 diabetes 

nor the APOE ε4 gene, study participants 

with both factors had a significantly higher 

risk of AD. The study found that having 

both diabetes and APOE ε4 increased 

the risk of dementia, especially for AD 

and mixed AD, more than each risk factor 

alone. Several clinical trials are underway 

to determine whether various diabetesrelated treatments will slow the onset of 

AD or its progression. 

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Examining Diabetes and AD from Two Angles

2OO8 PROGRESS REPORT on ALZHEIMER’

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progression of this complex disease. A number of 

nongenetic factors may contribute to or lessen AD 

risk. Many epidemiologic and experimental studies 

have been conducted to identify and understand these 

factors. The biggest value of the knowledge gained 

from this research is that it points to new therapeutic 

approaches, both pharmacological and lifestyle. In the 

past year, a number of scientific teams reported on 

their findings in this exciting area of AD research.

Metabolic and Vascular Risk Factors

Over the past decade, considerable evidence has emerged 

that the body’s network of blood vessels—the vascular 

system—may contribute significantly to the disease 

process in AD. A growing number of researchers are 

studying how the brain microvasculature changes during 

aging and as part of the disease process in AD, and how 

these changes impinge on disease progression. Other 

scientists are focusing their research on understanding 

the relationship between AD and a variety of risk factors associated with vascular and metabolic diseases, 

such as heart disease, stroke, obesity, and type 2 diabetes. 

Aging is accompanied by a decrease in brain volume 

and by an increase in cerebrovascular diseases, such as 

stroke. A study conducted by scientists at Columbia 

University examined the effects of age, sex, race/ethnicity, 

and vascular disease history on brain volume, ventricular 

volume, hippocampus and entorhinal cortex volumes, 

and white matter hyperintensity (WMH) burden 

(Brickman et al., 2008b). (White matter is the part of 

the brain that is made up of axons, the projections 

from neurons that transmit messages to other neurons. 

WMH is seen on MRI scans and is thought to indicate 

cerebrovascular injury.) This study was conducted in a 

large community-based population of racially/ethnically 

diverse older adults without dementia. The team found 

that older age was associated with decreased brain volume 

and with increased ventricular and WMH volumes. 

Hispanic and African American participants had larger 

relative brain volumes and more WMH than did 

white participants. However, the associations of these 

variables with age were similar across racial/ethnic groups. 

Compared with men, women had larger relative brain 

volumes. Vascular disease was associated with smaller 

n

Production of estrogen, a hormone 

made by women’s ovaries, declines 

dramatically after the childbearing 

years. During the past 25 years, laboratory and animal research and human 

observational studies have suggested 

that estrogen may protect the brain. 

Experts have wondered whether using 

estrogen could reduce the risk of AD 

or slow its progression. 

Clinical trials have shown that 

estrogen does not slow the progression 

of already-diagnosed AD and does not 

effectively treat or prevent the disease 

if treatment begins in later life. However, 

questions remain as to whether some 

forms of estrogen might have helpful 

neuroprotective and anti-inflammatory 

effects if started somewhat earlier than 

the older ages already tested (i.e., nearer 

menopause). A recent study, conducted 

at the University of Washington Seattle, 

focused on this question (Suzuki et 

al., 2007).

This study, conducted in mice, found 

that estrogen given immediately after 

the removal of ovaries had a profound 

neuroprotective action and suppressed 

inflammation after a stroke. The beneficial effects did not occur when the 

estrogen was given 10 weeks after 

ovary removal, when the mice’s estrogen 

levels had been low for a long time. 

These findings demonstrate that a 

prolonged period of low estrogen levels 

in mice, such as that which occurs 

after menopause, disrupts both neuroprotective and anti-inflammatory actions 

of estrogen, and they may help to explain 

the results of earlier studies, such as 

the Women’s Health Initiative. In that 

study, which found no beneficial effect 

of estrogen against stroke, participants 

began estrogen therapy after an extended 

period of low estrogen levels. 

Based on the results of these human 

and animal studies, several ongoing 

clinical trials are now testing the effects 

of different kinds and delivery of hormones 

on cognition in perimenopausal women. 

This is a good example of the “bench 

to bedside to bench and back to 

bedside again” approach of AD 

translational research. 

Of Mice and Menopause: 

Studies Look at Estrogen and the Risk of AD

24 2OO8 PROGRESS REPORT on ALZHEIMER’

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relative brain volume and with higher WMH burden, 

particularly among African Americans. Future studies 

will examine these results in more detail to understand 

what leads to them and their importance to cognitive 

health and cognitive declines. 

Many studies show that an accumulation of belly 

fat is a more dangerous risk factor for heart disease and 

type 2 diabetes than is fat that is distributed elsewhere 

in the body. A research team at Kaiser Permanente 

Division of Research in Oakland, California, examined 

the association between belly fat in midlife and late-life 

dementia in 6,583 members of Kaiser Permanente in 

Northern California (Whitmer et al., 2008). The investigators were struck by the finding that people who had 

excess belly fat in midlife (ages 40 to 45 years) were 

three times as likely to develop dementia 30 to 36 years 

later compared to those with low levels of this fat. Even 

more striking was the finding that people who had an 

excess of belly fat but were not obese during midlife were 

twice as likely to develop dementia late in life compared 

to those with low levels of belly fat. The highest risk 

of late-life dementia was found in individuals who had 

excess belly fat and were obese during mid-life. 

Personality Traits and the Risk of AD

One of the most intriguing observations in clinical 

research that is focused on identifying new risk or 

protective factors for AD comes from studying the 

associations between various personality traits exhibited 

throughout life and the development of AD in late life.

A research team from the Rush Alzheimer’s Disease 

Center in Chicago has carried out a series of seminal 

studies in this area and continues to break new ground. 

In their previous work, they identified that neuroticism 

and proneness to psychosocial distress were associated 

with elevated risk of AD. In a recent epidemiologic 

study (Wilson et al., 2007), the Rush team explored the 

association between the development of AD and conscientiousness, a personality trait previously linked to 

morbidity and mortality in old age. The study participants were members of the Religious Orders Study, a 

long-running study involving 997 nuns, priests, and 

brothers. At the beginning of this 12-year study, the 

participants completed a 12-item measure of conscientiousness. In the course of the study, a number of participants were diagnosed with AD and others died 

with or without having the disease. The brains of clinically diagnosed participants were evaluated for the 

n

n

presence of AD pathology. The study found that a 

higher level of conscientiousness was associated with 

reduced risk of developing clinical AD, even after 

controlling for other personality traits and risk factors 

for AD. Similar to observations for other personality 

traits and AD, conscientiousness did not have any correlation with the pathologic hallmarks of AD. This 

suggests that the mechanisms by which these factors 

elevate or reduce AD risk have yet to be discovered 

and that novel neurodegenerative and neuroprotective 

processes may be at play. 

The Mystery of Cognitive Reserve

Scientists have long been fascinated by the question of 

why some people develop dementia while others remain 

cognitively healthy all their lives. Another conundrum 

is why some people remain cognitively healthy even 

though they may have significant AD-related lesions 

such as deposits of amyloid plaques in their brains. One 

possible explanation for these puzzling observations 

revolves around the concept of “cognitive reserve.” This 

term refers to the brain’s ability to operate effectively 

despite apparent damage. Variations in reserve may 

reflect genetic differences or differences in life experience, 

such as education, occupational experience, or leisure 

activities. A recent study has focused on the role of 

education in cognitive reserve. 

A research team from the Washington University 

School of Medicine evaluated the cognitive reserve 

hypothesis by examining whether people with greater 

educational attainment have better cognitive function 

than individuals with less education when both have 

elevated beta-amyloid plaque levels (Roe et al., 2008). 

The investigators studied 198 people between 2003 

and 2008 at the Washington University Alzheimer’s 

Disease Research Center. Study participants were divided 

into two groups—participants without dementia and 

participants with AD. All participants underwent cognitive and neuropsychological testing. The extent of 

beta-amyloid deposition in their brains was measured 

with PiB PET scans. The study found that the participants with greater education maintained better global 

cognitive functioning in the presence of beta-amyloid 

pathology. These findings support the cognitive reserve 

hypothesis and present evidence that education could 

be used as an indicator of cognitive reserve. 

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Extinguishing the Flares of the 

Disease Process

Inflammation is a dynamic and complex biological 

process that affects cells and tissues throughout the 

body. It occurs in response to many types of injuries 

and abnormal situations, from a scrape on the knee to 

rheumatoid arthritis. Chronic inflammation in the 

brain is part and parcel of AD pathology, and many 

scientists are examining its role in the development and 

progression of the disease. They do not always agree on 

its significance, however. Some scientists believe that 

inflammation is part of a vicious cycle that harms neurons. Others think that aspects of inflammation may be 

valuable to the brain by counteracting the detrimental 

aspects of the AD process. Epidemiologic studies 

have suggested that long-term use of non-steroidal 

anti-inflammatory drugs (NSAIDs), such as naproxen, 

ibuprofen, and indomethacin, are associated with 

decreased AD risk. However, clinical trials have not 

yet detected any beneficial effect of NSAIDs on AD 

prevention or progression. A recent study examined 

epidemiological findings on NSAIDs and AD.

Scientists at the Johns Hopkins University Bloomberg 

School of Public Health conducted a study funded by 

NHLBI and NIA to analyze data from six prospective 

epidemiologic studies (Szekely et al., 2008) to test the 

hypothesis that only NSAIDs known to have betaamyloid-lowering activity would be associated with 

diminished AD risk. The investigators confirmed previous observations that study participants who used 

NSAIDs were less likely than those who did not use 

NSAIDs to develop AD. However, NSAIDs with betaamyloid-lowering activity were no better than other 

NSAIDs when it came to their association with lower 

AD risk. The researchers concluded that all conventional 

NSAIDs, including aspirin, are associated with a similar 

lowered AD risk in humans. Studies are continuing to 

determine whether NSAIDs might lessen the risk of 

AD if given earlier in the disease process.

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Other 2008 advances in AD nongenetic risk and protective 

factors include:

Buchman AS et al. Physical frailty in older persons is associated 

with Alzheimer disease pathology. Rush Alzheimer’s Disease Center 

in Chicago. Research supported by NIA. www.ncbi.nlm.nih.gov/

pubmed/18695161 

Dai W et al. Abnormal regional cerebral blood flow in cognitively normal elderly subjects with hypertension. University of 

Pittsburgh School of Medicine. Research supported by NIA. www.

ncbi.nlm.nih.gov/pubmed/18174483 

Martin B et al. Conserved and differential effects of dietary 

energy intake on the hippocampal transcriptomes of females 

and males. NIA Intramural Research Program. www.ncbi.nlm.

nih.gov/pubmed/18545695 

Troncoso JC et al. Effect of infarcts on dementia in the Baltimore 

Longitudinal Study of Aging. NIA Intramural Research Program. 

www.ncbi.nlm.nih.gov/pubmed/18496870 

See the References section for complete citations.

Exploring All Possibilities to 

Improve AD Diagnosis

The only way to diagnose AD definitively is after death, 

when a clinical examination of the brain can reveal the 

defining characteristics of the disease—an abundance 

of beta-amyloid plaques and tau tangles, atrophied brain 

tissue, and enlarged ventricles. However, scientists know 

that damage to the brain caused by AD begins to develop 

long before clinical symptoms are readily apparent. Finding 

a way to detect the disease early in its development 

would allow clinicians to intervene as soon as they can. 

Ambitious efforts are underway to develop sensitive 

screening instruments and neuropsychological tests to 

diagnose cognitive decline, MCI, and AD as early as 

possible. In a complementary effort, many investigators 

are seeking new ways to measure changes in the structure and function of the brain and in biomarkers, such 

as substances in cerebrospinal fluid (CSF) and blood. 

These methods may hint at pathological changes that 

occur before MCI or AD becomes evident. 

Improvements in a third area—brain imaging—

also are yielding exciting results. For example, the 

development of PiB has enabled scientists to visualize 

beta-amyloid plaques in the living brain. Advances like 

26 2OO8 PROGRESS REPORT on ALZHEIMER’

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this may lead to very early diagnosis of AD and will 

help researchers and clinicians monitor the effectiveness 

of experimental treatments. Following are just a few 

highlights from studies concerned with early diagnosis 

that were reported in 2008 and 2009.

Many studies have demonstrated that the hippocampus and entorhinal cortex (structures deep in 

the brain) shrink when a person has AD. Changes in 

the cerebral cortex (the outer surface of the brain) have 

been harder to study in living people. A research team 

at Massachusetts General Hospital and Harvard Medical 

School used MRI scans to map the thinning of gray 

matter in the cerebral cortex (a “signature” of abnormal 

cortical anatomy in living people with AD) in people 

with mild AD (Dickerson et al., 2009). The signature 

paralleled cortical regions already known to be involved 

in AD. Thinning in the cerebral cortex was associated 

with severity of symptoms even in the earliest stages of 

clinical decline, and subtle thinning also was present 

in older adults without cognitive symptoms who had 

beta-amyloid deposits detected by PiB. Cortical thinning may potentially be useful as an imaging biomarker. 

Not everyone with MCI develops AD, and scientists 

have long been interested in determining indicators that 

might reliably predict which people with MCI will go 

on to develop AD. A research team at Columbia University assessed 148 people with MCI every 6 months 

for 3 years (Devanand et al., 2008). Five baseline measures, when combined, strongly and accurately predicted 

whether a person with MCI would develop AD. The 

five measures were performance on verbal memory tests, 

reports by a family member or close friend of functional 

impairments, performance on a smell identification test, 

MRI scan of hippocampal volume, and MRI scan of 

entorhinal cortex volume. If the results of this study 

are replicated, this five-measure combination could be 

useful in early AD detection. 

White matter hyperintensities called periventricular 

hyperintensities (PVH) can be found in axons next to 

the ventricles and in axons deep in the brain. Recently, 

investigators at the VU Medical Center in Amsterdam, 

The Netherlands, as well as NIA-funded investigators 

conducted a study of the role of WMH in the progression from MCI to AD. They used data from a 3-year 

clinical trial conducted as part of the Alzheimer’s 

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Disease Cooperative Study, which compared the 

effectiveness of vitamin E, donepezil (Aricept®), and a 

placebo in delaying the onset of AD in people with 

MCI (van Straaten et al., 2008). The researchers found 

that only PVH, not deep WMH, was associated with 

an increased risk of developing AD. Cerebrovascular 

disease, particularly PVH, may contribute to the onset 

of AD in vulnerable individuals. 

As scientists have sharpened their focus on the early 

stages of AD, they have begun to discover hints that 

changes other than memory loss may signal a developing AD process. For example, movement difficulties, 

trouble identifying odors, and hearing problems may 

indicate that the AD process is underway. These findings suggest possible new targets for diagnostic tests for 

MCI and AD. Such tools can help scientists answer 

questions about causes and very early development of 

AD, track changes in brain and cognitive function over 

time, and track responses to treatments. Two studies 

reported in 2008 focused on such early changes.

A University of Wisconsin–Madison team followed 

1,920 participants in a population-based study of sensory loss and aging (Schubert et al., 2008). The researchers 

found a significant association between difficulty identifying smells at baseline and incidence of cognitive 

impairment 5 years later, and the association remained 

even after adjusting for possible confounders. The authors 

concluded that their findings are promising and may be 

useful clinically but cautioned against using olfaction as 

a screening test in the general population.

Researchers at the University of Washington Seattle 

examined the effects of memory impairment on the 

brain’s ability to understand and interpret speech among 

313 older adults participating in a dementia surveillance 

research program (Gates et al., 2008). The scientists 

divided the participants into three groups: cognitively 

healthy participants, participants with MCI, and participants with diagnosed dementia. Results showed that 

even after adjusting for age and peripheral hearing loss, 

ability to understand and interpret speech was poorest 

in the dementia group and moderately reduced in the 

MCI group compared with the cognitively healthy group.

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Other 2008 advances in AD diagnosis include:

Brickman AM et al. Measuring cerebral atrophy and white 

matter hyperintensity burden to predict the rate of cognitive 

decline in Alzheimer disease. Taub Institute for Research on 

Alzheimer’s Disease and the Aging Brain, Columbia University. 

Research supported by NIA. www.ncbi.nlm.nih.gov/pubmed/

18779424 

Davatzikos C et al. Detection of prodromal Alzheimer’s disease 

via pattern classification of magnetic resonance imaging. University 

of Pennsylvania. Research supported by NIA. www.ncbi.nlm.nih.

gov/pubmed/17174012 

Desikan RS et al. MRI measures of temporoparietal regions 

show differential rates of atrophy during prodromal AD. 

Boston University School of Medicine. Research supported by NIA. 

www.ncbi.nlm.nih.gov/pubmed/18672473 

Esposito G et al. Imaging neuroinflammation in Alzheimer’s 

disease with radiolabeled arachidonic acid and PET. NIA 

Intramural Research Program. www.ncbi.nlm.nih.gov/pubmed/

18703605 

Fan Y et al. Structural and functional biomarkers of prodromal 

Alzheimer’s disease: A high-dimensional pattern classification 

study. University of Pennsylvania. Research supported by NIA. 

www.ncbi.nlm.nih.gov/pubmed/18400519 

O’Bryant SE et al. Detecting dementia with the Mini-Mental 

State Examination in highly educated individuals. Texas Tech 

University Health Sciences Center. Research supported by NIA. 

www.ncbi.nlm.nih.gov/pubmed/18625866 

Pan S et al. Application of targeted quantitative proteomics 

analysis in human cerebrospinal fluid using a liquid chromatography matrix-assisted laser desorption/ionization time-offlight tandem mass spectrometer (LC MALDI TOF/TOF) 

platform. University of Washington, Seattle. Research supported 

by NIEHS. www.ncbi.nlm.nih.gov/pubmed/18186601 

Ringman et al. Biochemical markers in persons with preclinical familial Alzheimer disease. University of California Los 

Angeles. Research supported by NIA. www.ncbi.nlm.nih.gov/

pubmed/18509095 

Whitwell JL et al. MRI correlates of neurofibrillary tangle 

pathology at autopsy: A voxel-based morphometry study. 

Mayo Clinic, Rochester, Minnesota. Research supported by NIA. 

www.ncbi.nlm.nih.gov/pubmed/18765650 

See the References section for complete citations.

Boosting the Search for 

Effective AD Therapies

NIA has a longstanding interest and commitment to 

supporting research aimed at ensuring that promising 

new leads in basic science are developed into drugs that 

can be clinically tested in people. These efforts shifted 

into high gear in 2004 when NIA launched a set of 

translational research initiatives focused on supporting 

early drug discovery and preclinical drug development 

for AD. NIA is in a unique position to support the 

translation of basic research into new therapies because 

its funded academic research is fertile ground for the discovery of potential therapeutic targets. These research 

initiatives have resulted in a diverse portfolio of funded 

projects aimed at the discovery and preclinical development of novel compounds for a variety of therapeutic 

targets in AD. In addition, the program supports the 

repurposing and reformulation of existing drugs already 

approved for other disease conditions as well as the 

development of therapeutics based on natural products. 

Since the inception of the AD translational research 

initiatives, NIA has supported more than 60 projects 

aimed at discovering and developing novel compounds 

for more than a dozen different therapeutic targets. 

Evidence from numerous clinical observations and 

experimental studies has indicated that some antihypertensive medicines might be useful in AD treatment. 

Researchers at the Mount Sinai School of Medicine 

examined the ability of the antihypertensive drug valsartan (Diovan®) to alleviate AD pathology in a transgenic mouse model of AD. The study showed that 

valsartan reduced the amount of beta-amyloid plaques 

and attenuated the learning deficits that accompany 

this pathologic feature (Wang et al., 2007). 

Curcumin, the yellow pigment of the spice turmeric, 

has been shown in studies with mice to have multiple 

neuroprotective activities, such as anti-inflammatory and 

antioxidant properties. In addition, in mouse models 

of AD exhibiting plaque pathology and learning deficits, 

curcumin reduced the deposition of beta-amyloid and 

diminished the learning deficits. A considerable challenge in developing curcumin as an AD therapeutic is 

its chemical instability and a tendency to change metabolically in the human body. A research team at the 

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University of California Los Angeles is working to 

develop a curcumin formulation with more desirable 

physico-chemical properties and is investigating whether 

one of curcumin’s more stable metabolites (known as 

tetrahydrocurcumin, THC) mediates curcumin’s neuroprotective activities (Begum et al., 2008). The study 

found that despite the structural similarities between 

curcumin and THC, THC had few of the neuroprotective properties of curcumin, further emphasizing 

the need for a more refined curcumin formulation. 

A research team at the Center for Drug Discovery and 

Chemical Biology at Northwestern University in Chicago 

is seeking to develop a novel class of anti-inflammatory 

drug that can halt the progression of the disease process 

in the brain without altering the body’s ability to fight 

infection. One result of these efforts is a candidate therapeutic called Minozac. Given that persistent brain 

inflammation is a hallmark of a number of neurodegenerative diseases, including AD, the team initiated 

a preclinical study to test the effectiveness of Minozac 

in curtailing the deleterious consequences of traumatic 

brain injury (TBI). These consequences include a marked 

increase in inflammatory molecules such as cytokines, 

which are thought to cause acute and long-term damage 

to the brain (Lloyd et al., 2008). Mice treated with 

Minozac up to 9 hours after TBI showed suppressed 

inflammatory response in the brain. This response precluded the long-term neurological consequences of the 

injury and abolished the neurobehavioral deficits 

measured up to 1 month after injury. TBI is gaining 

recognition as a condition of major public health 

concern and an enormous unmet medical need because 

effective therapies for TBI are currently lacking.

NIA-funded investigators also continue to take on the 

challenge of developing safe and effective gene therapy 

and immunotherapy for AD. 

Gene therapy. A research team from the University 

of San Diego has been pursuing a gene-vector therapy 

to deliver nerve growth factor (NGF) to brain areas 

showing loss of cholinergic transmission, which is critical for cognitive function (Nagahara et al., 2008). Most 

recently, these investigators reported on the efficacy and 

safety of long-term NGF therapy using a new lentiviral 

vector for NGF delivery to the cholinergic basal forebrain neurons of aged rhesus monkeys. This area is very 

vulnerable in AD, with neurons subject to shrinkage in 

normal aging as well. The result was a reversal of agen

n

related neuronal shrinkage, compared to that of untreated 

aged monkeys. Importantly, the delivery method did 

not lead to any adverse side effects, which had previously 

hindered the effectiveness of this approach. These findings 

support the safety and feasibility of lentiviral NGF gene 

transfer for potential testing in human clinical trials.

Immunotherapy approaches. Two recent advances 

highlight the progress made in developing a safe and 

effective AD immunization therapy. The goal of immunization therapies is to remove the toxic beta-amyloid 

peptides from the brains of people with AD without 

causing dangerous brain inflammation. NINDS- and 

NIA-supported researchers from the Institute for Molecular 

Medicine in Huntington Beach, California, and the 

University of California Irvine sought to achieve this 

goal by developing a novel vaccine that used DNA as 

an immunogen. The DNA drove the synthesis of a 

fragment of the beta-amyloid peptide as well as an 

inflammatory mediator that stimulated a strong antiinflammatory response (Movsesyan et al., 2008). AD 

transgenic mice exhibiting both beta-amyloid and tau 

lesions were prophylactically immunized at a young 

age. Seven days later, the researchers tested the animals’ 

cognitive performance, and then analyzed their immunological response and changes in amyloid and tau

pathology. In the short period after the immunization, 

the vaccine produced a robust anti-beta-amyloid immune 

response associated with reduced levels of toxic betaamyloid oligomers as well as reduction in amyloid 

plaques. Tau pathology remained unaltered. Notably, 

the vaccine treatment led to improved cognitive function in the treated mice and resulted in reduced brain 

inflammation without adverse effects. Using a related 

approach, a research team at the University of Rochester 

School of Medicine and Dentistry used a modified herpes 

simplex virus (HSV) that makes beta-amyloid, along 

with the inflammatory mediator interleukin-4 (IL-4), 

to help the body generate the desired anti-inflammatory 

immune response (Frazer et al., 2008). The team tested 

this approach in the same AD transgenic model used by 

researchers in the previous study. The transgenic mice 

that expressed both amyloid and tau pathology received 

an initial vaccination at 2 months of age, before the 

development of the AD pathologic hallmarks, and two 

additional booster injections. The treated mice showed 

an anti-inflammatory, anti-beta-amyloid immune 

n

2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE 29
response, improved learning and memory, and reduced 

AD-related amyloid and tau pathology 9 months after 

the initial vaccination. Brain neuroinflammation also 

was reduced without signs of micro-bleeding in the brain. 

These two preclinical studies are important steps toward 

the development of a safe and effective AD vaccine.

In addition to funding initiatives that support early 

drug discovery and preclinical drug development for 

AD, NIA continues to provide investigational new drug 

(IND)-enabling toxicology services for novel therapeutics and imaging ligands through a longstanding contract. 

This contract supports the development of the amyloid 

imaging agent PiB, which enables visualization of betaamyloid pathology in living human brains. AL-108, a 

drug that was evaluated for safety under that contract 

to help provide the data for IND approval from the 

FDA, is now being tested in human clinical trials. 

AL-108, or davunetide, is the intranasal formulation of 

NAP (an eight amino acid peptide). The Allon Therapeutics 

Phase IIa clinical trial results showed intranasal davunetide 

positively affected memory function in people with MCI. 

A Phase IIb clinical trial in people with AD is under 

development. 

NIA also co-funds a number of aspects of preclinical development for AD through the trans-NIH Rapid 

Access to Interventional Development (NIH-RAID) 

Program (http://nihroadmap.nih.gov/raid/). NIA and 

the NIH-RAID Program co-funded the completion of 

critical IND-enabling steps for the novel AD therapeutic 

MCD-386, discovered by Dr. William Messer at the 

University of Toledo. MCD-386 belongs to a second 

generation of drugs that activate particular receptors 

for acetylcholine on neuronal cells. These drugs are 

more effective than the first generation of drugs and are 

very specific for the receptors they are targeting. As a 

result, they lack some of the side effects that prevented 

the development of the first generation of the drugs. 

MCD-386 was licensed by the Wisconsin-based biotech 

company Mithridion, Inc., and is in early stages of 

clinical testing for AD treatment.

Other 2008 advances in AD translational research include:

Faghihi MA et al. Expression of a noncoding RNA is elevated 

in Alzheimer’s disease and drives rapid feed-forward regulation 

of beta-secretase. The Scripps Research Institute, Jupiter, Florida. 

Research supported by NIA. http://www.ncbi.nlm.nih.gov/

pubmed/18587408 

Ghosh AK et al. Potent memapsin 2 (beta-secretase) inhibitors: 

Design, synthesis, protein-ligand X-ray structure, and in vivo 

evaluation. Purdue University. Research supported by NIA. 

www.ncbi.nlm.nih.gov/pubmed/18180160 

Head E et al. A two-year study with fibrillar β-amyloid (Aβ) 

immunization in aged canines: Effects on cognitive function 

and brain Aβ. University of California Irvine. Research supported 

by NIA. www.ncbi.nlm.nih.gov/pubmed/18385314 

See the References section for complete citations.

Supporting the Gold Standard: 

AD Clinical Trials

Clinical trials, which compare a potential new treatment 

with a standard treatment or with a placebo (an inactive 

substance), are the only way to demonstrate whether a 

drug or other type of treatment is safe and effective in 

people. These complex and expensive studies can involve 

hundreds or even thousands of people and often are 

conducted over a long period of time. Some clinical 

trials are focused on prevention—strategies to help reduce 

the risk of developing AD in the future. Other clinical 

trials are focused on AD treatment—strategies to preserve cognitive function for as long as possible, slow 

disease progression, delay progression from MCI to AD, 

or alleviate behavioral or psychiatric problems. In 2008, 

several research teams reported on studies in this latter area. 

Sleep disturbances and disordered breathing during 

sleep are common in the elderly. Sleep apnea (a sleep 

disorder characterized by pauses in breathing during 

sleep) affects nearly 42 percent of older adults. Scientists 

have already demonstrated a strong relationship between 

severity of sleep apnea and cognitive impairment in 

older adults and in people with dementia. A large study 

of nursing home residents showed that those with severe 

dementia had significantly more-severe sleep apnea, and 

those with more-severe sleep apnea had significantly 

more-severe dementia. The continuous positive airway 

pressure (CPAP) mask is an inexpensive and effective 

treatment for sleep apnea. In a clinical trial, researchers 

from the University of California San Diego demonstrated 

n

30 2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE
that CPAP treatment in people with AD significantly 

improved their ability to learn and memorize, as well 

as to adapt their cognitive processing strategies to face 

new and unexpected conditions in the environment 

(Ancoli-Israel et al., 2008). The researchers also found 

a significant enhancement of mental processing speed 

in AD patients after CPAP treatment.

The Clinical Antipsychotic Trials of Intervention 

Effectiveness—Alzheimer’s Disease (CATIE-AD), funded 

by NIMH, examined atypical antipsychotic medications 

(olanzapine, quetiapine, and risperidone) or placebo in 

421 outpatients with AD and psychosis or agitated/

aggressive behavior (Sultzer et al., 2008). Results indicated 

that some clinical symptoms improved with atypical 

n

antipsychotic use and suggest that they may be especially 

effective for particular symptoms, such as anger, aggression, 

and paranoid ideas. However, these drugs do not appear 

to improve functioning, care needs, or quality of life in 

people with AD. 

Although results may not demonstrate that a particular treatment is effective, scientists can gain a wealth 

of knowledge from clinical trials for use in future trials. 

A good case in point is the recently concluded Ginkgo 

Evaluation of Memory Study. 

Early studies suggested that extracts of leaves from 

the Ginkgo biloba tree have beneficial effects on brain 

function, especially those related to dementia and AD. 

n

Researchers conducting clinical trials 

 with people who may have memory 

problems, MCI, or AD must consider the 

declining memory and cognitive capacity 

of the participants. They must evaluate 

the ability of potential participants to 

understand, consent to, and participate 

in the research. Three studies reported 

in 2008 examined this issue.

Researchers from the University of 

Pennsylvania School of Medicine developed a semistructured interview technique 

that assesses four decisionmaking abilities 

(Karlawish et al., 2008). They found that 

scores from this instrument, called the 

MacArthur Competency Assessment Tool 

for Clinical Research (MacCAT-CR), and 

especially scores on the “understanding” 

domain, can be used to help determine 

which people with mild to moderate AD 

are capable of giving informed consent. 

However, the researchers caution that results 

could vary depending on the risk of the 

study and the techniques interviewers use 

to administer the MacCAT-CR. Therefore, 

the tool should not be used alone but in 

concert with other measures to determine 

a person’s ability to provide informed consent. 

n

A study led by scientists at the 

Boston University Alzheimer’s Disease 

Center and funded by NIMH and NIA 

compared 40 older adults (ages 60-90) 

with MCI to 40 with normal cognitive 

functioning. They looked at participants’ 

scores on a comprehensive neuropsychological battery of tests and their 

capacity to provide informed consent for 

participation in a hypothetical clinical 

trial (Jefferson et al., 2008). The results 

showed that many of those with MCI 

performed more poorly than the normal 

controls on most of the decisional 

capacity measures examined. People 

with MCI who were deemed to be 

capable of providing informed consent 

had higher education levels than those 

rated as not capable. These findings 

suggest that impaired capacity to provide informed consent for research participation may be present relatively early 

in the trajectory of cognitive decline to 

AD and that researchers should be cautious when evaluating the decisional 

capacities of potential research participants who are at risk of AD. The 

researchers further note that methods 

used to obtain research consent should 

n take into account the participants’ educational background.

Scientists at the University of Alabama 

at Birmingham assessed changes over 

time in the medical decisionmaking 

capacity of people with MCI (Okonkwo 

et al., 2008). The investigators were 

interested in determining participants’ 

capacity at the beginning of the study 

and investigating the impact of progressing from MCI to AD on this capacity. 

Participants were followed for up to 

3 years. The researchers found that 

the decline in medical decisionmaking 

capacity in people with MCI is a 

relatively slow but detectable process. 

Over a 3-year period, participants with 

MCI also showed progressive decline 

in their ability to understand consent 

information. This decline accelerated 

after diagnosis of AD, reflecting increasing 

vulnerability to decisional impairment. 

The study authors suggest that clinicians 

and researchers working with MCI 

patients should give particular attention 

to the informed consent process when 

progression to AD is suspected or 

confirmed. 

n

Decisionmaking Capacity: An Issue for Clinical Trials Participation

2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE 31
Discoveries and progress would not be possible 

without the many thousands of volunteers who participate in research.

In 2000, the National Center for Complementary and 

Alternative Medicine, NIA, and NHLBI funded a 

clinical trial to compare ginkgo to placebo in people 

older than 75 who were cognitively healthy or had MCI 

(DeKosky et al., 2008). The main goal was to determine 

whether ginkgo was helpful in preventing or delaying 

the onset of dementia, but researchers also were interested in assessing participants’ rate of cognitive and 

functional decline, the incidence of cardiovascular and 

cerebrovascular events, and causes of death. In 2008, 

the University of Pittsburgh research team leading the 

trial reported that ginkgo did not reduce the incidence 

of dementia or AD in either the cognitively healthy 

participants or those with MCI. Despite these results, 

the investigators learned much about subgroups of 

participants who may have been at increased risk of 

developing dementia, and they learned about ginkgo’s 

effects on diseases other than dementia and AD. They 

also gained insights into ways of designing and conducting large dementia prevention trials in older adults, 

such as the number of participants needed to yield 

clinically significant results. These trial findings and 

lessons learned will be used in planning and conducting 

future AD prevention trials. 

A number of other NIA-funded Phase II and Phase 

III clinical trials have been completed, and publication 

of the primary results is pending. These trials include:

Cholesterol Lowering Agent (Simvastatin) to Slow 

Progression of AD (CLASP)—Alzheimer’s Disease 

Cooperative Study (ADCS); Mary Sano, Principal 

Investigator (PI)

n

Docosahexaenoic Acid (DHA, Omega 3 fatty acid) 

in AD—ADCS; Joseph Quinn, PI

Antioxidants (vitamins E and C, alpha lipoic acid, 

coenzyme Q) in AD—ADCS; Douglas Galasko, PI

Valproate in Dementia (VALID)—ADCS; Pierre 

Tariot, PI

Huperzine A in AD—ADCS; Paul Aisen, PI

Transdermal Nicotine Treatment of MCI—Paul 

Newhouse, PI

Federal and non-Federal agencies and industry are 

supporting more than 50 AD-relevant clinical trials. 

Table 1, beginning on page 33, lists ongoing prevention 

and treatment trials funded by NIA, as well as several 

jointly supported by NIA and other NIH Institutes. The 

ADCS, a consortium of about 75 sites in the U.S. and 

Canada (see page 41 for more on the ADCS), is a cornerstone of NIA’s efforts in clinical trials research. 

Table 2, beginning on page 36, lists NIA-funded 

clinical trials examining prevention of age-related cognitive decline. Currently, it is unclear whether any 

intervention that effectively slows age-related cognitive 

decline also will slow the onset of AD.

n

n

n

n

n

32 2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE
Trial Name Principal Investigator Intervention Population

Antioxidants

PREADVISE (Prevention of Alzheimer’s 

Disease by Vitamin E and Selenium)*

William Markesbery Vitamin E, selenium, Vitamin 

E + selenium

Men ages 60-90

Vitamin E in Aging Persons With Down 

Syndrome

Arthur Dalton Vitamin E People ages 50+ with Down 

syndrome, at high risk of 

developing AD

Cardiovascular

ACCORD-MIND (Action to Control 

Cardiovascular Risk in Diabetes—

Memory in Diabetes)*

Lenore Launer Intensive glucose, blood 

pressure, and lipid management

People ages 40-79 with type 2 

diabetes mellitus

Effects of Simvastatin on CSF AD 

Biomarkers 

Cynthia Carlsson Simvastatin People ages 45-65 at high risk 

of AD (family history, APOE ε4) 

ESPRIT (Evaluating Simvastatin’s 

Potential Role in Therapy)

Cynthia Carlsson Simvastatin People ages 35-69 at high risk 

of AD (family history)

SPRINT-MIND (Systolic Blood Pressure 

Intervention Trial-MIND)*

Lawrence Fine Blood pressure lowering to 

<140 mm Hg versus <120 

mm Hg

Adults age 55 years or older 

with systolic blood pressure of 

130 mm Hg or higher, history of 

cardiovascular disease, high risk 

for heart disease 

Statin Effects on Beta-Amyloid and 

Cerebral Perfusion in Adults at Risk 

for AD

Gail Li Simvastatin Cognitively normal people ages 

45-64

Hormones

Alzheimer’s Disease: Potential Benefit 

of Isoflavones

Carey Gleason Novasoy (soy isoflavones–

phytoestrogens)

People with AD

ELITE (Early versus Late Intervention 

with Estradiol)

Howard Hodis 17β-estradiol Healthy early (less than 6 years) 

or late (10 years +) menopausal 

women

KEEPS-CA (Kronos Early Estrogen 

Prevention Study–Cognitive and 

Affective Study)*

Sanjay Asthana Oral conjugated equine 

estrogen (CEE or Premarin®) 

and transdermal 17βestradiol (tE2)

Healthy perimenopausal women 

ages 42-58

Raloxifene for Women with 

Alzheimer’s Disease

Victor Henderson Raloxifene (selective 

estrogen receptor modulator or SERM)

Older women with AD

SMART (Somatotrophics, Memory, 

and Aging Research Trial)

Michael Vitiello Growth hormone releasing 

hormone (GHRH)

People with MCI and healthy 

older adults ages 55-80

Testosterone Supplementation in Men 

with MCI

Monique Cherrier Testosterone Older men with MCI and low 

testosterone

T A B L E 1. Ongoing NIA-Funded AD/MCI Prevention and 

Treatment Clinical Trials (as of November 2009)

2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE 33
Trial Name Principal Investigator Intervention Population

Diabetes

Glucose Regulation and Memory in 

Alzheimer’s Disease

Suzanne Craft Diet, triglyceride emulsion, 

rosiglitazone

People with AD (all studies), 

age-matched healthy older 

adults (diet study)

Metformin in Amnestic MCI Jose Luchsinger Metformin Overweight/obese older 

people with MCI 

RECALL (Rosiglitazone Effects on 

Cognition for Adults in Later Life)

Suzanne Craft Rosiglitazone People with MCI

SNIFF 120 (Study of Insulin to Fight 

Forgetfulness, 120 Days)

Suzanne Craft Intranasal insulin People with MCI and AD

Diabetes and Exercise

POEM (Pioglitazone or Exercise to 

Treat Mild Cognitive Impairment) 

Robert Schwartz Pioglitazone, endurance 

exercise training

Older people with MCI and 

metabolic syndrome

Exercise

Effects of Standardized Aerobic 

Exercise Training on Neurocognition 

and Neurodegeneration

Thomas Obisesan Aerobic exercise training African Americans with AD

Exercise and Health Promotion for 

MCI: A Controlled Trial

Linda Teri Two exercise programs People with MCI

MCI: Cerebrovascular Dysfunction and 

Exercise Training

Rong Zhang Endurance exercise training People with MCI

Exercise and Cognitive Training

Exercise Versus Cognitive 

Interventions for Elders at Risk for 

Dementia

David Loewenstein Cognitive training, aerobic 

exercise training

People with MCI

Neural Effects of Exercise, Cognitive, 

or Combined Training in AD At-Risk 

Elders

Stephen Rao Cognitive training, aerobic 

exercise training

Healthy people ages 65-85

SHARP-P (Seniors Health and Activity 

Research Program Pilot)

Mark Espeland Physical activity, cognitive 

training

Older people ages 70-85 

at risk of developing MCI

Treatment for Behavioral Issues

ADMET (Apathy in Alzheimer’s 

Disease Methylphenidate Trial)

Jacobo Mintzer

Krista Lanctot

Paul Rosenberg

Methylphenidate People with AD 

Antipsychotic Discontinuation in 

Alzheimer’s Disease

Davangere Devanand Risperidone People with AD

CITAD (Citalopram Treatment for 

Agitation in Alzheimer Dementia)

Constantine Lyketsos Citalopram People with AD

Light Treatment for Sleep/Wake 

Disturbances in AD

Jerome Yesavage Light treatment People with AD and 

their caregivers

34 2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE
Trial Name Principal Investigator Intervention Population

Treatment for Behavioral Issues (continued)

Prazosin Treatment for Disruptive 

Agitation in Alzheimer’s Disease

Elaine Peskind Prazosin People with AD 

TREA (Treatment Routes for Exploring 

Agitation)

Jiska Cohen-Mansfield Systematic approach 

to individualizing nonpharmacological interventions for persons with 

dementia

Nursing home residents with 

AD/dementia

Other Interventions

AAV-NGF Gene Delivery in Alzheimer’s 

Disease

Paul Aisen Nerve growth factor (NGF) 

gene delivery

People with AD

AREDS2 (Age-Related Eye Disease 

Study 2)** 

Emily Chew

John Paul San Giovanni

Macular xanthophylls (lutein 

and zeaxanthin) and/or 

omega-3 fatty acids (DHA 

and EPA)

People ages 50-85 with agerelated macular degeneration 

(AMD) in both eyes or 

advanced AMD in one eye

fMRI Activation in Mild Cognitive 

Impairment

Michela Gallagher Levetiracetam People with MCI

GAP (Gammaglobulin Alzheimer’s 

Partnership)†

Norman Relkin Immune globulin intravenous (IVIg), passive 

immunization 

People with AD

Study on Thalidomide as BACE1 

Inhibitor in Alzheimer’s Disease

Yong Shen Thalidomide People with AD 

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

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

National Heart, Lung, and Blood Institute’s ACCORD trial); SPRINT-MIND (add-on to NHLBI’s SPRINT trial); KEEPS-CA 

(add-on to Kronos Longevity Research Institute’s KEEPS trial).

** NIA co-funded trial: AREDS2 (National Eye Institute, lead institute).

† Alzheimer’s Disease Cooperative Study (ADCS) trial. 

2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE 35
Trial Name Principal Investigator Intervention

Cognitive Training

A Brain-Based Approach to Enhancing Executive Control 

Functions in Healthy Aging

Mark D’Esposito Cognitive training

Active Interventions for the Aging Mind Denise Park Cognitive enrichment through training in 

digital photography or quilting

Expanding the Implementation of an Effective Cognitive 

Aging Intervention

Helga Noice Cognitive enrichment through training in 

acting 

Randomized Clinical Trial of Two Speed of Processing 

Modes to Prevent Cognitive Decline in Older Adults

Frederic Wolinsky Comparison of standard versus enhanced 

visual processing training

The Senior Odyssey: A Test of the Engagement 

Hypothesis of Cognitive Aging

Elizabeth Stein-Morrow Cognitive enhancement through 

participation in the Odyssey of the 

Mind program

Aerobic and Other Exercise

Dose-Response Study of Exercise in Older Adults Jeffrey Burns Aerobic exercise

Examining the Effects of Improved Physical Fitness on 

Cognitive/ Psychological Function

Adrienne Morgan Aerobic exercise

Influence of Fitness on Brain and Cognition Arthur Kramer Aerobic exercise

LIFE (Lifestyle Interventions and Independence for Elders) Marco Pahor Aerobic exercise, resistance, and 

flexibility exercises

Aerobic Exercise and Cognitive Training

Brain and Cognitive Changes After Reasoning or 

Physical Training 

Sandra Chapman Aerobic exercise and 

cognitive training

Combining Exercise and Cognitive Training to 

Improve Everyday Function 

Ellen Binder

Mark McDaniel

Aerobic exercise and 

cognitive training

Combined Exercise and Cognitive Training Intervention in 

Normal Aging

Yaakov Stern Aerobic exercise and 

cognitive training

Impact of Exercise and Engagement on 

Cognition in Older Adults

Denise Park Addition of exercise to a 

cognitive enrichment trial

Improvement of Visual Processing in Older Adults Karlene Ball Combination of visual 

processing training and exercise

Tai Chi and Guided Autobiography for Remediation of 

Age-Related Cognitive Decline

Victor Henderson Low-impact Tai Chi exercise and 

autobiographical writing

T A B L E 2. Ongoing NIA-Funded Age-Related Cognitive Decline Trials 

with Healthy Older Adults (as of November 2009)

36 2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE
Helping People Cope with AD

Caring for a person with AD presents unique challenges, 

and considerable research has explored the physical, 

emotional, and mental stresses on AD caregivers. This 

area of research is an important component of NIH’s 

overall AD research effort. Investigators supported by 

NIA, NIMH, and the National Institute of Nursing 

Research (NINR) continue to study ways to understand 

the effects of caring for a loved one with AD and to 

find ways to support both caregivers and people with AD.

Issues with Diagnosis

The traditional view is that receiving a diagnosis of 

AD is a devastating experience for the person and his 

or her family. That might not always be true, however. 

To gauge psychological reactions to a dementia diagnosis, 

researchers from Washington University in St. Louis 

conducted telephone interviews with patients a few days 

after they received a dementia diagnosis (Carpenter et 

al., 2008). Participants with AD and their companions 

took two tests that measured depression and anxiety. 

The research team also conducted comprehensive physical 

and neurological examinations of the people with AD. 

The researchers found no significant increase in depression 

in individuals or their companions. The participants’ 

n

anxiety also did not increase after receiving the diagnosis, 

and in some cases, even decreased. One explanation for 

this latter result is that an AD diagnosis may provide 

relief because it explains symptoms, and knowing the 

cause of the behaviors, being able to plan for the future, 

and having the support available at an Alzheimer’s 

disease research center may improve people’s ability to 

cope with their changing situation.

Increasingly, because of both greater numbers of 

patients and insufficient access to specialists, people with 

dementia are diagnosed and treated by primary care 

physicians. Previous research about dementia care in 

primary care settings has shown significant obstacles to 

optimum care. These obstacles include high rates of 

underdiagnosis, inappropriate use of medications, lack 

of referrals to social service agencies, and insufficient 

time to provide information. A research team at the 

University of California Davis interviewed 40 primary 

care physicians to determine challenges that clinicians 

face after the point of a dementia diagnosis (Hinton et 

al., 2007). The results suggested several possibilities 

for improved care. This study extended prior findings 

of lack of time, demonstrating that dementia creates 

n

Trial Name Principal Investigator Intervention

Other Interventions

ASPREE (Aspirin in Reducing Events in Elderly) Richard Grimm 

John McNeil

Aspirin

Guanfacine Treatment for Prefrontal Cognitive Dysfunction Christopher Van Dyck Guanfacine

Hormones and Cognitive Processing Yolanda Smith Estradiol or progesterone in postmenopausal women

Omega-3 and Blueberry Supplementation in Age-Related 

Cognitive Decline

Robert Krikorian Omega-3 and blueberry supplements

The Testosterone Trial Peter Snyder Testosterone gel in older men living in 

the community

Note: For information on new and currently recruiting trials, visit www.ClinicalTrials.gov.

2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE 37
greater paperwork demands due to need for referrals. 

Further, family members can have real and intense 

social and psychological needs. Long delays for scheduling with a specialist, lack of feedback from specialists, 

and variations in insurance coverage of mental health 

needs were all identified as barriers to care. Some even 

suggested that dementia patients are excluded from 

certain practices due to the high demands. Medicare 

billing rules also were identified as problematic. Different 

codes are reimbursed at dramatically different rates, and 

many of the activities that physicians and their staff must 

do when caring for people with dementia (or their 

families) are not reimbursable. Ongoing work by other 

groups is beginning to produce cost-effective models 

for improved, proactive interdisciplinary care of 

dementia patients.

Advance Planning Concerns

Scientists at the University of Pittsburgh conducted 

a study to examine the prevalence and sociodemographic 

correlates of written advance planning among people 

who were unable to make decisions because of dementia 

n

or who were at risk of this incapacity (Lingler et al., 2008). 

Study participants included 112 people with MCI, 

549 people with AD, and 84 cognitively healthy people. 

The investigators found that 65 percent of participants 

had a durable power of attorney and 56 percent had a 

living will. Advance planning rates did not vary by 

diagnosis. The authors conclude that a majority of 

persons with and at risk for the sustained and progressive decisional incapacity of AD are formally planning 

for the future, but a substantial minority are not.

Behavioral Problems

Disrupted sleep is a common complaint among family 

members who care for older adults with AD. These 

disturbances are often thought to be linked to the sleep 

disturbances in the person with AD. This study, conducted by investigators at the University of Washington 

and supported by NIMH, used special monitoring 

methods to examine the sleep patterns over 1 week of 

44 older adults with probable or possible AD and the 

family caregivers living with them (McCurry et al., 2008). 

The researchers found that people with AD and caren

Researchers at Kentucky’s Sanders-

 Brown Center on Aging have been 

working closely with the local African 

American community to develop a model 

of community outreach and quality AD 

care. Founded in 2003, the African 

American Dementia Outreach 

Partnership (AADOP) found that a conveniently located clinic and access 

by study personnel to the home of 

a person with AD were first steps in 

achieving quality of care (Danner et 

al., 2008). During the study, research 

staff made 66 in-home safety checks 

for individuals with suspected memory 

loss who were living alone. Educating 

families about the distinction between 

normal aging and signs of disease was 

another critical component of successful care. 

The Center has worked to build trust 

in the community by collaborating with 

African American churches. This collaboration has encouraged people with AD 

and their families to receive help with 

memory problems and to feel comfortable in seeking help for other medical 

problems. An additional benefit of this 

approach is earlier identification of 

dementia among community residents, 

who then have access to drug treatments that work best early in the course 

of the disease and the opportunity to 

plan future care. 

The AADOP team recognizes that 

the next challenge for the program is to 

maintain the Center’s involvement with 

and responsiveness to the community 

over the long term. 

Kentucky’s African American Dementia Outreach Partnership: 

A Model for High-Quality Care

38 2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE
givers both experienced considerable variability in sleep 

disturbances from night to night. However, contrary to 

assumptions, the sleep disruptions experienced by the 

person with AD and the caregiver did not necessarily 

match. When one person was sleeping poorly, the other 

may have been sleeping well and vice versa. The 

researchers also found that whether the pair’s sleeping 

patterns matched or not, sleep disturbance was associated 

with depression in the people with AD and with differences in caregivers’ reported problem-management 

styles (criticism, encouragement, active management). 

More research to clarify the complex interrelationships 

between sleep in AD patients and their caregivers will 

help in developing effective personalized intervention 

approaches. Such research also will be essential to 

understand more fully the roles that depression in people 

with AD and caregiver management styles may play. 

Supporting Caregivers

One of the most difficult decisions families face is 

whether and when to place a loved one in a nursing 

home or other care setting. This decision is driven by 

the needs of the person with AD and the ability of the 

family to meet those needs. The costs of care in an 

institutional setting are always an important consideration in this decision. Two recent studies conducted by 

researchers at the James J. Peters Veterans Affairs Medical 

Center in Bronx, New York, examined this issue. Their 

results provide important insights that can assist communities and policymakers to determine the costs of 

AD and develop appropriate services. In the first study, 

the researchers estimated the incremental effects of 

dependence on others and the ability to function on 

costs of care during the early stages of AD (Zhu et al., 

2008a). They found that dependence on others and 

functional ability of people with early AD related differently to direct medical and to informal caregiving 

costs. These results suggest that these two measures 

provide unique information for explaining variations 

in cost of care for people with AD and highlight the 

value of measuring both constructs.

In the second study, the VA research team examined 

the incremental effect of dependence on others by people 

n

with AD and the cost of medical and non-medical care 

and informal caregiving hours over time (Zhu et al., 

2008b). They found both functional impairment and 

patient dependence to be associated with higher costs 

of care and caregiving over time. These results demonstrate that measures of functional impairment and patient 

dependence provide unique and incremental information 

on the overall impact of AD on people with the disease 

and their caregivers.

A study by scientists at the University of North 

Carolina at Chapel Hill found that appropriately timed 

community-based support services for older adults with 

dementia and their caregivers may reduce caregiver burden 

and postpone nursing home placement (Beeber et al., 

2008). This NINR-supported study also found that 

having adequate financial resources, private insurance, 

access to sufficient programs and physicians in the area, 

more functional and behavioral problems, or a diagnosis 

of AD (rather than other types of dementias) increased 

the likelihood of using adult day care services. Similarly, 

use of home-based services was more likely among households with more highly educated caregivers, older care 

recipients, and care recipients or caregivers with greater 

functional limitations. Determining the long-term 

outcomes of support-service use may identify specific 

groups and geographical locations at risk of lower 

quality of life outcomes, which, in turn, could inform 

the design of interventions to improve assessment for 

and delivery of community-based support services.

Other 2008 advance in AD research to help people cope 

with AD include:

Gitlin LN et al. Tailored activities to manage neuropsychiatric 

behaviors in persons with dementia and reduce caregiver burden: 

A randomized pilot study. Thomas Jefferson University. Research 

supported by NIMH. http://www.ncbi.nlm.nih.gov/pubmed/

18310553 

See the References section for complete citations.

n

2OO8 PROGRESS REPORT on ALZHEIMER’

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Alzheimer’s research continues to move 

 ahead with purpose, always pushing 

against the boundaries of current knowledge. 

Today, scientists are increasingly optimistic 

about the promise of AD research and the hope 

that it brings for new treatment and prevention 

interventions. A critical element in keeping 

the momentum in science going is the careful 

cultivation of the AD research infrastructure. 

Nurturing the AD Research 

Infrastructure 

Thoughtful development of and sustained support 

for the AD research infrastructure has allowed 

NIH to continue to make rapid progress in AD. 

This support takes a variety of forms.

Coordinating Mechanisms

Alzheimer’s Disease Centers. The 30 NIA-funded 

Alzheimer’s Disease Centers (ADCs) (www.nia.nih.

gov/Alzheimers/ResearchInformation/ResearchCenters) 

are multidisciplinary centers that promote research, 

training and education, and technology transfer. 

With participation by the community, the Centers 

conduct longitudinal multicenter and collaborative 

studies of diagnosis and treatment in AD, age-related 

neurodegenerative diseases, and normal aging. 

Complementary studies, such as imaging studies and 

autopsy evaluations, also are conducted at ADCs. 

National Alzheimer’s Coordinating Center 

(NACC). In 1999, NIA established the NACC so 

data on participants in ADC studies could be 

Outlook

for the Future

Scientists 

are increasingly optimistic 

about the promise of 

AD research and the hope 

that it brings for new 

treatment and prevention 

interventions.

40 2OO8 PROGRESS REPORT PROGRESS REPORT on ALZHEIMER ALZHEIMER’

S DISEASE S DISEASE
pooled and shared (www.alz.washington.edu). By 2009, 

information on more than 90,000 ADC study participants and neuropathologic data on more than 10,000 

brains from autopsied participants had been collected. 

Much of this material is available to qualified AD 

researchers at institutions worldwide. 

Alzheimer’s Disease Cooperative Study (ADCS). 

The ADCS, launched in 1991, is a cornerstone of NIA’s 

clinical trials research efforts (www.adcs.org). This 

consortium of about 75 sites in the United States and 

Canada was developed in response to a perceived need 

to advance research in the development of drugs that 

might be useful for treating patients with AD, particularly drugs that otherwise might not be developed by 

industry. The ADCS focuses on trials of compounds 

developed by individual investigators or small companies that have limited resources for clinical trials. A 

recent focus has been on partnering with larger 

companies. In addition to testing new compounds, 

the ADCS is developing new methods for conducting 

dementia trials.

Initiatives

Alzheimer’s Disease Neuroimaging Initiative 

(ADNI). ADNI, a research partnership supported 

primarily by NIA with private-sector support through 

the Foundation for NIH, seeks to find neuroimaging 

and other biological markers that can be used to detect 

AD progression and measure the effectiveness of potential therapies. Begun in 2004, ADNI is following 

approximately 200 cognitively healthy individuals and 

400 people with MCI for 3 years, and 200 people 

with early AD for 2 years. Participants are being evaluated using clinical and neuropsychological measures; 

MRI, FDG-PET, and PiB PET scans; CSF measures 

of beta-amyloid and tau; and genetic assessments. 

The data generated from these visits and clinical 

testing will help in evaluating disease progression and 

may reduce the time and expense of clinical trials by 

improving methods and developing uniform standards 

by which imaging and biomarkers might track the disease and measure effects of interventions. ADNI also 

has created a publicly accessible database containing 

thousands of MRI and PET scan brain images as well 

as clinical, genetic, and fluid biomarker data. This 

database is available to qualified researchers worldwide. 

Hundreds of researchers already have accessed ADNI 

data and images, and ADNI has inspired similar efforts 

in Europe, Japan, and Australia. 

Alzheimer’s Disease Genetics Initiative (ADGI) 

and Alzheimer’s Disease Genetics Consortium 

(ADGC). Launched in 2003, ADGI aims to identify 

at least 1,000 families with members who have lateonset AD and members who do not have the disease. 

Investigators are collecting blood samples and other 

clinical data from participants to use in genetic analyses to identify additional late-onset AD risk-factor 

genes. The ADGC was launched in 2007 to accelerate 

the application of genetics technologies to late-onset 

AD through collaborations among leading researchers 

in AD genetics and genetic epidemiology. The 

ultimate goal of this effort is to obtain genetic material 

from 10,000 people with AD and 10,000 cognitively 

healthy people and then to scan the entire genome for 

the remaining AD risk-factor genes, as well as genes 

for age-related cognitive decline and genes associated 

with related risk and protective factors.

Cognitive Aging Initiative. In partnership with 

the McKnight Brain Research Foundation and the 

Foundation for NIH, NIA convened a Cognitive 

Aging Summit in 2007 to highlight scientific research 

2OO8 PROGRESS REPORT PROGRESS REPORT on ALZHEIMER ALZHEIMER’

S DISEASE 41 ’S DISEASE 41
on healthy brain aging and function, galvanizing the 

field and serving as a catalyst for two research initiatives. The first, “Remediation of Age-Related Cognitive 

Decline,” provides funding for pilot interventions 

examining normal age-related decline. The second, 

“Neural and Behavioral Profiles of Cognitive Aging,” 

provides funding for studies to delineate the neural 

and behavioral mechanisms involved in maintaining a 

healthy brain. This initiative also encourages projects 

designed to help distinguish normal age-related change 

from pathological decline. 

Cognitive and Emotional Health Project (CEHP). 

A large number of people are at substantial risk for 

cognitive impairment and emotional disorders as they 

age. CEHP’s goal is to assess the state of longitudinal 

and epidemiologic research on demographic, social, 

and biologic determinants of cognitive and emotional 

health in aging adults, and to accelerate identification 

of ways to maintain cognitive and emotional health. 

NIH Toolbox for Assessment of Neurological 

and Behavioral Function. In 2006, a contract was 

awarded through the NIH Blueprint for Neuroscience 

Research to develop a set of brief, psychometrically 

sound measures to assess cognitive, sensory, motor, 

and emotional function in large cohort studies (longitudinal and epidemiological) and clinical trials. NIA 

has taken the lead on this project, which will produce 

assessments, in English and Spanish, for use in 

individuals from ages 3 to 85 years.

AD Translational Initiative. The AD 

Translational Initiative, launched in 2004, supports 

early drug discovery and drug development research 

by academic scientists and small biotechnology 

companies, with the goal of finding ways to treat 

and prevent AD, MCI, and age-related cognitive 

decline. This effort is broadening the range of 

potential treatments and expanding the number of 

therapeutic targets by providing support at critical 

steps of translational research that are traditionally 

not supported by the pharmaceutical industry. 

Collaborations 

Recent discoveries and continued progress in 

Alzheimer’s research would not be possible without 

close collaboration between NIH and other Federal 

agencies and among NIH Institutes and Centers, 

scientists in laboratories and academic centers around 

the country and the world, non-profit education 

and advocacy organizations, and private-sector 

groups. Discoveries and research progress also 

would not be possible without the many thousands 

of people with AD and their families, as well as 

healthy volunteers, who participate in research 

studies and clinical trials. A growing emphasis on 

developing standardized data collection systems and 

sharing data and biological samples is improving 

the efficiency with which research is conducted 

today and laying the groundwork for even more 

productive collaborative research tomorrow.

Solving the puzzle of this disease will depend on 

harnessing the power of all avenues of science and medicine. Our task is 

to build on recent discoveries through continued support for 

multidisciplinary, collaborative AD research.

42 2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE
AD Research Advances: 

A Look to the Future

Research advances are providing important clues to 

what may cause and influence the development of 

AD. These advances suggest a number of directions 

for future research:

Genetic analysis technologies. Because the 

genetic links to late-onset Alzheimer’s, other than 

APOE ε4, are relatively weak, inheritance patterns 

are less clear than they are for early-onset AD. This 

means that investigators must search through the 

genetic profiles of thousands of people to find genes 

that may influence a person’s susceptibility to AD. 

Developments in genetic analysis technologies have 

played a huge role in pushing forward this area of 

research. GWAS technologies let scientists use highpowered computers to associate individual gene variations with observable traits, such as the presence of 

AD. Today, for just a few hundred dollars, scientists 

can rapidly test 500,000 to a million sites in one 

person’s genes using a computer chip the size of a 

postage stamp. These types of studies will give scientists 

unprecedented insights into the genetic links to AD, 

and thus into the earliest biochemical pathways that 

lead to the disease. 

Biomarkers and neuroimaging. Researchers are 

intensely focused on developing ever more sensitive 

screening instruments, neuropsychological tests, 

biomarkers in CSF and blood, and neuroimaging 

methods that can be used to diagnose cognitive 

decline, MCI, and AD as early as possible.

Translational research and clinical trials.

Translational initiatives and federally supported clinical trials should provide important new approaches 

for prevention and treatment because they will ensure 

that researchers with promising therapies have opportunities to develop them. Many compounds that test 

well in animal models and that have a sound theoretical basis fail in clinical trials because of safety or 

efficacy problems. The bidirectional collaboration 

between basic science and clinical application that is at 

the heart of translational research is essential to helping 

investigators understand why this happens and then 

to develop improved compounds. Support for this area 

of research will allow investigators to pursue many 

different therapeutic targets besides the now-obvious 

ones of beta-amyloid and tau. By funding pilot clinical 

trials, NIA also hopes to provide the necessary foundation 

for private industry or NIH to support larger follow-up 

clinical trials of the most promising leads.

In recent years, we have learned much about the aging brain, and Alzheimer’s disease research 

has opened many new windows into our understanding. Much of what we have learned about 

how and why the brain ages normally can be applied to elucidating the underlying processes of 

AD. Studies into other neurodegenerative diseases, such as Parkinson’s disease, frontotemporal 

dementia, and dementia with Lewy bodies, also are shedding light on AD. 

We’ve made tremendous progress in recent years, but there is still much to learn about AD. 

Clearly, solving the puzzle of this disease will depend on harnessing the power of all avenues 

of science and medicine. Our task is to build on recent discoveries through continued support 

for multidisciplinary, collaborative AD research so that its promise will become a reality for all 

older adults.

Conclusion

2OO8 PROGRESS REPORT on ALZHEIMER’

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Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas 

ND, Ziolko SK, James JA, Snitz BF, Houch PR, Bi W, Cohen AD, 

Lopresti BJ, DeKosky ST, Halligan EM, Klunk WE. Frequent 

amyloid deposition without significant cognitive impairment among 

the elderly. Archives of Neurology 2008;65(11):1509-1517. 

www.ncbi.nlm.nih.gov/pubmed/19001171

Ancoli-Israel S, Palmer BW, Cooke JR, Corey-Bloom J, Fiorentino L, 

Natarajan L, Liu L, Ayalong L, He F, Loredo JS. Cognitive effects 

of treating obstructive sleep apnea in Alzheimer’s disease: A randomized 

controlled study. Journal of the American Geriatrics Society 2008;

56(11):2076-2081. www.ncbi.nlm.nih.gov/pubmed/18795985

Banwait S, Galvan V, Zhang J, Gorostiza OF, Ataie M, Huang W, 

Crippen D, Koo EH, Bredesen DE. C-terminal cleavage of the 

amyloid-beta protein precursor at Asp664: A switch associated with 

Alzheimer’s disease. Journal of Alzheimer’s Disease 2008;13(1):1-16. 

www.ncbi.nlm.nih.gov/pubmed/18334752

Beeber AS, Thorpe JM, Clipp EC. Community-based service 

use by elders with dementia and their caregivers: A latent class 

analysis. Nursing Research 2008;57(5):312-321. www.ncbi.nlm.nih.

gov/pubmed/18931639

Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, 

Rock CL, Pruitt MA, Yang F, Hudspeth B, Hu S, Faull KF, Teter B, 

Cole GM, Frautschy SA. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s 

disease. The Journal of Pharmacology and Experimental Therapeutics

2008;326(1):196-208. www.ncbi.nlm.nih.gov/pubmed/18417733

Bekris LM, Millard SP, Galloway NM, Vuletic S, Albers JJ, Li G, 

Galasko DR, DeCarli C, Farlow MR, Clark CM, Quinn JF, Kaye JA, 

Schellenberg GD, Tsuang D, Peskind ER, Yu CE. Multiple SNPs 

within and surrounding the apolipoprotein E gene influence 

cerebrospinal fluid apolipoprotein E protein levels. Journal of 

Alzheimer’s Disease 2008:13(3):255-266. 

www.ncbi.nlm.nih.gov/pubmed/18430993

Berchtold NC, Cribbs DH, Coleman PD, Rogers J, Head E, Kim R, 

Beach T, Miller C, Troncoso J, Trojanowski JQ, Zielke HR, Cotman 

CW. Gene expression changes in the course of normal brain aging are 

sexually dimorphic. Proceedings of the National Academy of Sciences of 

the United States of America 2008;105(40):15605-15610. 

www.ncbi.nlm.nih.gov/pubmed/18832152

Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, 

Schjeide BM, Hooli B, DiVito J, Ionita J, Jiang H, Laird N, 

Moscarillo T, Ohlsen KL, Elliott K, Wang X, Hu-Lince D, Ryder M, 

Murphy A, Wagner SL, Blacker D, Becker KD, Tanzi RE. Genomewide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. American Journal of Human Genetics

2008;83(5):623-632. www.ncbi.nlm.nih.gov/pubmed/18976728

Bieschke J, Siegel SJ, Fu Y, Kelly JW. Alzheimer’s Abeta peptides containing an isostructural backbone mutation afford distinct aggregate 

morphologies but analogous cytotoxicity. Evidence for a common 

low-abundance toxic structure(s)? Biochemistry. 2008;47(1):50-59. 

www.ncbi.nlm.nih.gov/pubmed/18078350

Brickman AM, Honig LS, Scarmeas N, Tatarina O, Sanders L, Albert 

MS, Brandt J, Blacker D, Stern Y. Measuring cerebral atrophy and 

white matter hyperintensity burden to predict the rate of cognitive 

decline in Alzheimer disease. Archives of Neurology 2008a;65(9):1202-

1208. www.ncbi.nlm.nih.gov/pubmed/18779424 

Brickman AM, Schupf N, Manly JJ, Luchsinger JA, Andrews H, 

Tang MX, Reitz C, Small SA, Mayeux R, DeCarli C, Brown TR. 

Brain morphology in older African Americans, Caribbean Hispanics, 

and whites from northern Manhattan. Archives of Neurology

2008b;65(8):1053-1061. www.ncbi.nlm.nih.gov/pubmed/18695055

Buchman AS, Schneider JA, Leurgans S, Bennett DA. Physical frailty 

in older persons is associated with Alzheimer disease pathology. 

Neurology 2008;71(7):499-504. www.ncbi.nlm.nih.gov/pubmed/18695161

Burdo JR, Chen Q, Calcutt NA, Schubert D. The pathological 

interaction between diabetes and presymptomatic Alzheimer’s disease. 

Neurobiology of Aging 2009;30(12):1910-1917. 

www.ncbi.nlm.nih.gov/pubmed/18372080

Calderón-Garcidueñas L, Solt AC, Henríquez-Roldán C, TorresJardón R, Nuse B, Herritt L, Villarreal-Calderón R, Osnaya N, 

Stone I, García R, Brooks DM, González-Maciel A, Reynoso-Robles R, 

Delgado-Chávez R, Reed W. Long-term air pollution exposure 

is associated with neuroinflammation, an altered innate immune 

response, disruption of the blood-brain barrier, ultrafine particulate 

deposition, and accumulation of amyloid beta-42 and alpha-synuclein 

in children and young adults. Toxicologic Pathology 2008;36(2):289-

310. www.ncbi.nlm.nih.gov/pubmed/18349428

Carpenter BD, Xiong C, Porensky EK, Lee MM, Brown PJ, Coats M, 

Johnson D, Morris JC. Reaction to a dementia diagnosis in 

individuals with Alzheimer’s disease and mild cognitive impairment. 

Journal of the American Geriatrics Society 2008;56(3):405-412. 

www.ncbi.nlm.nih.gov/pubmed/18194228

Cenini G, Sultana R, Memo M, Butterfield DA. Elevated levels 

of pro-apoptotic p53 and its oxidative modification by the lipid 

peroxidation product, HNE, in brain from subjects with amnestic 

mild cognitive impairment and Alzheimer’s disease. Journal of Cellular 

and Molecular Medicine 2008;12(3):987-994. www.ncbi.nlm.nih.gov/

pubmed/18494939 

Chen K, Zhang L, Huang J, Gong W, Dunlop NM, Wang JM. 

Cooperation between NOD2 and Toll-like receptor 2 ligands in 

the up-regulation of mouse mFPR2, a G-protein-coupled Abeta42 

peptide receptor, in microglial cells. Journal of Leukocyte Biology

2008;83(6):1467-1475. www.ncbi.nlm.nih.gov/pubmed/18299458 

References

44 2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE
Christensen KD, Roberts JS, Royal CD, Fasaye GA, Obisesan T, 

Cupples LA, Whitehouse PJ, Butson MB, Linnenbringer E, Relkin 

NR, Farrer L, Cook-Deegan R, Green RC. Incorporating ethnicity 

into genetic risk assessment for Alzheimer disease: The REVEAL 

study experience. Genetics in Medicine 2008;10(3):207-214. 

www.ncbi.nlm.nih.gov/pubmed/18344711

Dai W, Lopez OL, Carmichael OT, Becker JT, Kuller LH, Gach HM. 

Abnormal regional cerebral blood flow in cognitively normal elderly 

subjects with hypertension. Stroke 2008;39(2):349-354. www.ncbi.

nlm.nih.gov/pubmed/18174483

Danner DD, Smith CD, Jessa P, Hudson J. African Americans 

with memory loss: Findings from a community clinic in Lexington, 

Kentucky. Nursing Clinics of North America 2008;43(3):437-447, ix-x. 

www.ncbi.nlm.nih.gov/pubmed/18674674

Davatzikos C, Fan Y, Wu X, Shen D, Resnick SM. Detection of 

prodromal Alzheimer’s disease via pattern classification of magnetic 

resonance imaging. Neurobiology of Aging 2008;29(4):514-523. 

www.ncbi.nlm.nih.gov/pubmed/17174012

DeKosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, 

Saxton JA, Lopez OL, Burke G, Carlson MC, Fried LP, Kuller LH, 

Robbins JA, Tracy RP, Woolard NF, Dunn L, Snitz BE, Nahin RL, 

Furberg CD; Ginkgo Evaluation of Memory (GEM) Study Investigators. 

Ginkgo biloba for prevention of dementia: A randomized 

controlled trial. JAMA 2008;300(19):2253-2262. 

www.ncbi.nlm.nih.gov/pubmed/19017911

Desikan RS, Fischl B, Cabral HJ, Kemper TL, Guttmann CR, 

Blacker D, Hyman BT, Albert MS, Killiany RJ. MRI measures of 

temporoparietal regions show differential rates of atrophy during 

prodromal AD. Neurology 2008;71(11):819-825. www.ncbi.nlm.nih.

gov/pubmed/18672473 

Devanand DP, Liu X, Tabert MH, Pradhaban G, Cuasay K, Bell K, 

de Leon MJ, Doty RL, Stern Y, Pelton GH. Combining early markers 

strongly predicts conversion from mild cognitive impairment to 

Alzheimer’s disease. Biological Psychiatry 2008;64(10):871-879. 

www.ncbi.nlm.nih.gov/pubmed/18723162

Dickerson BC, Bakkour A, Salat DH, Feczko E, Pacheco J, Greve DN, 

Grodstein F, Wright CI, Blacker D, Rosas HD, Sperling RA, Atri A, 

Growdon JH, Hyman BT, Morris JC, Fischl B, Buckner RL. 

The cortical signature of Alzheimer’s disease: Regionally specific 

cortical thinning relates to symptom severity in very mild to mild 

AD dementia and is detectable in asymptomatic amyloid-positive 

individuals. Cerebral Cortex 2009;19(3):497-510. www.ncbi.nlm.nih.

gov/pubmed/18632739

Esposito G, Giovacchini G, Liow JS, Bhattacharjee AK, Greenstein D, 

Schapiro M, Hallett M, Herscovitch P, Eckelman WC, Carson RE, 

Rapoport SI. Imaging neuroinflammation in Alzheimer’s disease with 

radiolabeled arachidonic acid and PET. Journal of Nuclear Medicine

2008;49(9):1414-1421. www.ncbi.nlm.nih.gov/pubmed/18703605

Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, 

Morgan TE, Finch CE, St Laurent G 3rd, Kenny PJ, Wahlestedt C. 

Expression of a noncoding RNA is elevated in Alzheimer’s disease and 

drives rapid feed-forward regulation of beta-secretase. Nature Medicine

2008;14(7):723-730. www.ncbi.nlm.nih.gov/pubmed/18587408

Fan Y, Resnick SM, Wu X, Davatzikos C. Structural and functional 

biomarkers of prodromal Alzheimer’s disease: A high-dimensional 

pattern classification study. Neuroimage 2008;41(2):277-285. 

www.ncbi.nlm.nih.gov/pubmed/18400519

Frazer ME, Hughes JE, Mastrangelo MA, Tibbens JL, Federoff HJ, 

Bowers WJ. Reduced pathology and improved behavioral performance 

in Alzheimer’s disease mice vaccinated with HSV amplicons expressing 

amyloid-b and interleukin-4. Molecular Therapy 2008;16(5):845-853. 

www.ncbi.nlm.nih.gov/pubmed/18388924

Gates GA, Anderson ML, Feeney MP, McCurry SM, Larson EB. 

Central auditory dysfunction in older persons with memory impairment 

or Alzheimer dementia. Archives of Otolaryngology—Head & Neck Surgery

2008;134(7):771-777. www.ncbi.nlm.nih.gov/pubmed/18645130

Geda YE, Roberts RO, Knopman DS, Petersen RC, Christianson TJ, 

Pankratz VS, Smith GE, Boeve BF, Ivnik RJ, Tangalos EG, Rocca WA. 

Prevalence of neuropsychiatric symptoms in mild cognitive impairment 

and normal cognitive aging: Population-based study. Archives of 

General Psychiatry 2008;65(10):1193-1198. www.ncbi.nlm.nih.gov/

pubmed/18838636 

Ghosh AK, Kumaragurubaran N, Hong L, Kulkarni S, Xu X, Miller 

HB, Reddy DS, Weerasena V, Turner R, Chang W, Koelsch G, Tang 

J. Potent memapsin 2 (beta-secretase) inhibitors: Design, synthesis, 

protein-ligand X-ray structure, and in vivo evaluation. Bioorganic & 

Medicinal Chemistry Letters 2008;18(3):1031-1036. www.ncbi.nlm.

nih.gov/pubmed/18180160

Gitlin LN, Winter L, Burke J, Chernett N, Dennis MP, Hauck WW. 

Tailored activities to manage neuropsychiatric behaviors in persons 

with dementia and reduce caregiver burden: A randomized pilot 

study. American Journal of Geriatric Psychiatry 2008;16(3):229-239. 

www.ncbi.nlm.nih.gov/pubmed/18310553

Greco SJ, Sarkar S, Johnston JM, Zhu X, Su B, Casadesus G, 

Ashford JW, Smith MA, Tezapsidis N. Leptin reduces Alzheimer’s 

disease-related tau phosphorylation in neuronal cells. Biochemical and 

Biophysical Research Communications 2008;376(3):536-541. 

www.ncbi.nlm.nih.gov/pubmed/18801339

Hall KS, Gao S, Baiyewu O, Lane KA, Gureje O, Shen J, Ogunniyi A, 

Murrell JR, Unverzagt FW, Dickens J, Smith-Gamble V, Hendrie HC. 

Prevalence rates for dementia and Alzheimer’s disease in 

African Americans: 1992 versus 2001. Alzheimer’s & Dementia

2009;5(3):227-233. www.ncbi.nlm.nih.gov/pubmed/19426950

2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE 45
Head E, Pop V, Vasilevko V, Hill M, Saing T, Sarsoza F, Nistor M, 

Christie LA, Milton S, Glabe C, Barrett E, Cribbs D. A two-year 

study with fibrillar β-amyloid (Aβ) immunization in aged canines: 

Effects on cognitive function and brain Aβ. Journal of Neuroscience

2008;28(14):3555-3566. www.ncbi.nlm.nih.gov/pubmed/18385314

Hinton L, Franz CE, Reddy G, Flores Y, Kravitz RL, Barker JC. 

Practice constraints, behavioral problems, and dementia care: Primary 

care physicians’ perspectives. Journal of General Internal Medicine

2007;22(11):1487-1492. www.ncbi.nlm.nih.gov/pubmed/17823840

Iacono D, O’Brien R, Resnick SM, Zonderman AB, Pletnikova O, 

Rudow G, An Y, West MJ, Crain B, Troncoso J. Neuronal hypertrophy in asymptomatic Alzheimer disease. Journal of Neuropathology 

and Experimental Neurology 2008;67(6):578-589. www.ncbi.nlm.nih.

gov/pubmed/18520776

Irie F, Fitzpatrick AL, Lopez OL, Kuller LH, Peila R, Newman AB, 

Launer LJ. Enhanced risk for Alzheimer disease in persons with 

type 2 diabetes and APOE ε4: The Cardiovascular Health Study 

Cognition Study. Archives of Neurology 2008;65(1):89-93. 

www.ncbi.nlm.nih.gov/pubmed/18195144

Jefferson AL, Lambe S, Moser DJ, Byerly LK, Ozonoff A, Karlawish 

JH. Decisional capacity for research participation in individuals with 

mild cognitive impairment. Journal of the American Geriatrics Society

2008;56(7):1236-1243. www.ncbi.nlm.nih.gov/pubmed/18482298 

Jin JJ, Kim HD, Maxwell JA, Li L, Fukuchi K. Toll-like receptor 

4-dependent signaling in animal model of Alzheimer’s disease. 

Journal of Neuroinflammation 2008;29:23. www.ncbi.nlm.nih.

gov/pubmed/18510752 

Jones CK, Brady AE, Davis AA, Xiang Z, Bubser M, Tantawy MN, 

Kane AS, Bridges TM, Kennedy JP, Bradley SR, Peterson TE, 

Ansari MS, Baldwin RM, Kessler RM, Deutch AY, Lah JJ, Levey AI, 

Lindsley CW, Conn PJ. Novel selective allosteric activator of the 

M1 muscarinic acetylcholine receptor regulates amyloid processing 

and produces antipsychotic-like activity in rats. Journal of 

Neuroscience 2008;28(41):10422-10433. www.ncbi.nlm.nih.gov/

pubmed/18842902

Karlawish J, Kim SY, Knopman D, van Dyck CH, James BD, 

Marson D. Interpreting the clinical significance of capacity scores 

for informed consent in Alzheimer disease clinical trials. American 

Journal of Geriatric Psychiatry 2008;16(7):568-574. www.ncbi.nlm.

nih.gov/pubmed/18556397

Katzman R. The prevalence and malignancy of Alzheimer’s disease: 

A major killer. Archives of Neurology 1976;33(4):217-218. [Editorial]. 

www.ncbi.nlm.nih.gov/pubmed/1259639

Kauwe JS, Cruchaga C, Mayo K, Fenoglio C, Bertelsen S, Nowotny P, 

Galimberti D, Scarpini E, Morris JC, Fagan AM, Holtzman DM, 

Goate AM. Variation in MAPT is associated with cerebrospinal fluid 

tau levels in the presence of amyloid-beta deposition. Proceedings of 

the National Academy of Sciences of the United States of America

2008;105(23):8050-8054. www.ncbi.nlm.nih.gov/pubmed/18541914

Kester MI, Scheltens P. Dementia: The bare essentials. Practical Neurology

2009;9(4):241-251. www.ncbi.nlm.nih.gov/pubmed/19608778

Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, 

Bergström M, Savitcheva I, Huang GF, Estrada S, Ausén B, Debnath ML, 

Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, 

Mathis CA, Långström B. Imaging brain amyloid in Alzheimer’s 

disease with Pittsburgh compound-B. Annals of Neurology

2004;55(3):306-319. www.ncbi.nlm.nih.gov/pubmed/14991808

Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu HY, Hyman BT, 

Bacskai BJ. Abeta plaques lead to aberrant regulation of calcium 

homeostasis in vivo resulting in structural and functional disruption 

of neuronal networks. Neuron 2008;59(2):214-225. www.ncbi.nlm.

nih.gov/pubmed/18667150 

Langa KM, Larson EB, Karlawish JH, Cutler DM, Kabeto MU, 

Kim SY, Rosen AB. Trends in the prevalence and mortality of cognitive 

impairment in the United States: Is there evidence of a compression 

of cognitive morbidity? Alzheimer’s & Dementia 2008;4(2):134-144. 

www.ncbi.nlm.nih.gov/pubmed/18631957

Lee JH, Cheng R, Graff-Radford N, Foroud T, Mayeux R; National 

Institute on Aging Late-Onset Alzheimer’s Disease Family Study Group. 

Analyses of the National Institute on Aging Late-Onset Alzheimer’s 

Disease Family Study: Implication of additional loci. Archives of 

Neurology 2008;65(11):1518-1526. www.ncbi.nlm.nih.gov/

pubmed/19001172

Lim J, Balastik M, Lee TH, Nakamura K, Liou YC, Sun A, Finn G, 

Pastorino L, Lee VM, Lu KP. Pin1 has opposite effects on wild-type 

and P301L tau stability and tauopathy. Journal of Clinical Investigation

2008;118(5):1877-1889. www.ncbi.nlm.nih.gov/pubmed/18431510

Lingler JH, Hirschman KB, Garand L, Dew MA, Becker JT, Schulz R, 

DeKosky ST. Frequency and correlates of advance planning among 

cognitively impaired older adults. American Journal of Geriatric Psychiatry

2008;16(8):643-649. www.ncbi.nlm.nih.gov/pubmed/18669942

Lloyd E, Somera-Molina K, Van Eldik LJ, Watterson DM, 

Wainwright MS. Suppression of acute proinflammatory cytokine 

and chemokine upregulation by post-injury administration of a 

novel small molecule improves long-term neurologic outcome in a 

mouse model of traumatic brain injury. Journal of Neuroinflammation

2008;5:28. www.ncbi.nlm.nih.gov/pubmed/18590543

Martin B, Pearson M, Brenneman R, Golden E, Keselman A, Iyun T, 

Carlson OD, Egan JM, Becker KG, Wood W 3rd, Prabhu V, de Cabo R, 

Maudsley S, Mattson MP. Conserved and differential effects of dietary 

energy intake on the hippocampal transcriptomes of females and males. 

PLoS One 2008;3(6):e2398. www.ncbi.nlm.nih.gov/pubmed/18545695

46 2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE
McCurry SM, Pike KC, Vitiello MV, Logsdon RG, Teri L. Factors 

associated with concordance and variability of sleep quality in persons 

with Alzheimer’s disease and their caregivers. Sleep 2008;31(5):741-

748. www.ncbi.nlm.nih.gov/pubmed/18517044

Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, 

de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman 

DM, Bacskai BJ, Hyman BT. Rapid appearance and local toxicity of 

amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature

2008;451(7179):720-724. www.ncbi.nlm.nih.gov/pubmed/18256671

Mormino EC, Kluth JT, Madison CM, Rabinovici GD, Baker SL, 

Miller BL, Koeppe RA, Mathis CA, Weiner MW, Jagust WJ; 

Alzheimer’s Disease Neuroimaging Initiative. Episodic memory loss is 

related to hippocampal-mediated beta-amyloid deposition in elderly 

subjects. Brain 2009;132(Pt 5):1310-1323. www.ncbi.nlm.nih.gov/

pubmed/19042931

Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan 

H, Olkhanud PB, Head E, Biragyn A, Cribbs DH, Agadjanyan MG. 

Reducing AD-like pathology in 3xTg-AD mouse model by DNA 

epitope vaccine—A novel immunotherapeutic strategy. PLoS One

2008;3(5):e2124. www.ncbi.nlm.nih.gov/pubmed/18461171

Nagahara AH, Bernot T, Moseanko R, Brignolo L, Blesch A, 

Conner JM, Ramirez A, Gasmi M, Tuszynski MH. Long-term reversal 

of cholinergic neuronal decline in aged non-human primates by 

lentiviral NGF gene delivery. Experimental Neurology

2008;215(1):153-159. www.ncbi.nlm.nih.gov/pubmed/19013154

Nichol KE, Poon WW, Parachikova AI, Cribbs DH, Glabe CG, 

Cotman CW. Exercise alters the immune profile in Tg2576 

Alzheimer mice toward a response coincident with improved 

cognitive performance and decreased amyloid. Journal of 

Neuroinflammation 2008;5:13. www.ncbi.nlm.nih.gov/

pubmed/18400101

O’Bryant, S.E., Humphreys JD, Smith GE, Ivnik RJ, GraffRadford NR, Petersen RC, Lucas JA. Detecting dementia with the 

Mini-Mental State Examination in highly educated individuals. 

Archives of Neurology 2008;65(7):963-967. www.ncbi.nlm.nih.gov/

pubmed/18625866

Okonkwo OC, Griffith HR, Copeland JN, Belue K, Lanza S, 

Zamrini EY, Harrell LE, Brockington JC, Clark D, Raman R, 

Marson DC. Medical decision-making capacity in mild 

cognitive impairment: A 3-year longitudinal study. Neurology

2008;71(19):1474-1480. www.ncbi.nlm.nih.gov/pubmed/18981368

Pan S, Rush J, Peskind ER, Galasko D, Chung K, Quinn J, Jankovic J, 

Leverenz JB, Zabetian C, Pan C, Wang Y, Oh JH, Gao J, Zhang J, 

Montine T, Zhang J. Application of targeted quantitative proteomics 

analysis in human cerebrospinal fluid using a liquid chromatography 

matrix-assisted laser desorption/ionization time-of-flight tandem mass 

spectrometer (LC MALDI TOF/TOF) platform. Journal of Proteome 

Research 2008;7(2):720-730. www.ncbi.nlm.nih.gov/pubmed/18186601

Parikh V, Sarter M. Cholinergic mediation of attention: Contributions 

of phasic and tonic increases in prefrontal cholinergic activity. 

Annals of the New York Academy of Sciences 2008;1129:225-235. 

www.ncbi.nlm.nih.gov/pubmed/18591483

Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, 

Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, 

Steffens DC, McArdle JJ, Willis RJ, Wallace RB. Prevalence of 

cognitive impairment without dementia in the United States. 

Annals of Internal Medicine 2008;148(6):427-434. 

www.ncbi.nlm.nih.gov/pubmed/18347351

Reiman EM, Chen K, Caselli RJ, Alexander GE, Bandy D, Adamson JL, 

Lee W, Cannon A, Stephan EA, Stephan DA, Papassotiropoulos A. 

Cholesterol-related genetic risk scores are associated with hypometabolism 

in Alzheimer’s-affected brain regions. NeuroImage 2008;40(3):1214-1221. 

www.ncbi.nlm.nih.gov/pubmed/18280754

Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, 

Keppler J, Reeder SA, Langbaum JB, Alexander GE, Klunk WE, 

Mathis CA, Price JC, Aizenstein HJ, DeKosky ST, Caselli RJ. Fibrillar 

amyloid-beta burden in cognitively normal people at 3 levels of genetic 

risk for Alzheimer’s disease. Proceedings of the National Academy of 

Sciences of the United States of America 2009;106(16):6820-6825. 

www.ncbi.nlm.nih.gov/pubmed/19346482

Ringman JM, Younkin SG, Pratico D, Seltzer W, Cole GM, 

Geschwind DH, Rodriguez-Agudelo Y, Schaffer B, Fein J, Sokolow S, 

Rosario ER, Gylys KH, Varpetian A, Medina LD, Cummings JL. 

Biochemical markers in persons with preclinical familial Alzheimer 

disease. Neurology. 2008;71(2):85-92. www.ncbi.nlm.nih.gov/

pubmed/18509095

Roe CM, Mintun MA, D’Angelo G, Xiong C, Grant EA, Morris JC. 

Alzheimer disease and cognitive reserve: Variation of education effect 

with carbon 11-labeled Pittsburgh Compound B uptake. Archives of 

Neurology 2008;65(11):1467-1471. www.ncbi.nlm.nih.gov/

pubmed/19001165

Saczynski JS, Jónsdóttir MK, Garcia ME, Jonsson PV, Peila R, 

Eiriksdóttir G, Olafsdóttir E, Harris TB, Gudnason V, Launer LJ. 

Cognitive impairment: An increasingly important complication of 

type 2 diabetes: the age, gene/environment susceptibility—Reykjavik 

study. American Journal of Epidemiology 2008;168(10):1132-1139. 

www.ncbi.nlm.nih.gov/pubmed/18836152

Sanchez-Mejia RO, Newman JW, Toh S, Yu GQ, Zhou Y, Halabisky B, 

Cissé M, Scearce-Levie K, Cheng IH, Gan L, Palop JJ, Bonventre JV, 

Mucke L. Phospholipase A2 reduction ameliorates cognitive deficits 

in a mouse model of Alzheimer’s disease. Nature Neuroscience

2008;11(11):1311-1318. www.ncbi.nlm.nih.gov/pubmed/18931664

2OO8 PROGRESS REPORT on ALZHEIMER’

S DISEASE 47
Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain 

pathologies account for most dementia cases in community-dwelling 

older persons. Neurology 2007;69(24):2197-2204. www.ncbi.nlm.nih.

gov/pubmed/17568013

Schubert CR, Carmichael LL, Murphy C, Klein BE, Klein R, 

Cruickshanks KJ. Olfaction and the 5-year incidence of cognitive 

impairment in an epidemiological study of older adults. Journal of the 

American Geriatrics Society 2008;56(8):1517-1521. www.ncbi.nlm.

nih.gov/pubmed/18662205

Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, 

Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, 

Walsh DM, Sabatini BL, Selkoe DJ. Amyloid-beta protein dimers 

isolated directly from Alzheimer’s brains impair synaptic plasticity and 

memory. Nature Medicine 2008;14(8):837-842. www.ncbi.nlm.nih.gov/

pubmed/18568035

Sojkova J, Beason-Held L, Zhou Y, An Y, Kraut MA, Ye W, 

Ferrucci L, Mathis CA, Klunk WE, Wong DF, Resnick SM. Longitudinal 

cerebral blood flow and amyloid deposition: An emerging pattern? 

Journal of Nuclear Medicine 2008;49(9):1465-1471. www.ncbi.nlm.

nih.gov/pubmed/18703614

Sultzer DL, Davis SM, Tariot PN, Dagerman KS, Lebowitz BD, 

Lyketsos CG, Rosenheck RA, Hsaio JK, Lieberman JA, Schneider LS 

for the CATIE-AD Study Group. Clinical symptom responses to 

atypical antipsychotic medications in Alzheimer’s disease: Phase I 

outcomes from the CATIE-AD Effectiveness Trial. American Journal 

of Psychiatry 2008;165(7):844-854. www.ncbi.nlm.nih.gov/

pubmed/18519523

Suzuki S, Brown CM, Dela Cruz CD, Yang E, Bridwell DA, Wise PM. 

Timing of estrogen therapy after ovariectomy dictates the efficacy of 

its neuroprotective and anti-inflammatory actions. Proceedings of the 

National Academy of Sciences of the United States of America

2007;104(14):6013-6018. www.ncbi.nlm.nih.gov/pubmed/17389368

Szekely CA, Green RC, Breitner JC, Østbye T, Beiser AS, Corrada 

MM, Dodge HH, Ganguli M, Kawas CH, Kuller LH, Psaty BM, 

Resnick SM, Wolf PA, Zonderman AB, Welsh-Bohmer KA, Zandi PP. 

No advantage of Aβ42-lowering NSAIDs for prevention of Alzheimer 

dementia in six pooled cohort studies. Neurology 2008;70(24):2291-2298. 

www.ncbi.nlm.nih.gov/pubmed/18509093

Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, 

O’Brien RJ. Effect of infarcts on dementia in the Baltimore 

Longitudinal Study of Aging. Annals of Neurology 2008;64(2):168-

176. www.ncbi.nlm.nih.gov/pubmed/18496870

van Straaten EC, Harvey D, Scheltens P, Barkhof F, Petersen RC, 

Thal LJ, Jack CR Jr, DeCarli C; Alzheimer’s Disease Cooperative 

Study Group. Periventricular white matter hyperintensities increase 

the likelihood of progression from amnestic mild cognitive impairment to dementia. Journal of Neurology 2008;255(9):1302-1308. 

www.ncbi.nlm.nih.gov/pubmed/18825439

Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, Humala N, Seror I, 

Bartholomew S, Rosendorff C, Pasinetti GM. Valsartan lowers brain 

beta-amyloid protein levels and improves spatial learning in a mouse 

model of Alzheimer disease. The Journal of Clinical Investigation

2007;117(11):3393-3402. www.ncbi.nlm.nih.gov/pubmed/17965777

Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, 

Gunderson EP, Yaffe K. Central obesity and increased risk of dementia 

more than three decades later. Neurology 2008;71(14):1057-1064. 

www.ncbi.nlm.nih.gov/pubmed/18367704

Whitwell JL, Josephs KA, Murray ME, Kantarci K, Przybelski SA, 

Weigand SD, Vemuri P, Senjem ML, Parisi JE, Knopman DS, 

Boeve BF, Petersen RC, Dickson DW, Jack CR Jr. MRI correlates 

of neurofibrillary tangle pathology at autopsy: A voxel-based 

morphometry study. Neurology 2008;71(10):743-749. 

www.ncbi.nlm.nih.gov/pubmed/18765650 

Wilson RS, Schneider JA, Arnold SE, Bienias JL, Bennett DA. 

Conscientiousness and the incidence of Alzheimer disease and 

mild cognitive impairment. Archives of General Psychiatry. 

2007;64(10):1204-1212. www.ncbi.nlm.nih.gov/pubmed/17909133

Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, 

Harry J, Rice DC, Maloney B, Chen D, Lahiri DK, Zawia NH. 

Alzheimer’s disease (AD)-like pathology in aged monkeys after 

infantile exposure to environmental metal lead (Pb): Evidence for a 

developmental origin and environmental link for AD. Journal of 

Neuroscience 2008;28(1):3-9. www.ncbi.nlm.nih.gov/pubmed/18171917

Zheng J, Jang H, Ma B, Nussinov R. Annular structures as intermediates 

in fibril formation of Alzheimer Aβ17−42. Journal of Physical Chemistry B

2008;112(22):6856-6865. www.ncbi.nlm.nih.gov/pubmed/18457440

Zhu CW, Leibman C, McLaughlin T, Scarmeas N, Albert M, Brandt 

J, Blacker D, Sano M, Stern Y. The effects of patient function and 

dependence on costs of care in Alzheimer’s disease. Journal of the 

American Geriatrics Society 2008a;56(8):1497-1503. www.ncbi.nlm.

nih.gov/pubmed/18662215

Zhu CW, Leibman C, McLaughlin T, Zbrozek AS, Scarmeas N, 

Albert M, Brandt J, Blacker D, Sano M, Stern Y. Patient dependence 

and longitudinal changes in costs of care in Alzheimer’s disease. 

Dementia and Geriatric Cognitive Disorders 2008b;26(5):416-423. 

www.ncbi.nlm.nih.gov/pubmed/18946219

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S DISEASE
IMAGE CREDITS 

The National Institute on Aging extends sincere appreciation to 

Brian J. Bacskai, Ph.D., and his optical imaging lab at Massachusetts 

General Hospital/Harvard Medical School for providing the 

Alzheimer’s disease microscopy images shown throughout the 

2008 Progress Report on Alzheimer’s Disease. 

Thanks also to Stacy Jannis, Jannis Productions, for the neuron images 

on the covers, page 7, and throughout the report, and to Michael 

Weiner, M.D., of the VA Medical Center, San Francisco/University of 

California San Francisco, and William Jagust, M.D., of the University 

of California Berkeley for the images on page 11.
U.S. Department of Health and Human Services

National Institutes of Health

National Institute on Aging

NIH Publication Number: 09-7378

December 2009