Research

NIH

DISEASE

PROGRESS REPORT ON

2003

U.S. Department of 

Health and Human Services

advances at

ALZHEIMER’S
Moving

future

toward a

brighter
DISEASE

PROGRESS REPORT ON

ALZHEIMER’S

2003

National Institute on Aging

National Institutes of Health

U.S. Department of Health and Human Services
ii 2003 PROGRESS REPORT ON ALZHEIMER’S DISEASE

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

National Institutes of Health (NIH), has primary responsibility for basic

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 

2003 Progress Report on Alzheimer’s Disease summarizes recent AD research 

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

■ National Cancer Institute (pages 12, 50)

■ National Center for Complementary and Alternative Medicine (page 51)

■ National Center for Research Resources (page 32)

■ National Heart, Lung, and Blood Institute (pages 40, 42-43)

■ National Human Genome Research Institute (page 32)

■ National Institute of Child Health and Human Development (page 25)

■ National Institute on Deafness and Other Communication Disorders

(pages 12, 42)

■ National Institute of Environmental Health Sciences (page 24)

■ National Institute of Mental Health (pages 26, 28, 29, 40, 44, 51, 59)

■ National Institute of Neurological Disorders and Stroke (pages 11, 20, 28,

41, 42, 59)

■ National Institute of Nursing Research (pages 17, 45, 51, 53)

Modest AD research efforts also are supported by the National Institute 

of Arthritis and Musculoskeletal and Skin Diseases, National Institute 

on Alcohol Abuse and Alcoholism, National Institute for Biomedical

Imaging and Bioengineering, National Center on Minority Health and 

Health Disparities, and the John E. Fogarty International Center. 
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

CONTENTS

PART 1 Introduction

1 The Impact of AD

3 AD: An Urgent National Health

and Research Priority

PART 2 Alzheimer’s Disease:

Current Knowledge Provides a Firm

Foundation for New Research

7 What are the Main Brain

Characteristics of People with AD?

7 Amyloid Plaques

8 Neurofibrillary Tangles

10 Loss of Connections Between 

Cells and Cell Death

10 What Causes AD?

12 What Do We Know About

Diagnosing AD?

13 How is AD Treated?

PART 3 2003 AD Research

Advances: The Process of 

Discovery Continues

15 What Happens in the Brain to

Cause the Transformation from

Healthy Aging to AD?

18 Earliest Cognitive and

Pathological Changes 

that Indicate Potential

Development of AD

21 Neuroimaging

23 Biological Markers and 

Oxidative Stress

25 Beta-amyloid

28 Presenilins

30 Can Certain Factors Increase 

Risk of or Protect Against AD?

31 Genetics

34 Lifestyle

34 Dietary Factors

36 Inflammation

37 Cardiovascular Factors

43 What Can Be Done to Slow 

the Progression of AD or Lessen 

its Effects?

45 AD Clinical Trials

47 Treatment Trials

50 Prevention Trials

51 Improving Support for Caregivers

PART 4 Outlook for the Future

59 Cognitive and Emotional Health

Project

60 Neuroimaging Initiative

61 Genetics Initiative

63 Prevention Instrument Project

63 National Alzheimer’s 

Coordinating Center

PART 5 References

iii

2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

PART 1

Alzheimer’s disease is an age-relatedand irreversible brain disorder that

develops gradually and results in memory

loss, behavior and personality changes,

and a decline in other cognitive abilities,

such as thinking, decision-making, and

language skills. These losses are related 

to the breakdown of the connections

between certain nerve cells in the brain

and the eventual death of many of these

cells. AD is one of a group of disorders,

termed dementias, that are characterized

by cognitive and behavioral problems. 

The course of this disease varies from

person to person, as does the rate of

decline. On average, patients with AD

live for 8 to 10 years after they are diagnosed, though the disease can last for up

to 20 years. AD advances progressively,

from mild forgetfulness to a severe loss

of mental function. In most people with 

AD, symptoms first appear after age 60.

Although the risk of developing AD

increases with age, AD and dementia

symptoms are not part of normal aging.

AD and other dementing disorders are

caused by diseases that affect the brain. 

The Impact of AD 

AD is the most common cause of

dementia among people age 65 and

older. It presents a major health problem

for the United States because of its enormous impact on individuals, families, the

health care system, and society as a

whole. Scientists estimate that 4.5 million

people currently have the disease, and

the prevalence (the number of people

with the disease at any one time) doubles

for every 5-year age group beyond age 65.

These numbers are significant now 

and will become even more so in the

future because of dramatic increases 

in life expectancy since the early 1900s.

Researchers estimate that by 2050, 

13.2 million Americans will have AD if

current population trends continue and

no preventive treatments become available

(Hebert et al., 2003). Approximately 

4 million Americans are 85 years old or

older, and this age group is the fastest

growing segment of the population. It 

also is the group with the highest risk of

AD. The U.S. Census Bureau estimates

that nearly 19 million Americans will be

1

Introduction
2 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

aged 85 and older by the year 2050. 

Some experts who study population

trends suggest that the number could 

be even greater. This trend is not only

apparent in the U.S. but also worldwide.

As more and more people live longer, the

number of people affected by diseases 

of aging, including AD, will continue to

grow. For example, one study shows that

nearly half of all people age 85 and older

have some form of dementia (Evans et 

al., 1989). 

The increasing number of people

with AD and the costs associated with 

the disease mean that AD puts a heavy

economic burden on society. The 

annual national direct and indirect 

costs of caring for people with AD are 

estimated to be as high as $100 billion

(Ernst and Hay, 1994; Ernst et al., 

1997; Huang et al., 1988).

AD’s impact is seen not only in the

numbers who develop the disease and

the cost to society, but also in its effects

on people with the disease, their families, friends and caregivers. Slightly 

more than half of AD patients receive

care at home, while the remainder are

cared for in a variety of health care 

institutions. During their years of caregiving, these spouses, relatives, and

friends experience emotional, physical,

and financial stress. They watch their

loved ones become more and more 

forgetful, frustrated, and confused.

Eventually, the person with AD will 

not even recognize his or her nearest

and dearest relatives and friends.

Dementia often goes

unrecognized or is misdiagnosed during its early stages,

and this seems to be especially true for some racial and

ethnic groups, where cultural

or language barriers may 

prevent people and their families from seeking a diagnosis.

To ensure the development

of more effective health care

access and diagnostic

approaches, it is important to

obtain information about the

prevalence and types of

dementias among diverse

populations. This issue is

becoming increasingly

important because the U.S.

Census Bureau projects that

between 1999 and 2030, the

Hispanic population older

than 65 will increase more

than 300 percent, compared

to increases of 81 percent for

older whites and 131 percent

for older African Americans.

A recent study conducted by

investigators at the University

of California at Los Angeles

School of Medicine has provided valuable new information on

the frequency of different types

of dementia in a community

outreach sample of Mexican

and Central American Hispanics

living in California (Fitten et al.,

2001). Hispanics from Mexico

and Central America constitute

about 70 percent of all

Hispanics in the United States.

California was chosen for this

study because about one-third

of all Hispanics in the U.S. live

in the State, and 80 percent of

older California Hispanics 

are of Mexican origin.

AD Prevalence 

in Hispanics
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 3

Caregivers—most of whom are women—

must juggle child care, jobs, and other

responsibilities along with caring for

relatives with AD who cannot function

on their own. As the disease runs its

course and the abilities of people with

AD steadily decline, family members 

face difficult decisions about the

long-term care of their loved ones.

Frequently, they turn to assisted living

facilities, then nursing homes for care

and support. The numbers of caregivers—and their needs—can be

expected to grow significantly as the 

population ages and as the number 

of people with AD increases.

AD: An Urgent National 

Health and Research Priority 

Given our aging population, the 

magnitude of AD as a national health

problem is steadily increasing. This

makes the disease an urgent research 

priority. Interventions that could delay

the onset of AD would have an enormous positive public health impact

because they would greatly reduce the

number of people with the disease. 

This in turn would reduce the personal

and financial costs associated with 

caring for them. 

AD research supported by the Federal

Government is divided into three broad,

Because Hispanics tend 

not to go to memory clinics,

the investigators worked with

local churches, social service

agencies, and other community groups to devise culturally

comfortable strategies to

recruit individuals with 

possible dementia. These

strategies included flyers, 

24-hour answering services,

and articles in Spanish newspapers. A fully bilingual and

bicultural staff worked with

potential participants, and

were especially careful to

avoid creating any cultural or

social stigma associated with

mental health problems. One

hundred men and women

aged 55 and older and their

caregivers participated and

were evaluated in Spanish. 

The presence of dementia was

established using neurological

evaluation, neuropsychological

tests, questionnaires, laboratory tests, and brain imaging.

Of the 100 participants, 

65 met the research criteria 

for a diagnosis of dementia. 

Of these individuals, 25 were

diagnosed with probable 

AD, 25 were diagnosed with

vascular dementia (a type of

dementia associated with

strokes), 3 had mixed AD and

vascular dementia, and the

remaining participants had

other dementia diagnoses. 

This study provides information about dementias affecting

a community of older California

Hispanics. The proportion of

study participants with AD was

lower and the proportion with

vascular dementia was considerably higher than expected

based on previous data on

whites. The percentage of

depressed, non-demented 

individuals also was high. 

This study illustrates the

need for accurate and culturally

relevant diagnostic evaluations

and points to the importance

of more effective health 

care access and diagnostic

approaches for this important

U.S. population.

Annual national costs of caring for people with

AD are as high as $100 billion.
4 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

overlapping areas: causes/risk factors,

diagnosis, and treatment/caregiving.

Research into the basic biology of 

the aging nervous system is critical 

to understanding what goes wrong 

in the brain of a person with AD.

Understanding how nerve cells lose

their ability to communicate with each

other and the reasons why some nerve

cells die and others do not is a central

part of scientific efforts to discover 

what causes AD. Assessing factors that

may increase or decrease the risk of

developing AD is a growing component 

of this research effort.

Many researchers also are looking for

better ways to diagnose AD in the early

stages and to identify the first brain

changes that eventually result in AD.

Investigators are striving to identify 

markers of dementia, improve ways

to test patient function, improve 

neuroimaging technologies, and 

improve case-finding and sampling 

methods for population studies.

Other researchers are working hard 

to discover and develop interventions

that may help treat symptoms, slow the

progress of the disease, delay the onset

of, or even prevent AD. Many of these

interventions are now being tested in

clinical trials (see p.45 for descriptions 

of AD clinical trials). Finally, scientists

and many health care professionals are

seeking better ways to help people with

AD and caregivers cope with the decline
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 5

in mental and physical abilities and 

the difficult behaviors that accompany

the disease. 

An important complement to the

National Institutes of Health’s (NIH)

research initiatives in AD are its efforts 

to educate and inform people with AD,

their families, the public, providers, and

others interested in the disease. The 

NIA Alzheimer’s Disease Education 

and Referral (ADEAR) Center

(www.alzheimers.org) provides a 

variety of outstanding resources on 

AD, including information about caregiving, diagnosis and treatment, and

results of research findings. For example,

NIA’s booklet for the general public,

Alzheimer’s Disease: Unraveling the Mystery,

uses illustrations and text to explain AD,

highlight ongoing research, and describe

efforts to support caregivers of people

with AD. ADEAR also maintains a

database of AD clinical trials, develops

reading lists, and provides referrals to

local AD resources. In addition, all of 

the NIA-supported Alzheimer’s Disease

Centers (ADCs) have Education and

Information Transfer Cores that work

locally to disseminate information about

AD (see p.53 for more about the work 

of these Centers). 

We now know a lot about AD—what

it is, who can get it, how it develops, 

and what course it follows. We also 

have made significant progress in the critical area of early diagnosis and have some

promising leads on possible treatments.

All of this research has deepened our

understanding of this devastating disease.

It also has expanded our knowledge

about other late-life neurodegenerative

diseases, brain function in healthy older

people, and ways to minimize normal

age-related cognitive decline. 

The 2003 Progress Report on Alzheimer’s

Disease describes this important research

effort. It begins with a description of 

our current knowledge about AD. This

provides the backdrop for the next 

section, which highlights recent research

conducted by NIA and other NIH

Institutes. The report closes with a section called “Outlook for the Future,”

which takes a look at some exciting new

AD research initiatives. These initiatives

are designed to accelerate laboratory 

and clinical research and collaboration

across the Federal Government and in

association with the private sector so 

that research findings can be translated

expeditiously into real advances for 

people with AD, families, and caregivers. 

The ADEAR Center provides a variety of 

outstanding resources on AD.

I

n normal aging, nerve cells (neurons)

in the brain are not lost in large numbers. In AD, however, many nerve cells

stop functioning, lose connections with

other nerve cells, and die. At first, AD

destroys neurons in parts of the brain

that control memory, including the hippocampus (a structure deep in the brain

that helps to encode short-term memories) and related structures. As nerve

cells in the hippocampus stop working

properly, short-term memory fails, and 

a person’s ability to do easy and familiar

tasks often begins to decline. AD later

attacks the cerebral cortex (the outer

layer of neurons in the brain), particularly the areas responsible for language

and reasoning. At this point, AD begins

to take away language skills and changes 

a person’s ability to make judgments.

Personality changes also may occur.

Emotional outbursts and disturbing

behaviors, such as wandering, begin to

happen and can become more frequent

as the disease progresses. Eventually,

many other areas of the brain are

involved and the person with AD

becomes bedridden, helpless, and 

unresponsive to the outside world. 

What are the Main Brain

Characteristics of People 

with AD?

The brain in AD is abnormal in three

major ways. Though scientists have known

about these abnormal characteristics for

many years, more recent research has

revealed much about their nature and their

possible roles in the development of AD.

Amyloid Plaques

In AD, plaques develop first in areas

of the brain used for memory and other

cognitive functions. They are found in

the spaces between the brain’s nerve

cells. Plaques consist of thick, sticky

deposits of beta-amyloid mixed with

other proteins, remnants of neurons,

non-nerve cells such as microglia (cells

that surround and digest damaged cells

or foreign substances that cause inflammation), and other glial cells. Betaamyloid is a soluble (can be dissolved)

protein fragment snipped, or cleaved,

from a larger protein called amyloid 

precursor protein (APP). APP is associated with the cell membrane and in

healthy brains, appears to be important

in helping neurons grow and survive. 

2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 7

PART 2

Alzheimer’s Disease: Current

Knowledge Provides a Firm

Foundation for New Research
8 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

Recent studies have helped scientists

learn that beta-amyloid fragments go

through several stages on their way to

becoming plaques: A small number of

the fragments cleaved from APP bind

with one another to become larger clusters of still soluble amyloid fragments

referred to as oligomers. The oligomers

then come together into even larger

aggregates that contain increasingly 

insoluble beta-amyloid. These later-stage

aggregates contain “fibrillar” insoluble

beta-amyloid. Fibrillar amyloid then 

coalesces into the insoluble plaques 

that are characteristic of the disease. 

Although researchers still do not know

whether amyloid plaques themselves cause

AD or whether they are a by-product of the

AD process, some evidence suggests that

amyloid deposition may be a central and

defining process of the disease. Many

researchers believe that the beta-amyloid

found in plaques is no longer the prime

suspect, but rather, the earlier-stage soluble

beta-amyloid clusters are the major culprit.

It is believed that these fibrillar beta-amyloid

clusters are toxic to neurons, though the

mechanisms for this are still unknown. 

Neurofibrillary Tangles

The second hallmark of AD pathology

consists of abnormal collections of twisted

protein threads found inside nerve cells.

The chief component of these neurofibrillary tangles is a protein called tau. Healthy

neurons are internally supported partly by

structures called microtubules. These microtubules act like conduits, guiding nutrients

and molecules from the body of the cell

down to the ends of the axon and back. Tau

binds to microtubules and stabilizes them.

In AD, tau is changed chemically. It does

not bind to microtubules but begins to

aggregate with other threads of tau.

APP is associated with the

cell membrane, the thin barrier that encloses the cell.

After it is made, APP sticks

through the neuron’s membrane, partly inside and

partly outside the cell.

Enzymes (substances that

cause or speed up a chemical reaction) act on the

APP and cut it into soluble

fragments of protein, one

of which is called betaamyloid.

These soluble beta-amyloid

fragments begin clustering

together into oligomers and

then into increasingly insoluble fibrillar beta-amyloid

aggregates.

Eventually, this process

leads to the beta-amyloid

plaques that are found in

abundance outside and

around neurons in the

brains of people with AD.
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 9

The brain is essential to our survival. With the

help of motor and sensory nerves throughout the

body, it integrates, regulates, initiates, and controls

all the body’s functions. The brain governs thinking,

personality, moods, the senses, and physical

action. We can speak, move, remember, and feel

emotions and physical sensations because of the

complex interplay of chemical and electrical processes that take place in our brains. The brain also

regulates body functions that happen without our

knowledge or direction, such as breathing and

digesting food.

The healthy human brain is made up of billions 

of neurons that share information with one another

through a diverse array of biological and chemical

signals. Each neuron has a cell body, an axon, and

many dendrites, all surrounded by a cell membrane. The nucleus, which contains genes composed of deoxyribonucleic acid (DNA), controls the

cell’s activities. The axon, which extends from the

cell body, transmits messages to other neurons, 

sometimes over very long distances. Dendrites,

which also branch out from the cell body, receive

messages from axons of other nerve cells or from

specialized sense organs. Axons and dendrites 

collectively are called neurites. Even more 

numerous are the glial cells, which surround, 

support, and nourish neurons.

Neurons communicate with each other and with

sense organs by producing and releasing special

chemicals called neurotransmitters. As a neuron

receives messages from surrounding cells, an 

electrical charge (nerve impulse) builds up within

the cell. This charge travels down the axon until it

reaches the end. Here, it triggers the release of the

neurotransmitters that move from the axon across

a gap, called a synapse, between it and the dendrites or cell bodies of other neurons. Scientists

estimate that the typical neuron has up to 15,000

synapses. The neurotransmitters bind to specific

receptor sites on cell bodies and the receiving end 

of dendrites of adjacent nerve cells. In this way, 

signals travel between neurons in a fraction of a 

second. Millions of signals flash through the brain 

at any one time.

Groups of neurons in the brain have specific

jobs. For example, some neurons are involved in

thinking, learning, remembering, and planning.

Others are responsible for vision or hearing, regulating the body’s biological clock, or managing 

the myriad other jobs that keep the human body

functioning.

The survival of neurons in the brain depends 

on the healthy functioning of several processes all

working in harmony. These processes are communication, metabolism, and repair. The first process,

communication between neurons, depends on the

integrity of the neuron and its synapses, as well as

the production of neurotransmitters. 

The second process is metabolism, the pathways by which cells and molecules break down

chemicals and nutrients to generate energy. This

chemical energy is then used to replenish the

building blocks necessary for optimal cell function.

Efficient metabolism requires adequate blood 

circulation to supply the cells with oxygen and

important nutrients, such as glucose (a sugar). 

The third process is the repair of injured neurons. Unlike most other body cells, neurons are

programmed to live a long time. Brain neurons

have the capacity to last more than 100 years. In

an adult, when neurons die because of disease or

injury, they are usually not replaced (see p.40 to

learn more about the advances in knowledge in this

area). To prevent their own death, living neurons

must constantly maintain and remodel themselves. 

Research shows that the damage seen in AD

involves changes in all three of these neuronal 

processes: communication, metabolism, and repair.

Structure and Function 

of the Brain
10 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

These tau threads become tangled up with

one another to form neurofibrillary tangles. When this happens, the microtubules

disintegrate, collapsing the neuron’s transport system. This may result first in malfunctions in communication between 

neurons and later in the death of the cells.

Loss of Connections Between 

Cells and Cell Death

The third major pathological feature

of AD is the gradual loss of connections

between neurons and eventually, neuron

death. As plaques and tangles proliferate,

they damage neurons to the point that

they cannot function properly or communicate with each other. Eventually, they

die. As this process continues and spreads

through the brain, affected regions begin

to shrink. By the final stage of AD, plaques

and tangles are widespread, and brain 

tissue has shrunk significantly, a process

called brain atrophy.

What Causes AD?

Most cases of AD develop in people

older than 60. This form of AD is called

“late-onset” AD. We don’t fully understand

the cause of late-onset AD. In contrast, in 

a very few families who develop early-onset

AD, we know exactly what causes the disease. In these families, affected people

(about half of the children of an affected

parent) get the disease in their 30s, 40s,

and 50s. These people have mutations in

one of three genes: the APP gene found

on chromosome 21, the presenilin 1 gene

on chromosome 14, or the presenilin 2

gene on chromosome 1. The APP gene is

responsible for making APP. The presenilin genes are responsible for making

an enzyme that plays an important 

part in clipping APP into fragments.

Presenilin gene mutations promote the

breakdown of APP, leading to beta-amyloid

production. So, in those rare cases in

which we know the cause of the disease,

the genetic findings show that the cause

relates to beta-amyloid production. 

These findings are supported by

knowledge gained from studying Down

syndrome. Most of us have two copies of

chromosome 21, but people with Down

syndrome have three. Therefore, they

have an extra copy of the APP gene,

which leads to more APP production. 

By studying the disease process in Down

syndrome and in the early-onset AD mutations, we have found that in all cases, too

much beta-amyloid is produced. Scientists

are divided into different camps on the

significance of this finding: Some think

that all cases of AD must be caused by

beta-amyloid accumulation, either by its

overproduction or failure to break it

down. Others think it is premature to

draw this conclusion from these rare

early-onset cases and from people with

Down syndrome, and that different 

mechanisms may operate in the more

common late-onset AD.

Because of the belief that beta-amyloid

might be the toxic molecule that starts the

disease, an enormous amount of work has

been aimed at learning more about this

protein. We now have a very clear understanding of the enzymes involved in betaamyloid production, and the process by

Perhaps the greatest mystery is why AD largely

strikes the elderly.
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 11

which beta-amyloid plaques are formed

and deposited in brain tissue. Although

there is some way to go, we are now developing a clearer understanding of betaamyloid breakdown as well. Obviously,

many believe that if we could slow betaamyloid production or speed up its

removal, this would have clinical benefit.

However, our knowledge still has some

surprising gaps. For example, we don’t yet

fully understand the normal function of

APP, presenilins, and beta-amyloid.

Certainly a better knowledge of normal

function would give us clues about the

causes of AD. Recent research is helping

scientists understand important functions 

of other parts of the APP molecule and of

the presenilins. Beta-amyloid production

appears to be increased when nerve cells

are damaged. Perhaps this increased production could explain the often reported

association between head injury and AD.

A recent study funded by NIA and the

National Institute of Neurological

Disorders and Stroke (NINDS) may shed

some light on this hypothesis. In this 

study, a research team at the University 

of Pennsylvania used a specially bred, or

transgenic, mouse model of AD to test the

effects of traumatic brain injury on risk of

AD (Uryu et al., 2002). They found that

repetitive mild trauma to the brain led to

accelerated deposition of beta-amyloid,

damage to affected neurons, and impairments in the animals’ cognitive function. 

Another important gap in our knowledge relates to the fact that we don’t

understand exactly how beta-amyloid leads

to nerve cell damage and death. In test

tube studies, scientists have shown that

beta-amyloid is toxic to nerve cells, but

there can be a big difference between test

tubes and animals. Until recently, most of

the AD animal models made only betaamyloid plaques, and the amount of 

damage caused by beta-amyloid seemed

rather limited. However, newer mouse models of AD also have tau mutations and make

neurofibrillary tangles. Recent data show

that most nerve cell death is related to tangles and that beta-amyloid is much more

toxic in mice that also make tangles. We still

do not understand the relationship between

beta-amyloid and plaques on the one hand

and tau and tangles on the other, but current and future studies in mice that have

both pathologies will help scientists solve

this puzzle.

Perhaps the greatest mystery is why AD

largely strikes the elderly. Why does it take

30 to 50 years for people to develop signs

of the disease, even those individuals who

are born with disease-causing mutations?

It is possible that the processes that cause

AD happen slowly and simply take a long

time to reach a critical magnitude. It also

is possible that the environment of the

aging brain is subtly different from 

that of the young brain. 

Scientists supported by the NIH are

working hard in laboratories and research

institutions all across the U.S. and in other

countries to assemble the myriad bits of

new knowledge that, combined with our

existing understanding, will some day fully

explain this complex biological puzzle.
12 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

What Do We Know 

About Diagnosing AD?

AD can be diagnosed conclusively 

only by examining in an autopsy the brain

of a person with dementia to determine

whether the plaques and tangles in certain

brain regions are characteristic of AD.

However, clinicians today can use a 

range of tools to diagnose “possible AD”

(dementia could also be due to another

condition) or “probable AD” (no other

cause of dementia can be found) in a living person who is having difficulties with

memory or other mental functions. These

tools include a patient history; physical

exam; tests that measure memory, language skills, and other abilities related to

changes in brain functioning; and sometimes, brain scans. Much is known about

the clinical and behavioral characteristics

of the disease, and this also helps in diagnosing AD. The diagnostic process is crucial to identify AD accurately as well as to

rule out other conditions that might be

causing cognitive problems or dementia,

such as stroke, tumors, Parkinson’s disease,

or side effects of medications. For example, a recent review conducted by a

Dartmouth Medical School research team

and funded by the National Cancer

Institute (NCI), discussed the growing

body of evidence showing that cancer

chemotherapy can produce long-term 

cognitive changes (Ahles and Saykin,

2002). Given the growing numbers of

older cancer survivors, it is clearly important to understand this effect and to be

able to distinguish it from AD dementia 

or other causes of cognitive changes. 

An early, accurate diagnosis is especially

important to people with AD and their

families because it helps them plan for the

future and pursue care options while the

patient can still take part in making decisions. Researchers are making progress in

developing accurate diagnostic tests and

techniques. In specialized research facilities, trained clinicians can now diagnose

AD with up to 90 percent accuracy.

Scientists are working in several areas that

may improve the ability of clinicians to

make accurate diagnoses of AD even

sooner and that are providing important

insights into the earliest changes that

occur in the brain of a person with AD

even before a clinical diagnosis is made.

For example, neuropsychological diagnostic tests for AD, such as those that measure

delayed recall, verbal fluency, and overall

cognitive status, continue to improve. In

one study, researchers at the University of

California, San Diego, found that these

tests were highly accurate in distinguishing

between cognitively healthy individuals and

people with mild AD (Salmon et al., 2002). 

Studies also are pointing to other

intriguing clues that might help in early

diagnosis. For example, a study funded by

the National Institute on Deafness and

Other Communication Disorders (NIDCD)

and conducted by scientists at San Diego

State University, followed up on data 

suggesting that alterations in sensory or

motor function accompany the cognitive
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 13

symptoms of AD. Changes in the sense of

smell have been found in some studies to

be a very early sign in many people with

AD. This study involved a group of

healthy older adults and a group who

had probable AD. Investigators measured activity in brain regions that control the sense of smell while the groups

took part in odor identification tests

(Morgan and Murphy, 2002). Based on

the results of the test, the investigators

were able to accurately distinguish those

with AD from the healthy participants.

They also found that decreased activity

in these brain regions was related to

increased severity of dementia.

Insights from these and many other

studies will help scientists understand the

natural history of AD and the ways in which

changes in memory and other cognitive

functions differ in normal aging, AD, and

other dementias. This knowledge will help

clinicians diagnose AD earlier and more

accurately and also will help researchers

pinpoint early changes that could be 

targets for drug therapy. 

How Is AD Treated?

For those who are already suffering

from the effects of AD, the most immediate

need is for treatments to control cognitive

loss as well as problem behaviors, such as

verbal and physical aggression, agitation,

wandering, depression, sleep disturbances,

and delusions. Treatments are needed that

work on many people with AD, remain

effective for a long time, ease a broad

range of symptoms, improve a person’s

cognitive function and ability to carry out

activities of daily living, and have no serious

side effects. Eventually, scientists also hope

to develop drugs that attack fundamental

AD processes, preventing them from progressing to the state where they damage

cognitive function and quality of life.

The Food and Drug Administration

(FDA) has approved five medications 

to treat AD symptoms. The first drug

approved has been replaced by three others

that are commonly used to treat mild to

moderate AD symptoms. The fifth and

newest drug is used to treat moderate to

severe symptoms. However, these medications will not stop or reverse AD (for 

more on these medications, see p.43).

Helping people with AD live their daily

lives and maintain their cognitive abilities

is one of the most important goals of AD

treatment research. Many investigators are

working to develop new and better drugs

that can preserve this critical function for

as long as possible. Many other investigators are improving the quality of life 

for patients as well as caregivers through

research to develop better behavioral

management techniques and caregiver skills.

One of the primary characteristics of

the NIH AD research effort over the past 

25 years has been support for a wide range

of studies conducted by a large and multidisciplinary cadre of researchers. All of

these studies have contributed to building

the solid base of knowledge that exists

today. The continuing expansion of this

base is pointing scientists in new and productive research directions. It is also helping investigators ask more incisive questions

about the issues that still remain unclear. 

An early, accurate diagnosis is especially 

important to people with AD and their families.

2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 15

PART 3

2003 AD Research 

Advances: The Process 

of Discovery Continues

During the last year, scientists supported by NIH made advances in a

number of areas important to AD. This

section of the Progress Report focuses on

recent research that has attempted to

answer three key questions:

■ What happens in the brain to cause

the transformation from healthy

aging to AD?

■ Can certain factors increase the risk of

or protect against AD?

■ What can be done to slow the progression of AD or lessen its effects?

These questions are important

because they focus on the central issues

of AD: What happens at the very beginning of the disease process, what might

we be able to do to prevent AD, and

what can be done once the disease process has started. They can be asked only

because of the knowledge that has accumulated through past research. Answers

to these questions are slowly emerging,

and they hold the key to future prevention, treatment, and caregiving strategies.

What Happens in the Brain to

Cause the Transformation from

Healthy Aging to AD?

Many studies are underway to clarify

the changes that occur during normal

aging and their effects on memory and

thinking skills. Learning more about 

the changes that occur in aging will help

scientists decipher the transformation

from healthy aging to AD. For example,

researchers at the University of Michigan

conducted a study that examined vocabulary knowledge and the ability to process,

learn, and remember information

among a group of people ranging in age

from 20 to 90 (Park et al., 2002). They

found that subtle declines in the ability

to process and remember information

started as early as the 20s and that the

declines continued throughout adulthood. In contrast, indicators of vocabulary and general knowledge improved

across the 20 to 90 age range. These

results are surprising because they indicate that cognitive decline starts early in
adulthood and because it seems to happen at the same rate for many different

cognitive tasks. The finding of increasing

general knowledge in the face of declining memory performance suggests that

older adults may process information 

and react to it more slowly than younger

adults. However, this lag may be offset by

knowledge accumulated over the years.

Because the investigators examined a

group of people at different ages between

20 and 90 during one time period rather

than following the same people over time

from age 20 to 90, they caution that 

factors other than age may have been

responsible for the pattern of steady 

cognitive decline. These factors, such 

as illnesses or differences in life experiences, need to be considered to be sure

that the changes seen are age-related.

A second study, conducted by

researchers at Washington University in

St. Louis, followed up on earlier research

that has consistently found that different

brain regions are activated in older than

in younger adults during cognitive tasks,

even when they are performing the same

task (such as taking a memory test). The

reasons for this difference are unknown,

16 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

The progress that has

occurred over the past 25 years 

in AD research would not have

been possible without the various threads of scientific inquiry

that, together, have provided 

a firm foundation for today’s

treatment and prevention clinical trials. These threads include

studies of populations, basic

research in laboratories, and

animal studies.

Epidemiologic studies

Studies of groups of people

allow scientists to examine

characteristics, lifestyles, and

disease rates. This information

often provides valuable clues

about the disease or the factors

that could increase or decrease

the risk of developing it. Some

epidemiologic studies compare

two different groups; such studies help investigators understand

factors that influence why some

people get a disease and others

do not. Other “epi” studies follow one group over time, and the

data gathered can reveal important clues about the origin or

development of a disease. Epi

studies cannot determine exactly

what causes a disease, however.

Clinical trials are necessary to

achieve this objective.

Basic research in laboratories

Scientists in laboratories all

over the world are working with

the most up-to-date tools in an

effort to seek answers to the

mysteries of AD at the cellular

and molecular level. Many of

the studies described in this

report are laboratory studies 

in animal or human tissue.

Studies of animals

Studies of animals, an important component of laboratory

research, give investigators

another crucial way to examine a

scientific problem. As this report

describes, animal studies are

used to explore the major questions in AD—what causes the

transformation from healthy

aging to AD, what factors

increase or decrease risk of developing AD, and what can be done

to treat the disease. Because no

one animal represents humans

exactly, scientists work with a

variety of models. Mice are by 

far the most common model.

The Matrix of Scientific Inquiry 
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 17

but the increasingly sophisticated use of

imaging technology is allowing scientists

to observe patterns of brain activation 

in humans and to learn more about 

the areas of the brain necessary for 

performing specific cognitive tasks. This

improved knowledge will help scientists

understand what areas of the brain may

be most vulnerable, and at what times.

In this study, the researchers used functional magnetic resonance imaging

(fMRI) to image brain activity in the

frontal cortex of younger and older

adults as they performed memory tasks

(Logan et al., 2002). The investigators

found that certain regions of the frontal

cortex were less activated in the older

adults than in the younger adults.

However, this “under-recruitment” of 

specific areas in the frontal cortex in the

older adults was reversed when they had

more time to study and think about the

information before being tested on it.

Older adults also showed activation of

additional and different regions in the

frontal cortex than did the younger

adults during their performance of 

the memory task. This “nonselective

recruitment” of other brain regions did

not change when the older adults were

allowed extra time to prepare before 

the test. These findings suggest that two

distinct forms of age-related change

occur in this brain region in older adults.

One is when neural resources are available but not spontaneously engaged

(under-recruitment) unless training or

cueing occurs. The other is when neural

resources are no longer available (nonselective recruitment) so the brain must

make use of other regions to accomplish the task. The researchers also

found that older adults in their 

late 60s and in their 80s both showed

under-recruitment, but that nonselective

recruitment was most likely to emerge

only in the oldest adults. This underrecruitment finding suggests that cognitive training strategies in late middle age

could help to lessen age-related cognitive

decline in some adults.

Another study, conducted by investigators at the University of Alabama at

Birmingham and other institutions, also

demonstrated the potential of cognitive

training. In this Advanced Cognitive

Training for Independent and Vital

Elderly (ACTIVE) intervention, which

was co-funded by the National Institute 

of Nursing Research (NINR) and NIA,

certified trainers provided 10 sessions 

of memory training, reasoning training,

or speed of processing training to

healthy adults 65 years old and older

(Ball et al., 2002). The sessions improved

participants’ cognitive ability in the 

area in which they were trained. Even

better, the improved abilities persisted 

for 2 years after the training ended,

although the interventions did not make

any real improvement in the daily functioning of the participants. The study

investigators do not know whether these

strengthened abilities might help a 

Different brain regions are activated in older than

in younger adults during cognitive tasks.
18 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

person who develops cognitive problems

later in life, but the findings do provide

encouraging evidence that it is possible 

to conserve or improve some cognitive

abilities in healthy older adults.

By identifying the changes that occur

in the brain as it ages normally, investigators hope to be able to understand the

additional pathological changes that lead

to AD. Complementing this area of

research, other scientists are focusing 

on learning more about the very earliest

stages of AD. They hope that findings in

this area may eventually open doors to

treatments that may delay the onset of

the disease or prevent its progression. 

In the past year, scientists have continued to explore the early stage of AD

from several perspectives. They have

examined cognitive and pathological

changes that could signal potential AD

development. They have refined neuroimaging techniques and neuropsychological tests that can reveal what happens in

the brain in the early stages. They have

studied biomarkers of oxidative stress,

which may provide clues to essential

parts of the disease process. And they

have worked to answer pressing questions about beta-amyloid and presenilins.

Earliest Cognitive and Pathological

Changes that Indicate Potential

Development of AD

The transition from normal aging 

to dementia is characterized by subtle

changes that indicate a gradual decline

in cognitive function. These early

changes are difficult to differentiate

from those that occur in healthy aging.

Although declining cognitive function is

not the same as AD or dementia, learning more about these changes is key to

understanding the early stages of AD.

Several teams of scientists have conducted community-based studies in which

they have followed groups of older individuals for 6 to 10 years to explore patterns of cognitive decline in people with

no obvious symptoms 

of dementia. In one of

these studies, a research

team from the University

of Pittsburgh School of

Public Health conducted

clinical and neuropsychological evaluations of a group of more than 1,400

older adults every 2 years for 10 years

(Chen et al., 2001). The study indicated

that those who eventually developed

dementia were significantly older and

tended to have low educational levels

compared to those who remained cognitively healthy. The test scores of those

who did not develop dementia improved

over time. In contrast, among the older

adults who eventually developed dementia, a decline on the same tests during the

two evaluation periods before symptoms

appeared predicted the development 

of the symptoms. In a smaller but more

in-depth study, researchers studied 108

older adults from the Oregon Alzheimer’s

Disease Center (see p.53 for more on the

work of the Alzheimer’s Disease Centers)

for at least 6 years (Marquis et al., 2002).

They found that poor recall on a memory

test, small hippocampal volume, and the

time needed to walk 30 feet predicted

cognitive decline in this group of adults,

some of whom eventually developed AD.

Scientists continue to explore the early

stages of AD.
Similar to the other team, these

researchers found that performance on

the memory test improved over time for

those participants who remained cognitively healthy. This suggests that practice

over time might partly counteract the

effects of age in those who remain 

cognitively healthy.

Another way that scientists are investigating the early stages of AD is by characterizing the biochemical and pathological

changes that occur during this period.

Two changes are of particular interest.

The first is change in levels of choline

acetyltransferase (ChAT), the enzyme

that makes acetylcholine, a neurotransmitter important in the formation of

memories. In the 1970s, scientists discovered that levels of acetylcholine fall

sharply in people with AD. Four of the

five current AD medications work to

inhibit acetylcholinesterase, an enzyme

that breaks down this neurotransmitter.

Until recently, we did not know whether

cognitive decline in the very early stages

of the disease is also associated with

falling acetylcholine levels. However, 

a University of Pittsburgh School of

Medicine team of investigators working

with Religious Orders Study participants

set out to see whether this connection

exists (DeKosky et al., 2002). The

Religious Orders Study is a long-term

study involving more than 30 religious

communities in a dozen States. The study

is being conducted through the Rush

Alzheimer’s Disease Center of the RushPresbyterian-St. Luke’s Medical Center in

Chicago, Illinois. Since 1993, scientists

have been tracking the mental and physical capacities of the participants through

annual physical and mental function

tests. This study is providing a rich source

of data on the process of normal aging 

as well as the development of AD. The

investigators originally hypothesized that

ChAT activity would be decreased in the

hippocampus of participants with mild

AD or mild cognitive impairment (MCI),

a condition in which a person experiences significant memory problems but

not the other cognitive problems found 

in AD (see the box on p.20 for more on

MCI). However, they found that hippocampal ChAT activity levels in those

with MCI were higher than in cognitively

healthy participants and had not

decreased even in those with mild AD.

Advances in Basic 

Research Suggest Avenues

for Future AD Therapies

Scientists are rapidly improving their understanding

of very early changes in the brain that eventually result

in full-blown AD. This knowledge is suggesting a number of avenues that may someday be used to prevent 

or treat AD. These avenues involve preventing the

development of AD’s three main features—plaques, 

tangles, and loss of connections between neurons.

Prevent build up of plaques

■ Slow or prevent beta-amyloid production 

■ Slow aggregation of beta-amyloid into plaques

■ Dissolve plaques

Prevent build up of neurofibrillary tangles 

■ Slow or prevent tau aggregation and dysfunction

■ Dissolve neurofibrillary tangles

Prevent brain cell dysfunction and death

■ Slow or prevent oxidative stress, inflammation,

reduced blood flow

■ Increase levels of protective molecules in the brain

■ Maintain viable connections between cells

2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 19
20 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

They theorized that an initial compensation had occurred in that part of the

brain to make up for developing deficits.

These findings clearly show that there 

is still much to learn about the early

stages of AD.

The second set of changes of particular interest to scientists occurs in tau, 

the primary component of neurofibrillary

tangles. In one study, a team of researchers

gave extensive neuropsychological tests

to 31 Religious Orders Study participants.

Some of these participants had MCI; 

others were cognitively healthy. After

their deaths, the study team, which was

led by researchers from the University of

Pennsylvania School of Medicine, examined their brain tissue for signs of tau

tangles (Mitchell et al., 2002). The study

confirmed that those with MCI had a

higher average number of tangles than

did the cognitively healthy participants.

Those with mild AD had even more

tangles than those with MCI. These

findings support the notion that the

destructive changes that occur in the

brain develop in parallel with outwardly apparent cognitive changes. They also

show that characterizing the biochemical and pathological changes that are

responsible for the earliest stages of the

AD disease process is important because

they point to potential targets for therapies aimed at very early AD.

In a second tau study, scientists from

the Northwestern University Institute for

Neuroscience in Chicago, learned more

about the relationship between changes

in tau and beta-amyloid (Rapoport et 

al., 2002). This research was supported

by NIA, NINDS, and the Alzheimer’s

Association. Using nerve cell cultures

from mice with genetically altered tau,

As a person gets older, changes normally occur

throughout the body, including the brain:

■ Some neurons shrink, especially ones in areas

important to learning, memory, planning, and other

complex mental activities. In some brain areas, 

neurons actually die.

■ Tangles and plaques develop in neurons and 

surrounding areas, respectively, though in much smaller amounts than in AD. 

■ Inflammation in brain tissue increases.

■ Damage by free radicals increases (free radicals are

highly reactive oxygen molecules that combine easily

with other molecules; a build up of too many can damage neurons; see p.23 for more on free radicals).

As a result, healthy older people may notice a modest

decline in their ability to learn new things and retrieve

information, such as remembering names. Although

these declines may be frustrating, they do not interfere

with the ability of older adults to engage in what they

need to do or enjoy doing.

As some people grow older, however, they develop

memory problems greater than those expected for their

age. However, these problems do not necessarily meet

all the accepted criteria for AD. For example, a person

with memory problems might not experience the difficulties in other cognitive areas, such as making decisions,

that are required for a diagnosis of AD. These people

have a condition called mild cognitive impairment with

memory loss. Many people with MCI do go on to develop

AD. However, we do not yet know whether progressing

to AD is inevitable. Scientists are intensively studying

MCI in hopes that a greater understanding of this condition will shed light on the early stages in the development of AD as well as increase our knowledge of the

aging brain in general.

The Aging

Brain, Mild 

Cognitive

Impairment,

and AD
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 21

the investigators found that neurons 

containing either human or mouse tau

proteins degenerated if exposed to fibrillar beta-amyloid. However, neurons from

mice without the altered tau did not

degenerate when exposed to the betaamyloid. Although the genetically altered

tau used in this study is generally responsible for another neurodegenerative 

disease, frontotemporal dementia with

parkinsonism linked to chromosome 

17 (FDTP-17), these results suggest that

the effects of beta-amyloid on the degeneration of neurons in AD may involve 

the tau proteins to some degree.

Scientists are also learning about 

the early changes in AD by studying

changes in several sensory systems. 

For example, University of Rochester

Medical Center investigators have been

exploring the issue of optic flow for some

time (O’Brien et al., 2001). When people

move through a space, they see the environment around them change. It appears

to be flowing past them. This changing

“picture” is called optic flow. People can

orient themselves in space and know the

direction in which they are moving

because of the brain’s ability to process

optic flow information. Optic flow is

somewhat impaired in older adults 

compared with younger adults and is

even more damaged in people with AD.

In a study from the same University of

Rochester group, which was conducted

with monkeys, scientists found that 

neurons in particular regions of both

sides of the brain encode directional 

and location information, and may play 

a critical role in supporting one’s orientation in space (Froehler and Duffy, 2002).

The fact that these anatomical pathways

are associated with brain regions that

connect to the hippocampus suggests

that changes could play an important

role in the disorientation that develops 

in AD and other neurodegenerative 

diseases.

Neuroimaging

Investigators are continuing to use

neuroimaging techniques, such as magnetic resonance imaging (MRI) and

positron emission tomography (PET), to

assess whether it is possible to measure

aspects of brain structure or function

that will identify people who are at risk

of AD even before they develop the

symptoms of the disease. Over the past

year, research has expanded our understanding of the potential usefulness of

these techniques for research and diagnostic purposes. The research also has

increased our knowledge about early AD

changes in specific brain regions.

For example, a University of

Pittsburgh team of scientists working 

with transgenic mice that develop betaamyloid plaques, has developed a new

dye-based compound that has a particular

affinity for beta-amyloid present in the

In a major scientific breakthrough, scientists used PET to view

amyloid deposits in the brains of living humans.
22 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

brain (Mathis et al., 2002). The investigators found that this compound was

rapidly taken up by brain tissues and

bound to plaques. Very recently, in a

major scientific breakthrough, the same

team of scientists used PET to show

that the compound, referred to as

Pittsburgh Compound-B, or PIB, can 

be used to view amyloid deposits in the

brains of living humans. In this groundbreaking study, 16 patients diagnosed

with mild AD showed markedly more

retention of PIB in certain regions of the

cortex that are known to contain large

amounts of beta-amyloid, than did nine

cognitively healthy individuals (Klunk 

et al., 2004). Future studies with PIB 

or other similar compounds may contribute to our understanding of the role

of beta-amyloid in the natural history 

of AD, help with early diagnosis, and 

aid in following disease progression.

The damage to the brain that 

occurs in AD begins in an area called 

the entorhinal cortex. It then spreads 

to the hippocampus, the brain structure

that is essential to the formation of 

short- and long-term memories. Previous 

neuroimaging studies using MRI have

shown that the shrinkage in brain tissue

volume and loss of neuronal function

that occurs as the disease progresses can

be correlated with decreased performance on memory and other AD tests. 

Harvard Medical School and Boston

University scientists used MRI to see

which brain region—the entorhinal 

cortex or the hippocampus—might 

better predict which people with MCI

would progress to AD (Killiany et al.,

2002). Because a high percentage 

of people with MCI progress to AD

every year, a test that could reliably

predict this time course would be

extremely valuable. It might even be 

possible someday to develop a treatment

that could delay or prevent AD in these

individuals. This research team performed MRI scans on 137 individuals

with MCI and measured both the

entorhinal cortex and hippocampus.

They found that decreased volume in

the entorhinal cortex did a better job

of predicting which individuals would

progress to AD than did decreased 

hippocampal volume. 

A second study clearly shows the

progress of damage to brain regions as

AD worsens. In this imaging study, which

also included pathological data and

results from memory and other neuropsychological studies, investigators

from the Mayo Clinic in Rochester,

Minnesota, used MRI to study individuals

whose AD had been diagnosed through

memory and neuropsychological tests

(Jack et al., 2002). The AD diagnosis was

confirmed after death by pathological

analysis of brain tissue. The investigators

found that the brain tissue of these 

individuals, who had well-established 

AD, showed substantial hippocampal
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 23

shrinkage. In contrast, individuals

whose brains exhibited changes associated with normal aging did not have the

same degree of hippocampal shrinkage

and no memory decline or clinical 

diagnosis of AD. 

Biological Markers and 

Oxidative Stress

Scientists also are trying to discover

whether biological markers exist that

could indicate early changes in the brain

associated with AD. Understanding these

markers—what they are, how they function, and how and when their levels

change—will help investigators answer

questions about the cause and early

development of AD and may lead one

day to the identification of targets for

treatments to delay or prevent the onset

of the disease. 

One long-standing theory of aging

and neurodegeneration is that damage

from highly reactive molecules called

oxygen free radicals can build up in 

neurons over time. If unchecked, this

oxidative stress can modify or damage

cellular molecules such as proteins,

lipids, and nucleic acids. Oxidative stress

may play a role in the development of

several neurodegenerative disorders. In

the AD brain, in particular, such damage

has been observed, especially in the late

stages, when both beta-amyloid plaques

and neurofibrillary tangles are present 

in abundance. However, scientists do 

not know whether the oxidative stress 

causes or results from the process of

beta-amyloid plaque formation, or is

related to other triggers. 

Researchers from the University of

California at Irvine have studied the

impact of oxidative damage on cognitive

function in dogs (Cotman et al., 2002;

Milgram et al., 2002). As in humans,

dogs naturally accumulate beta-amyloid

plaques in their brains as they age, and

the amount of beta-amyloid plaques 

in dogs correlates with the severity of

cognitive decline. Oxidative changes are

also apparent in the brain tissue of old

dogs. The scientists speculated that if

beta-amyloid is related to the oxidative

changes seen in the brain in normal

aging and in disease, then a reduction

in oxygen free radicals should bring

about improvements in cognition. To 

test their hypothesis, the researchers

developed a series of increasingly 

difficult behavioral and learning tests

for 23 old and 16 young dogs. One

group of the young and old dogs ate 

a regular diet; a second group of 

young and old dogs ate the same diet

supplemented with antioxidants. The

antioxidant-enriched diet improved the

learning and memory in the old dogs

but it had little effect on young animals.

These results suggest that the impact 

on behavior of oxidative changes in the

brain occurs in later life and that this

can be modified in dogs by a diet high

in antioxidants. 

Oxidative stress may play a role in the development

of several neurodegenerative disorders.
24 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

Several recent studies, funded by 

the National Institute of Environmental

Health Sciences (NIEHS), explored

aspects of the oxidative stress process.

One area of study involves lipids, 

a substance found in all living cells. 

(Fats are a type of lipid.) Scientists are

interested in the extent to which lipids 

in the central nervous system

are affected by oxidative

stress. This can be assessed

by measuring levels of a newly

described class of lipids—the

isoprostanes. Isoprostanes are

formed by the addition of

oxygen to specific lipids,

and this process, called lipid

peroxidation, is a known

feature of AD. A University

of Pennsylvania team funded

by NIEHS and NIA quantified levels of a specific 

isoprostane—8,12-iso-iPF

(2alpha)-VI—in brain tissues from cognitively healthy

people, people with AD, and

people with frontotemporal

dementia (Yao et al., 2003).

They found that this particular isoprostane was a specific and sensitive

marker of brain oxidative stress in those

with AD but not in those with frontotemporal dementia or those who were cognitively healthy. Understanding and

identifying biological markers that 

can distinguish AD from other neurodegenerative diseases may one day lead

to new diagnostic and therapeutic tools.

Another NIEHS-supported study illustrates how basic research into molecular

pathways can provide potentially important insights into future treatment strategies. In this study, researchers from the

University of Wisconsin at Madison built

on knowledge that oxidative stress and 

its products can induce apoptosis (Lee 

et al., 2003). Apoptosis, also called programmed cell death, is a normal mechanism that allows a cell to self-destruct

under certain situations, such as when it

is no longer needed within the body or

when it becomes a threat to the health 

of the organism. Programmed cell death

can be prevented in many ways, such 

as by adding external growth factors, 

supplementing with antioxidants, and

inhibiting cell death pathways. These

investigators found an alternative way 

to protect cells from apoptosis through

coordinated upregulation of genes that

make different components of a cell

defense system (such as antioxidant and

detoxification products). The investigators refer to this process as “programmed

cell life.” The researchers hypothesize

that activating more programmed cell
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 25

life pathways can balance programmed

cell death. In combination with other

techniques known to prevent detrimental programmed cell death, this strategy

may be a powerful tool to control progressive neurodegenerative diseases 

like AD.

Beta-amyloid 

The study of beta-amyloid, the primary component of AD plaques, continues

to be a vital part of the quest to discover

what goes wrong in the brain as AD

develops. Investigators continue to pursue studies that will clarify the process 

by which APP is cleaved by enzymes 

to release beta-amyloid fragments, how

these fragments clump together and

accumulate in the brain to form plaques,

and whether and how plaques might be

cleared from the brain. In studies published during the past year, investigators

reported on several different issues related to beta-amyloid.

A team of scientists from the Mt. Sinai

School of Medicine in New York reported

on research that examined more closely

the toxicity of specific forms of betaamyloid (Parvathy et al., 2001). Their

study examined brain tissue after death

from individuals who had earlier been

shown through cognitive testing to have

had some level of dementia (questionable, mild, moderate, or severe) or no

dementia. The scientists discovered a

striking pattern in the deposition of three

common beta-amyloid fragments, or peptides. They found that some of these

peptides had accumulated in brain 

tissue before AD was diagnosed, and

they found that a significant number 

of plaques contained longer peptides.

This suggests the possible involvement

of at least these beta-amyloid peptides

early in the progression of AD, even

though these longer beta-amyloid 

fragments are generally found in lesser

amounts than are other fragments. 

The researchers hypothesize that 

the unique properties of each are 

keys to brain amyloid burden and, 

possibly, to the toxicity attributed 

to beta-amyloid.

In a related study using brain tissue

from rats, investigators from Northwestern

University Medical School in Chicago 

suggested that clusters of fibrillar betaamyloid might contribute to AD by

impairing the ways in which neurons

involved in the formation of memory 

signal to each other. Conceivably, these

clusters also could cause harm at the

structural level by interfering with 

the way in which brain neurons repair

damage to their connections with other

neurons (Wang et al., 2002).

Another study, supported by the

National Institute of Child Health and

Human Development, also focused on 

the way in which beta-amyloid may 

damage neurons (Grace and Busciglio,

2003). In this study, investigators from

the University of Connecticut Health

Center found that fibrillar beta-amyloid

may induce damage to neurons by

Beta-amyloid is a vital part of the quest to discover

what goes wrong in the brain as AD develops.
26 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

adversely affecting the function of key

proteins in the cell membrane called

focal adhesion proteins. Studies like this,

which clarify the cascade of events in

beta-amyloid biology, are making a critically important contribution to our

understanding of what happens in the

brain to cause the transformation from

healthy aging to AD. 

A multi-site collaborative study headed

by a research team at the Haldeman

Laboratory of Molecular and Cellular

Neurobiology at Sun Health Research

Institute in Sun City, Arizona, examined

beta secretase, an enzyme that is thought

to play a pivotal role in cleaving APP into

beta-amyloid fragments (Yang et al.,

2003). The scientists showed that both 

the amounts and activity level of this

enzyme were modestly higher in affected

brain regions (the temporal cortex and

hippocampus) of individuals with AD

compared to cognitively healthy individuals. These statistically significant correlations suggested that the higher levels 

of beta secretase are at least in part

responsible for more beta-amyloid 

being formed.

Stanford University scientists funded

by the National Institute of Mental

Health (NIMH) and NIA looked at

another aspect of beta-amyloid—whether

it is possible to remove plaques once they

have formed. In this study, the investigators examined whether a substance called

macrophage colony stimulating factor

receptor (M-CSFR) could induce a particular kind of brain cell called microglia 

to surround and destroy beta-amyloid

plaques (Mitrasinovic and Murphy,

2002). Using mice, the scientists demonstrated that these cells had an increased

A number of neurodegenerative 

diseases, including AD, dementia with

Lewy bodies (DLB), Parkinson’s disease

(PD), Huntington disease, amyotrophic

lateral sclerosis (ALS), and prion 

diseases such as Creutzfeldt-Jakob 

disease (CJD), are characterized by

excessive amounts of abnormally 

folded proteins being deposited in the

brain. Each disease has unique clinical

symptoms and pathological characteristics, and the way they progress and

develop over time are different.

However, they also share some characteristics with each other. For example,

some people with AD have slowed

movements and tremors, the most

obvious symptoms of Parkinson’s 

disease. People who have dementia

with Lewy bodies (abnormal structures

in the brain that contain a protein

called synuclein) experience cognitive,

behavioral, and psychotic symptoms

similar to AD as well as the slowed

movements and tremors that are 

characteristic of PD. 

Other

May Shed 
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 27

Many scientists are intensively studying these

diseases, and their growing knowledge about the 

characteristics of each is helping to answer questions about the others. Several recent studies

highlight the progress being made in this area.

One study conducted by scientists at a number

of institutions explored some of the factors that

might account for why disease progression and

survival vary so much in people with AD (Haan et

al., 2002). Previous research had found that people

with AD who have parkinsonian symptoms (for

example, shuffling gait, slowed movements, rigid

muscles, and tremors) and symptoms of delusions

and hallucinations experience faster cognitive

decline and shorter survival times than do people

with AD who do not have those symptoms. The

research team examined the relationship between

parkinsonian symptoms, delusions and hallucinations, age of death, and the presence of Lewy 

bodies in a group of 379 individuals with AD who

were evaluated during the time they had AD and

autopsied after death. Confirming previous work,

these findings suggested that parkinsonian symptoms may predict reduced survival in patients with

AD. The results also suggested that the presence

of Lewy bodies and of parkinsonian symptoms

may work together to reduce survival more than

either characteristic by itself.

One hypothesis about AD, PD, and other 

neurodegenerative diseases is that “misfolded”

proteins that accumulate in brain tissue cause the

disease. When a protein is first created, it exists 

as a long string of amino acids. Within a fraction

of a second, the amino acids fold themselves into

a distinctive three-dimensional shape. Each type 

of protein has a unique shape, which allows it 

to carry out its particular function. For example,

hemoglobin’s shape lets it carry oxygen in blood.

If a protein is not folded properly, it cannot function normally. A University of California at San

Francisco research team explored this issue in 

a study on the transmission of prion diseases

between different species of animals (Peretz et al.,

2002). Prions are infectious proteins that change

the shapes of normal cellular proteins, transforming them into abnormal proteins. CJD and other

fatal neurological diseases are caused by accumulations of prions in the brain, which somehow

cause sponge-like holes to develop in brain tissue.

This damage to brain tissue results in movement,

emotional, sleep, and cognitive disturbances and

premature death. By learning more about prion

diseases and protein misfolding, researchers hope

to understand the pathological mechanisms that

underlie the transformation of normal proteins

into abnormal ones, thereby shedding light on 

the disease process in AD and other diseases. 

In another study that reinforced the possible

commonality of misfolded proteins in neurodegenerative disorders, scientists from the

University of Pennsylvania conducted a study 

on a transgenic fruit fly with human genes inserted (see p.30 for more about the use of transgenic

animals in AD research). This fly makes human

synuclein protein in particular neurons (Auluck et

al., 2002). Mutations in the gene that directs the

production of the synuclein protein causes it to

misfold, resulting in one form of Parkinson’s disease in humans. Expression of both the normal

and the mutated human synuclein genes in these

fly neurons caused the neurons to die. Scientists

then studied transgenic flies that made both the

human synuclein protein and one called hsp70 

in these same neurons. Hsp70 protein refolds 

misfolded proteins and its expression in the 

synuclein-containing neurons prevented their

death. This is one approach scientists hope 

will be applicable to several major neurodegenerative diseases caused by protein 

misfolding, including AD.

Neurodegenerative Diseases 

Light on Early Changes in AD
28 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

capacity to clear beta-amyloid from brain

tissue. Activation of microglia to destroy

plaques was the concept behind the

recent development of the AD vaccine,

and the Stanford study provides an additional and valuable contribution to this

body of knowledge. Other studies have

important implications for future drug

and vaccine development. For example, a Mayo Clinic research team in

Minneapolis worked with mice to build

on earlier studies that suggested that the

presence of antibodies to beta-amyloid

could reduce the accumulation of this

toxic material in the brain and prevent

continued cognitive decline. This

team, funded by NIA, NINDS, and

NIMH, administered antibodies to mice

who had beta-amyloid plaques and

impaired memory, but not neuronal loss

(Kotilinek et al., 2002). This refinement

of earlier vaccine approaches reversed

the memory deficits without having a

significant impact on the overall

amount of beta-amyloid in the brain.

Another avenue of beta-amyloid

research has focused on finding or developing compounds that might inhibit APP

formation, thereby limiting beta-amyloid

formation. Under normal circumstances,

the amount of APP that a cell makes

appears to be regulated by a particular

sequence in its messenger RNA (mRNA).

This intermediary carries from the gene

a blueprint that is necessary to make 

a protein. A Massachusetts General

Hospital research team funded by NIMH

postulated that interfering with this

sequence would interfere with APP formation and ultimately with beta-amyloid

formation (Rogers et al., 2002). If a compound binding to this sequence could 

be developed, it would be important to

determine whether, in fact, it worked to

block APP formation. This research team

developed a fluorescent APP mRNA that

is easily visualized until it binds with a

drug that blocks the sequence that regulates APP formation. In theory, when the

fluorescence disappears, APP and betaamyloid formation are blocked. This simple, rapid screen for drugs that can block

APP formation may hasten the development of AD treatments. Some scientists

worry, however, that lowering levels of

APP might have unwanted side effects 

if APP itself has an important function

in brain cells.

Presenilins

During the past several years, scientists also have made major progress 

in clarifying the biology of presenilin 

proteins. Many mutations in the genes 

coding for the presenilin proteins have 

been found, and the mutations in the

presenilin 1 gene are responsible for 

the majority of early-onset forms of AD

(see p.10 for more on our understanding

of what causes AD). Scientists hope that

a deeper knowledge of the basic biology

of presenilins will help them understand

how these proteins are involved in the

development of AD. 

The presenilin proteins are part of 

a complex that includes three other 

Scientists have made major progress in clarifying the 

biology of presenilin proteins.
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 29

proteins (nicastrin, aph-1, and pen-2)

that are involved in causing the cleavage

of APP into beta-amyloid fragments. A

study in mice conducted by University of

Chicago scientists has helped 

to further elucidate the role

of presenilin proteins. Their

results suggest that in addition

to their role in cleaving the

APP protein, presenilins function as “chaperones,” which are

required to properly fold and

move proteins such as nicastrin

through intracellular “way 

stations,” where they may be further 

modified before being distributed to

other cellular compartments to do 

their jobs (Leem, J. Y. et al., 2002).

A second study explored a possible

relationship between the presenilin 1

gene and some of the most fundamental

concepts involved in memory formation.

Short-term memories are formed in the

hippocampus and are transferred to the

cortex for long-term memory storage.

Some scientists believe that the hippocampus has only so much storage

capacity for new memories. Therefore,

short-term memories that have limited

utility must be “cleared” so that storage

space remains for critical new information. In this study, a Princeton University

team of investigators funded by NIMH

and NIA selectively deleted the presenilin 1 gene from a particular kind of

neuron in the forebrain of mice (Feng 

et al., 2002). These “knockout” mice

were placed in an enriched environment, meaning that they were in cages

that contained toys, running wheels,

and small houses. The knockout mice 

grew normally but they made fewer

neurons from stem cells in the 

To determine what actually happens

in the brain during the transformation

from healthy aging to AD, scientists need

to know more about the ways in which

neurons interact. These interactions are

directed by genetic instructions about

where and when particular cellular 

proteins are produced. 

A case in point is research on a class

of genes called immediate-early genes

(IEGs). These genes are unique because

at certain times their expression is low

or undetectable. This means that they

are not actively giving instructions for

the creation of new proteins. However,

within minutes of an extracellular stimulation, such as addition of a growth 

factor, they begin to direct the 

production of new proteins. 

IEGs are useful markers in studies of behavior and 

cognition because changes in their expression level

can be used to identify those brain areas and neurons

that are activated after behavioral or learning tasks. 

At the Arizona Research Laboratories in Tucson, a

research team has developed a novel imaging method,

called cellular Compartment Analysis of Temporal activity

by Fluorescent In-Situ Hybridization, or catFISH for short

(Guzowski et al., 2001). This imaging technique provides

information about what happens when individual IEGs

are activated and what happens in the process of protein

formation after the IEG is activated.

In studies of rats exposed to two different environments, the researchers used catFISH to image the activation of two IEGs. From this, the scientists were able to

infer the activity history of individual hippocampal neurons in the rats. Their results suggest that behavioral experiences are linked to specific neural circuits in the brain.

The development of the catFISH imaging technique

now makes it possible to “visualize” single cells where

genes are turned on. It will help scientists understand the

molecular signaling pathways controlling changes in gene

expression. In future, imaging by catFISH may help identify the interactions of nerve cells in the brain that underlie

different cognitive and behavioral processes, and their

changes during normal aging.

Using catFISH to 

“See” Neurons at Work

This catFISH

image shows

IEG-activated

neurons (in

white) of the 

hippocampus

from an 

older rat.
30 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

hippocampus than did mice in the same

enriched environment but who still had

the presenilin 1 gene (see p.40 for new

discoveries about stem cells and the formation of new neurons in the brain).

The knockout mice also were able 

to learn normally, even when they 

were quite old, but they retained old

memories better than did the normal

mice. These results suggest that loss 

of the presenilin gene may result in 

an inability to clear old memories 

from the hippocampus (in other 

words, to free up “storage space”). 

In theory, this might result in an inability

to store or “remember” new memories,

just as happens with people who 

have AD.

Can Certain Factors Increase

Risk of or Protect Against AD?

We’ve known for some time that 

certain genetic, non-genetic, and 

biologic factors can increase the risk 

of developing AD. Recent evidence has

suggested that other factors may actually

help to reduce AD risk. Researchers are

investigating these risk and protective 

factors through a variety of studies,

including genetic studies and studies 

of individual lifestyles and behavioral

patterns. Scientists also are using 

epidemiologic studies to examine 

how lifestyle patterns may interact 

with genetic factors to change the 

likelihood that a person may develop

AD. Findings from these studies, 

particularly the genetics studies, are

important because they point to cellular

pathways that go wrong in AD. This

research eventually will be useful in

identifying people at increased risk 

of developing AD. 

For many years, scientists have worked with specially

bred mice that develop some of the characteristic pathological

features of AD. These “transgenic” animals contain normal or

mutated forms of human genes implicated in AD, such as the

APP gene. As they grow older, APP transgenic mice develop

AD-like plaques in the same regions of the brain as do people with AD. However, they do not show other AD changes,

such as the formation of neurofibrillary tangles or the death

of particular kinds of neurons. Newer animal models have

more of these AD-like pathologies.

APP transgenic mice can be used to find out the effects 

of other human genes on beta-amyloid production. Scientists

do this by breeding the APP transgenic mice to transgenic

mice containing a test human gene. This strategy was used to

discover the effect on beta-amyloid metabolism of different

forms, or alleles, of the risk factor gene for late-onset AD.

This gene is called apolipoprotein E, or APOE (see p.31 for

more on APOE and its forms).

Investigators at Washington University School of

Medicine in St. Louis, conducted a detailed analysis of the

various alleles of the APOE gene in transgenic mice. They

found that the APOE-4 allele influences beta-amyloid

metabolism early in the disease process by facilitating the formation of fibrillar beta-amyloid (Fagan et al., 2002). In a second study from the same laboratory, the researchers showed

that another apolipoprotein gene, APOJ, also influences the

deposition of beta-amyloid and the formation of plaques. In

the absence of APOJ, the researchers found that damage to

neurons usually seen in the presence of amyloid plaques was

markedly reduced. This suggests that apolipoproteins E and 

J appear to influence beta-amyloid structure and toxicity, and

that both are likely to play a role in the damage to neurons

caused by beta-amyloid deposits (DeMattos et al., 2002). 

Though many studies have demonstrated the huge contribution that transgenic mice make to our growing understanding of AD and of potential preventive and therapeutic strategies, another recent study provides a caveat that is important

to remember: Mice and humans are different, and AD pathology as it occurs in these animals is not exactly the same as 

AD in humans. Using transgenic mice, researchers at the Sun

Health Research Institute demonstrated that the beta-amyloid

deposits found in these mice were more soluble than the betaamyloid deposits found in human AD (Kalback et al., 2002).

These findings raise the possibility that it may be less easy to

prevent or remove beta-amyloid deposits in humans than it is

in transgenic mouse models. Therefore, treatments that work

to remove these deposits in mice may not do so in humans.

Use of Animal Models 

to Examine Early AD 

Changes in Neurons
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 31

Risk factor studies already have

pointed the way to potential preventive

approaches that are being investigated 

in controlled clinical trials. If confirmed

by the trials, these approaches may suggest ways that people can change their

lifestyles or environments to reduce 

the risk of developing AD. 

Genetics

Genetic studies generally have

focused on two key issues—whether a

gene might influence a person’s overall

risk of developing a disease, or whether 

a gene might influence some particular

aspect of a person’s risk, such as the 

age at which the disease begins (age 

at onset). A research team at Duke

University Medical Center explored

genetic links to AD through one of these

latter types of studies. The investigators

conducted a kind of genetic analysis

called a genomic screen on 449 families

affected with AD and 174 families affected with Parkinson’s disease (Li et al.,

2002). Because AD and PD share some

common clinical and pathological characteristics, the investigators hypothesized

that a gene or genes common to both

diseases might control age at onset.

Results showed that age at onset 

appears to be passed down through 

generations and that age at onset of 

both diseases may be controlled by a

common gene. The study also confirmed

that the analytic method used by these

researchers is feasible for this type of

genetics study. Clearly, further studies are

needed on this complex issue, but identifying the genes that regulate disease

onset is important because they will help

to uncover the molecular pathways

involved in its initial development. This

knowledge may eventually lead to effective prevention strategies. 

AD genetics researchers also have

compared risk in various racial and 

ethnic groups. Previous studies have

shown that ethnic and racial groups

appear to differ in their genetic risk of

AD, but these findings were difficult to

interpret because studies looked at different populations and different age

groups, and they differed in design 

and analytic approach. More recently,

investigators have completed studies that

have shed light on some aspects of our

knowledge of genetic background and

AD risk and how it might be more similar among certain populations than previously thought. It is important to clarify

similarities and differences in genetic

risk because they help us understand

more about the disease in general as 

well as help us as a society respond to 

the needs of all people with AD and

their families.

For example, the APOE-4 allele,

located on chromosome 19, is a risk 

factor for late-onset AD. Unlike the APP

and presenilin genes, whose mutation is

Identifying genes that regulate disease onset will 

help uncover the molecular pathways involved in 

its initial development.
32 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

associated with the rare early-onset AD,

APOE-4 increases the risk of developing

late-onset AD, rather than being its

cause. Investigators from Columbia

University who studied a population in

northern Manhattan over time found

that APOE-4 appeared to be less of a

risk factor among African Americans 

and Hispanics than in Caucasians 

(Tang et al., 1996). More recently, the

same team evaluated 203 Caribbean

Hispanic families in the Dominican

Republic and Manhattan to reexamine

the association between APOE-4 and

AD. They were searching for genes that

might be associated with increased risk

in Caribbean Hispanic families who 

had at least two living relatives with AD

(Romas et al., 2002). The investigators

found a stronger association between

APOE-4 and AD in elderly Caribbean

Hispanics than previous studies had

suggested. This may have occurred

because the AD patients were younger

than those in Manhattan and were in

families chosen for their high genetic

risk. The authors note that this strong

association between APOE-4 and 

risk of AD suggests that future genetic

analyses need to take this factor into

account in Hispanics.

In a related study conducted in the

Caribbean Hispanic families, the same

team of researchers looking for new risk

factor genes for late-onset AD found 

a modest linkage on chromosome 12

(Mayeux et al., 2002). The association

varied, depending on the age at onset in

the individuals and whether the individuals did or did not carry the APOE-4 risk

factor gene. Identifying populations that

have specific chromosome locations that

may harbor risk factor genes for AD

greatly enhances the likelihood of success in finding the risk factor genes.

Boston University School of Medicine

and Mayo Clinic investigators also evaluated APOE in a large group of African

Americans with AD and compared them

to their siblings and to unrelated 

cognitively healthy African Americans

(Graff-Radford et al., 2002). The study

found that the presence of one or two

APOE-4 genes increased the risk of

developing AD but the risk decreased

substantially with increasing age. The

investigators also found that having the

APOE-2 gene appeared to protect

against developing AD. All of these findings are true for Caucasians as well. 

In another APOE study, funded 

by the National Center for Research

Resources, scientists from Columbia

University determined the APOE alleles

in 87 people with AD who had psychiatric symptoms (Scarmeas et al., 2002).

The researchers found that the presence

of one or more APOE-4 alleles significantly increased the risk of delusions

among these study participants.

Increasing knowledge about the

genetics of AD has led to an urgent need

for accurate information and materials 

to educate and counsel families, health

care providers, and the public about 

this topic. University of Iowa scientists

supported by the National Human

APOE-4 is a risk factor gene for late-onset AD.
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 33

When Comparing 

Population Groups, Many Factors 

Must Be Considered

In studying possible differences in AD risk, 

incidence, and prevalence among various racial

and ethnic groups, researchers must keep in mind

that populations vary in many respects besides

their race or ethnicity. As a result, many factors

may be responsible for differing disease estimates.

Differences in socioeconomic status, health care,

education, events occurring before birth or right

around birth, and life history all may influence a

person’s eventual risk of AD. Even the ways in

which diagnostic tests that measure language,

memory, and cognitive function are constructed

and applied are important. For example, people

may be diagnosed with AD if their level of education or cultural assimilation affects their performance on the test in ways that are different from

the performance of people with a higher level of

education who are more culturally assimilated 

and for whom the tests were originally designed.

Clearly, further careful investigation is needed to

examine the role that all these factors may play 

in determining the risk of AD.

One recent study, conducted by a Columbia

University team of scientists, illustrates the complexity of comparative studies and the need for

careful analysis (Manly et al., 2002). The researchers

matched 192 African American and 192 Caucasian

older adults by their years of education and gender.

All were cognitively healthy and none had a history

of neurological disease, stroke, mental illness, or

head injury. Both groups took a comprehensive

battery of neuropsychological tests. Even though

the two groups had the same number of years of

education, the African American participants scored

lower than the Caucasian participants on measures

of word learning and memory, figure memory,

abstract reasoning, language fluency, and 

visual-spatial skills.

The investigators then reanalyzed the results

using an estimate of the quality of education rather

than number of years of education. After adjusting

the participants’ scores in light of this new parameter, the investigators found that the effect of race

was greatly reduced. All but two of the test score

differences between the two groups were significantly reduced if not eliminated.

This work suggests that the use of years of education alone to define the level of educational experience is inadequate. The research also weakens the

assumption that if groups are matched on socioeconomic variables, such as years of education, then

any persistent group differences are necessarily

biologically meaningful. This study has made an

important contribution to illuminating factors that

can account for ethnic group differences on cognitive tests, and these findings may guide the development of new cognitive tests and measures.
34 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

Genome Research Institute are conducting research to address the ethical, legal,

and social implications of the genetics 

of AD and genetic testing. They also are

developing related educational materials

for health care professionals who work

with AD families (Williams, 2002). 

Lifestyle 

One factor that is capturing an

increasing amount of attention from 

AD researchers is the possible impact 

of lifestyle factors, such as physically 

and intellectually stimulating activities,

on AD risk. A number of studies over the

past few years have provided intriguing

hints that these challenging activities

may be linked to a reduced risk of AD,

and they are consistent with what we

know about other health benefits associated with being physically and mentally

active throughout life. 

Physical exercise was the focus of 

two recent studies conducted on rats by

scientists at the University of California

at Irvine. These studies followed up on

previous animal research that had suggested that exercise or an enriched environment can increase resistance to brain

injury, stimulate the formation of new

neurons, and enhance cognitive and

behavioral performance. In the first

study, the investigators found that several

days of exercise increased levels of brainderived neurotrophic factor (BDNF), 

a growth factor that stimulates survival,

growth, and adaptability of some 

neurons in the hippocampus (Cotman

and Berchtold, 2002). The elevated levels

of BDNF remained high even after several

weeks of exercise. These findings support

the idea that exercise may have a pronounced effect on the brain. Exercise

appears to recruit brain processes that

contribute to cognitive functioning, 

and to activate cellular mechanisms that

protect the brain from damage and 

promote its repair. Scientific studies such

as these are providing a biological basis

for the premise that exercise may benefit

brain health, both during aging and 

possibly in decreasing risk of neurodegenerative diseases.

In other studies, the researchers

worked with female rats that were 

deficient in estrogen (Cotman and

Berchtold, 2002). They found that voluntary running on an exercise wheel did

not increase levels of BDNF protein in

the brain. However, when exercise was

combined with long-term estrogen

replacement, BDNF levels increased. 

To identify other possible molecular

effects of exercise, the researchers used

special techniques to examine changes 

in gene expression profiles of about

5,000 genes in the rat hippocampus.

In normal rats, 3 weeks of exercise 

led to changes in the expression of a

number of genes, particularly those

involved in neuronal activity and 

adaptability and those involved in 

controlling the structure of synapses. 

Dietary Factors 

Another exciting area of research

that is attracting attention involves possible links between dietary patterns and

AD risk. Two recent studies, conducted

Exercise may benefit brain health.
as part of the Chicago Health and Aging

Project (CHAP), a study of a large, racially diverse community of people age 65

and older, examined the potential preventive effects of vitamin E in foods and

supplements on development of AD.

Scientists are particularly interested in

vitamin E because it is an antioxidant

that might protect brain cells from oxidative stress caused by too many free radicals (see p.23 for more on free radicals).

In the first study, investigators followed

815 cognitively healthy participants for

an average of almost 4 years (Morris et

al., 2002a). About 18 months into the

study, participants completed a detailed

questionnaire about the kinds and quantities of foods and supplements they 

had consumed during the previous 

year. At the end of the study period, the

investigators examined the relationship

between intake of vitamin E and C from

foods and supplements, intake of beta

carotene (a substance from plants that

the body converts into vitamin A), multivitamin use, and development of AD.

The most significant association with

reduced risk of AD was found among

people in the top fifth of vitamin E

intake from foods. The scientists found

no significant change in risk of AD when

they looked at vitamin E supplements,

vitamin C and beta carotene, or the 

multivitamin. Data also were analyzed to

see whether age, gender, race, education,

or possible genetic risk of AD had any

effect. Only the presence or lack of

APOE-4 seemed to matter. The association between vitamin E from food and

decreased risk of AD was strongest

among people who did not have the

APOE-4 allele.

In the second study, the same

research team followed 2,889 community

residents for about 3 years. As in the

other study, they completed a detailed

questionnaire about their usual food

intake about 18 months into the study

(Morris et al., 2002b). Results from this

study indicated that the rate of cognitive

decline was reduced by 36 percent

among those in the highest fifth of 

total vitamin E intake (foods plus 

supplements) compared to the lowest

fifth. Cognitive decline was also less

2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 35

■ Vegetable oils, such as safflower, corn,

and soybean oil

■ Wheat germ

■ Nuts, such as almonds, peanuts, and

pistachio nuts

■ Green leafy vegetables, such as

spinach, turnip greens, and dandelion

greens

■ Some other green vegetables, such as

broccoli

■ Some fruits, such as mango and kiwi

■ Breakfast cereals fortified with vitamin E

Food Sources of

Vitamin E
36 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

among those with higher vitamin E

intake from foods alone. 

The findings from these two studies

suggest that a diet rich in foods containing vitamin E may help protect some

people against age-related cognitive

decline and AD. The reasons for the

inconsistent effect of vitamin E supplements are not clear, but may have to do

with the various forms of the vitamin as

well as why and when people start to take

supplements. Though these findings are

intriguing, it is important to note that

foods are more complex than just their

vitamin content and that many factors

may be involved. It is also important to

note that those with highest intake of 

vitamin E may have been different from

the other group in some other way that 

is protective against AD. 

These results have increased 

interest in the outcome of clinical trials

now underway or planned that are testing the effectiveness of vitamin E and

other antioxidants in foods and/or supplements in preventing or postponing 

cognitive decline and AD (see p.50 

for information about the PREADVISE

vitamin E clinical trial).

Inflammation 

Inflammation is a dynamic and complex biological process that affects cells

and tissues in all parts of the body. This

process occurs in response to many types

of injuries or abnormal situations, ranging from a simple scrape on the skin to 

a disease like rheumatoid arthritis that

affects the whole body. Scientists 

have become increasingly interested in

the role that inflammation plays in the

development and progression of AD, 

but they don’t always agree on its significance. Some scientists think that some

aspects of the inflammatory process may

be valuable to the brain by helping it

clear away beta-amyloid deposits. In

contrast, other scientists

think that when the

inflammatory process

begins in the brain, it 

sets off a vicious cycle that

is harmful to neurons. Support for this

hypothesis comes from studies such as

the NIA-funded Honolulu-Asia Aging

Study. In this long-term epidemiologic

study of stroke, neurodegenerative 

diseases, and aging in older Japanese

American men, researchers have found

that those with higher levels of C-reactive

protein (an indicator of inflammation) 

in their blood at mid-life had an

increased risk of AD 25 years later

(Schmidt et al., 2002). Risk of both 

AD and vascular dementia increased.

Whatever the final answer, it is clear

that inflammation is important to the

pathology of AD in several ways, and

recent studies are helping to explain 

this complex process. 

Epidemiologic studies have suggested

that non-steroidal anti-inflammatory

drugs (NSAIDs), including naproxen,

ibuprofen, and indomethacin, are associated with a decreased risk of AD. A 

study by researchers at Johns Hopkins

University found that the longer people

took NSAIDs, the more their risk of

developing AD in the future was reduced

(Zandi et al., 2002a). Risk was reduced

Scientists are interested in the role that 

inflammation plays in AD. 
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 37

by more than one-half, for example, in

people who took NSAIDs for 2 or more

years. These results indicate that longterm use of NSAIDs is correlated with

reduced dementia risk, provided that

NSAID use occurs well before the onset

of dementia. To explore further the 

idea that use must occur long before

disease onset, a clinical trial was designed

to determine whether naproxen (an

NSAID that includes Aleve, Anaprox,

and Naprosyn) or rofecoxib (Vioxx, an

NSAID that inhibits the production of

cyclooxygenase-2, or COX-2, an enzyme

involved in the inflammatory process)

slowed the rate of cognitive decline 

in people who already had mild to 

moderate AD. The trial found that 

neither NSAID had this

effect (Aisen et al., 2003).

Researchers hope that prevention trials underway

(see p.50 for details about

the ADAPT trial) will show

that longer-term use of

NSAIDs are effective in preventing AD 

in people who are at risk but who do 

not yet show symptoms of the disease.

Three recent animal studies by 

investigators at the University of South

Florida, Northwestern University, and 

the University of California at San Diego

focused on NSAIDs as a way to counteract this damaging response in brain tissues. Using different types of transgenic

mice and different types of NSAID compounds, all three studies showed benefits

from these compounds, either because

they reduced production of beta-amyloid

fragments or reduced production of stressrelated enzymes (Jantzen et al., 2002;

Mirzoeva et al., 2002; Weggen et al., 2001).

Cardiovascular Factors 

In recent years, a number of studies

have suggested a connection between

AD and various heart disease and stroke

risk factors, including high cholesterol

levels and high blood pressure (hypertension). Although the reasons for this

association are not fully understood, it

is known that even in relatively healthy

older adults, risk factors for stroke, such

as age, hypertension, diabetes, and cardiovascular disease, can damage brain

blood vessels (the cerebrovascular system) and reduce the oxygen supply to

the brain. This damage may disrupt

neural circuits thought to be important

in cognitive functions, such as decisionmaking, memory, and verbal fluency. 

Scientists have conducted animal and

epidemiologic studies to understand

the association between cardiovascular

risk factors and risk of AD. Results are

consistent with many other studies that

point to the benefits of maintaining

blood cholesterol and blood pressure at

healthy levels. Studies have examined

several aspects of this complex issue. 

For example, scientists at the

University of Washington in Seattle, 

conducted a study in mice to explore the

relationship between high cholesterol

levels and AD risk (Shie et al., 2002).

This study built on earlier epidemiologic 

studies that showed a correlation

between high blood cholesterol and 

Studies have suggested a connection 

between AD and heart disease and

stroke risk factors.
38 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

AD, and on studies in APP transgenic

mice in which animals fed a high cholesterol diet developed high levels of

cholesterol in the blood and the brain

and increased beta-amyloid deposits

(Refolo et al., 2001). The University of

Washington investigators found that the

burden of amyloid plaques was significantly higher in transgenic mice fed a

high fat/high cholesterol diet than in

those fed standard chow. Interestingly,

they also found that amyloid deposits

were directly correlated with levels of

APOE and inversely correlated with 

levels of HDL, the “good” cholesterol. 

Another research team from 

the Department of Veterans Affairs

Healthcare System in Boston, studied 

235 healthy older men enrolled in the

Normative Aging Study to explore relationships between stroke risk factors and

decline in verbal fluency, memory, and

visuospatial performance (Brady et al.,

2001). The investigators found that age

was associated with decline in all cognitive functions, whereas stroke risk was

associated with decline only on verbal 

fluency. The relationship between stroke

risk and fluency decline was almost as

great as the relationship between age

and fluency decline. These results 

suggest that stroke risk, independent 

of age, may be a strong predictor of

decline in a particular cognitive 

function in healthy older men.

New data from the HonoluluAsia Aging Study also have provided 

evidence to link damage to the cerebrovascular system and dementia 

(White et al., 2002). Investigators

from the Kuakini Medical Center in

Honolulu, Hawaii, analyzed clinical

and neuropathological data from autopsies of 285 older men. The investigators

assessed the prevalence 

at death of four types of

damage to brain regions,

including damage to 

the tiny blood vessels 

in the brain, loss of hippocampal tissue, and 

the presence of AD plaques and Lewy 

bodies. In 118 of the 285 men, definite

or probable dementia had been determined before death. The study found

that damage to the tiny blood vessels 

in the brain was as likely an explanation

for their dementia as was the presence

of AD plaques. The investigators concluded that a number of factors may 

be involved in the development of

dementia in this population, and 

that it is important to consider cerebrovascular risk factors in studies 

focusing on the causes of dementia.

A second study, conducted by investigators at Columbia University, examined

data from more than 1,200 Medicare

recipients to see what effect hypertension

might have on new cases of AD and vascular dementia (Posner et al., 2002). 

The study concluded that a history of

hypertension beginning at age 65, either

treated or untreated, does not contribute

to the development of AD and does not

contribute to a decline in cognitive function as people age. These findings are

consistent with other research showing

It is important to consider 

cerebrovascular risk factors

in studies of dementia.
39

that AD risk is more associated with

hypertension that begins in midlife than

to hypertension that begins in later life.

Another hypertension study, conducted in rhesus monkeys, provides

some support for the hypothesis that

hypertension in earlier life may contribute to later declines in cognitive function. This study involved 13 young adult

monkeys, seven of which had surgicallyinduced high blood pressure. Every 

6 months, a Boston University School 

of Medicine research team tested the

monkeys on two cognitive tasks—one

that required the animals to switch strategies during the task, and another that

required the animals to choose between

two options (Moore et al., 2002). After 

as few as 12 months, the hypertensive

monkeys showed a marked decline 

in their ability to switch strategies, 

a task that required cognitive flexibility.

These findings suggest that chronic,

untreated hypertension may have longterm consequences on certain aspects 

of cognitive function. 

Additional data come from the

Indianapolis-Ibadan Dementia Project,

which studied two populations aged 

65 and older—2,147 African Americans

in Indianapolis, Indiana, and 2,459

Yoruba in Ibadan, Nigeria. Initially, 

this epidemiologic study compared the

incidence and prevalence of AD in the

two groups (the Yoruba had much lower

AD incidence and prevalence than did

the African Americans). A number of

research teams are now using data 

from the study to examine genetic and

non-genetic factors to see how they may

have influenced the development of AD.

In one of these analyses, researchers

from the Indiana University School of

Medicine assessed the long-term effect 

of antihypertension medications on 

cognitive function in the older African

American participants (Murray et al.,

2002). They found that taking these

medications was correlated with a 38 

percent lower risk of developing cognitive impairment. 

A study conducted by Columbia

University investigators focused on

another important risk factor associated

with heart disease—dietary intake of fat

and calories—and their possible association with AD risk (Luchsinger et al.,

2002). This study was part of the

Washington Heights-Inwood Columbia

Aging Project, an epidemiologic study 

of aging and dementia

that currently includes

about 3,000 people. The

investigators found that

higher intake of fats

and calories over time

was associated with higher risk of AD in elderly

individuals, but only in

individuals carrying the

APOE-4 allele.

2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE
40 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

Finally, three major long-term 

cardiovascular disease epidemiologic

studies funded by the National Heart,

Lung, and Blood Institute (NHLBI)

have provided a rich harvest of data

that have allowed researchers to explore 

the relationships between cardiovascular

risk factors and AD. All three of these

studies included cognitive decline and

dementia related to vascular disease as

key elements of their designs. Another

distinguishing element of each of these

studies has been “add-on” components

funded by other Institutes, including

NIA and NIMH. These add-on components have provided a cost-effective

opportunity for investigators to examine

additional issues using existing study

populations. Over the years, participants

in these studies have made a valuable contribution to our understanding of cardiovascular disease, AD, and dementia. These

NHLBI studies are the Framingham Heart

Study, the Cardiovascular Health Study,

and the Atherosclerosis Risk in

Communities Study: 

■ The Framingham Heart Study,

begun in 1948, is a long-term investigation of physical and environmental 

factors that influence the development 

of cardiovascular disease in healthy individuals. The study is still following the

remaining members of the original 

study group (500 of the original 5,209),

as well as the remaining members of the

5,000 individuals recruited in 1971 into

the Framingham Offspring Study, and

approximately 3,500 individuals in a 

third generation group.

■ The Cardiovascular Health Study,

begun in 1988, is a long-term study of

risk factors for the development and progression of coronary heart disease (CHD)

Until recently, scientists thought

that neurons in mammals were

formed only during the fetal period

and for a short time after birth. The

thinking was that once a mammal had

reached a certain level of maturity

early in life, neurons could only be

lost. The notion that new neurons

could develop later in life was 

revolutionary.

However, this view has dramatically

changed in the last few years based

on a number of research studies

showing that neurogenesis (the formation of new neurons) does in fact

take place in the adult brain, at least

in a limited number of brain regions. 

Several recent studies have shown

that new neurons come from a population of dividing cells called neural

stem cells (NSC). For example, after

growing NSCs in a laboratory dish

and giving them special growth 

factors, scientists at the Salk Institute

for Biological Studies in La Jolla,

California, transplanted the NSCs 

into brain tissue and found that they

formed normally functioning neurons

and glial cells (Song et al., 2002; van

Praag et al., 2002). 

The story does not end there,

though. In a recent NIA-funded

study, scientists at the Salk Institute

and Humboldt University in Berlin,

Germany, gave one group of mice an

enriched environment that included

running wheels, plastic tubes, and

nesting materials. (Kempermann et

al., 2002). Another group of mice did

not receive these extras. The scientists

found that the mice exposed to the

Neurogenesis, and Brain 
Physical and Mental Activity, 

Repair 

enriched environment had more new neurons in

the hippocampus than did the mice not exposed

to that environment. Formation and survival 

of new neurons in the hippocampus were

increased, and this was correlated with improved

behavioral performance on learning tasks.

Scientists also have found that other conditions can affect neurogenesis. For example,

stressful experiences can decrease the formation

of new neurons in the hippocampus. Aging also

strongly influences neurogenesis in the hippocampus. The rate of neurogenesis declines

with age, but some level of neurogenesis persists

in the hippocampus in elderly rodents and

humans. Interestingly, increased physical and

mental activity, even when started in middle age,

can enhance the generation of new neurons in

the hippocampus of aged mice, and this neurogenesis is correlated with improved learning 

and exploratory behavior (Kempermann 

et al., 2002).

These exciting research findings mean that 

scientists now face an intriguing and important

question: Can NSC techniques be used to repair 

or replace cells that are lost because of trauma 

or a neurodegenerative disorder? Although clear

answers don’t exist yet, emerging data indicate

that NSCs may be mobilized to generate new

neurons in response to brain injury. When the

brain is injured, NSCs normally present are activated and migrate to the site of damage. The

same is true for NSCs transplanted into the brain.

Scientists are now identifying the signals responsible for the activation and growth of stem cells,

the way they home in to damaged areas, and

their ability to make specific kinds of neurons. 

Proteins called growth factors also are

increased in the brain during development and

after injury, and these factors support neurogenesis in the adult brain. One strategy being considered for repairing brain damage from injury or

disease is to identify the optimal combination of

growth factors that can activate an individual’s

own stem cells to repair damaged neurons. Such

strategies could include behavioral modifications,

such as exercise and mental stimulation, and/or

drugs, such as antidepressants, which increase

growth factors and stimulate neurogenesis in the

adult brain. 

The processes at work in diseases such as 

AD and Parkinson’s disease may overwhelm the

brain’s ability for self-repair, however. Alternative

strategies to promote repair may be needed. One

being tried is transplanting neural stem cells to

replace dying cells or to deliver critical nutrients.

One NINDS-funded study showed that embryonic

mouse stem cells that had been coaxed into neurons and then transplanted into a rat model of PD

made functional connections with surrounding

brain cells and reduced disease symptoms (Kim

et al., 2002). Such an approach can be envisioned

for other brain disorders as well. Because stem

cells might integrate effectively with the host tissue following transplantation, these cells might

be genetically engineered to deliver therapeutically important molecules, such as growth factors, to promote brain self-repair processes.

The discovery of neurogenesis and the presence of stem cells in the adult brain have dramatically altered the way scientists think of brain

function and its regenerative ability (Peterson,

2002). Neurogenesis may be a continuous process that maintains brain structure and function

throughout one’s life. Though much basic work

still needs to be done, researchers are hopeful

that effective repair strategies through neurogenesis or through other stem cell therapies can

one day be developed to restore nervous system

functions lost through trauma, disease, or normal

aging. The potential to rebuild a damaged adult

nervous system may be greater than we once

thought possible.

2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 41
42 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

and stroke in elderly adults.

The current phase of the

study is identifying risk 

associations with disease by

determining whether presence or progression of preclinical disease (the time

before a disease is clinically

recognizable) is a better

predictor of disease than

are traditional risk factors.

The study also is identifying

determinants of change 

in preclinical disease and

characteristics of subgroups

at low risk for developing

cardiovascular disease.

■ The Atherosclerosis

Risk in Communities Study,

begun in 1985, measures

associations of coronary

heart disease risk factors with atherosclerosis by race, gender, and geographic

location. It is focused on early detection

of cardiovascular disease before symptoms, heart attacks, or strokes occur. The

project consists of two parts—one studying the entire community and one studying four selected groups.

Highlights of recent findings from

these studies and their add-on components have shed light on the complex

interrelationships among lifestyle, genetic, and environmental factors; vascular

diseases; and dementia:

■ Framingham Heart Study scientists

at the University of Washington found

that abnormal hearing test results under

stressful conditions may suggest an early

manifestation of AD that precedes 

the diagnosis of dementia by many

years (Gates et al., 2002). This add-on

study was co-funded by NIA, NINDS,

and NIDCD. 

■ A Framingham Heart Study add-on 

study co-funded by NHLBI and NIA

found that obese men who were hypertensive were more likely to develop

declines in cognitive function than were

men who were not obese or hypertensive

(Elias et al., 2003). Interestingly, this

association was not found in women.

■ Two studies from the Atherosclerosis

Risk in Communities Study found that

other types of vascular changes were

associated with declining cognitive function in later years. University of North

Carolina investigators found that people

who had increased hypertension measurements over time were more likely to

develop declining cognitive function

than were people without such changes

(Alves de Moraes et al., 2002). Another

University of North Carolina team found
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 43

that middle-aged people with retinopathy, which is a disorder of the retina of

the eye caused by microvascular disease,

were more likely to develop declining

cognitive function than were people

without this disorder (Wong et al., 2002).

As retinal microvascular disease may indicate vascular disease in the brain of that

individual, the investigators suggest

that these results are further proof 

of a link between cerebrovascular 

disease and cognitive decline, AD, 

and perhaps dementia. 

■ Cardiovascular Health Study investigators at the University of Washington

used MRI scans to measure brain

infarcts (a lack of oxygen to the brain

that can lead to tissue damage; also

called “mini-strokes”) in older adults.

This study concluded that the older a

person becomes, the more likely it is

that the brain will have a number of

problems, including “silent” infarcts,

whose effects, such as declines in cognitive function, may ultimately not be 

so silent (Longstreth et al., 2002).

What Can Be Done to Slow 

the Progression of AD or 

Lessen its Effects?

Research described earlier in this

report has vastly increased our understanding of brain function, the transformation from healthy aging to AD, and the

factors that influence the development 

of AD. These findings have opened the

doors to a range of potential therapeutic

approaches. NIA, other NIH Institutes,

other research institutions, and private

industry are conducting studies on dozens

of compounds and strategies to:

■ Help people with AD maintain cognitive function over the short-term;

■ Treat AD-associated behavioral and

neuropsychiatric symptoms; 

■ Slow the progression of the disease;

and

■ Prevent AD.

By late 2003, the FDA had approved

five medications to treat AD symptoms.

Of these, four are known as cholinesterase inhibitors and are prescribed 

to treat mild to moderate AD symptoms.

The first, tacrine (Cognex), has been

replaced by three newer drugs—

donepezil (Aricept), rivastigmine

(Exelon), and galantamine (Reminyl).

These drugs act by stopping or slowing

the action of acetylcholinesterase, an

enzyme that breaks down acetylcholine.

Acetylcholine, a neurotransmitter that 

is critically important in the process 

of forming memories, is used by many

neurons in the hippocampus and cerebral cortex—regions devastated by AD.

These drugs improve some patients’ abilities to carry out activities of daily living;

may improve certain thinking, memory,

or speaking skills; and can help with 

certain behavioral symptoms. However,

these medications will not stop or reverse

AD and appear to help patients only for

months to a few years.

By 2003, five medications had been approved to treat

AD symptoms.
44 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

The fifth medication is memantine

(Namenda), which can be prescribed 

to treat moderate to severe AD symptoms. This drug appears to work by regulating excess glutamate in the brain.

Glutamate is another neurotransmitter

involved in memory function, but high

levels may damage neurons. Like the

cholinesterase inhibitors, memantine

will not stop or reverse AD. Studies 

have shown that memantine may delay

loss of daily functions in patients with

moderate to severe AD (Reisberg et al.,

2003; Tariot et al., 2004).

In addition to these medications,

physicians use a number of drug and

non-drug approaches to treat the behavioral and psychiatric problems that occur

frequently as AD progresses. These 

problems include agitation, verbal and

physical aggression, wandering, depression, sleep disturbances, and delusions.

Two recent analyses of data from two 

separate populations—5,092 older 

residents of Cache County, Utah, and

3,608 participants in the nationallyrepresentative Cardiovascular Health

Study—attest to the prevalence of these

problems. The Johns Hopkins University

investigators who conducted both analyses found that among those in the Utah

population who were diagnosed with 

AD, 60 percent suffered from neuropsychiatric disturbances (Lyketsos et al.,

2001). In the second population, 50 percent of those diagnosed with MCI and 

80 percent of those with dementia had

exhibited at least one neuropsychiatric

symptom since the beginning of their

cognitive decline (Lyketsos et al., 2002). 

One growing focus of work on 

therapies for behavioral and psychiatric

problems deals with depression among

people with AD. NIMH recently gathered

a group of investigators with extensive

research and clinical experience in 

late-life depression and AD to propose

criteria for identifying and managing 

this common problem (Olin et al.,

2002a; Olin et al., 2002b). The experts

identified useful indicators for diagnosing significant depressive symptoms in

people with AD. Based on substantial

research suggesting that the depression

that occurs in AD differs in some

respects from other depressive disorders,

the experts also defined a unique syndrome called Depression of AD. This 

syndrome is often less severe than Major

Depressive Disorder, but it still can have

an important effect on the course of AD.

These criteria, which are currently being

validated, will pave the way for additional

research to understand this syndrome

and its clinical implications. Studies 

are now underway to determine the syndrome’s responsiveness to standard

antidepressant treatment. 

In other NIMH-funded research, a

University of Pittsburgh study team compared the short-term (up to 17 days)

effectiveness of an antidepressant, an

antipsychotic medication, and a placebo

in treating psychotic symptoms and

behavioral disturbances in people with

Physicians use drug and non-drug treatments for the

behavioral and psychiatric problems of AD.
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 45

dementia (Pollock et al., 2002). The

researchers found that the antidepressant was possibly equal to or even better

than standard antipsychotic drugs at

treating psychosis and behavioral disturbances. The antidepressants also had 

a relatively low risk of side effects. 

A recent NINR-funded study of 

450 nursing home residents also examined treatment approaches for behavioral problems in people with dementia.

University of Pennsylvania investigators

found that 61 percent of those in 

the study showed physical and/or

verbal aggression at times (Talerico 

et al., 2002). An impaired ability to communicate, rather than overall cognitive

decline, was associated with all forms of

aggression. This finding led the study

team to propose that if a person is not

able to communicate fully, it is more 

likely that his or her needs may not be

met, and this may be expressed through

aggression. The investigators also found

that physical aggression was associated

with depression, whereas verbal aggression was associated with disorientation. 

It may be that these two forms of aggression may represent separate entities that

may respond to different treatments. The

correlation between physical aggression

and depression also implied that this

form of aggression may be a symptom

of inadequately treated depression. An

evaluation of the medications received 

by study participants suggested both 

that antipsychotic drugs alone were not

enough to effectively decrease aggression

and that antidepressant drug use was

suboptimal. This study’s findings support

the view that individualized mental

health interventions that go beyond

administering drugs or using restraints are

needed to treat aggression in dementia. 

AD Clinical Trials

As this report has shown, AD

research has progressed to a point

where scientists are increasingly able 

to think about how they can intervene

to treat AD or even perhaps to prevent

it. This has led them to consider the

importance of timing—when is it best to

intervene and what interventions are

most appropriate at what time? For

example, a physician would certainly

treat a patient who is having a stroke

differently from a patient who seems

healthy but who has a high risk of 

having a future stroke. AD develops

over the course of years or decades, 

and a person’s brain is affected well

before any symptoms are evident. 

It may be that one kind of intervention

with a particular compound or approach

may be most effective if it is applied well

before any symptoms are evident. Other

interventions may be most appropriate

for use after AD is established. 
Innovative Mechanisms 

for Conducting Research

46 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

NIH has used a number of

promising grant mechanisms 

to foster basic and clinical AD

research: 

■ Small Business Innovation

Research Grants (SBIR) are

designed to establish the value

and feasibility of ideas that provide an important link between

laboratory and clinical work and

possible commercial development. For example, recent projects have explored the feasibility

of isolating the active ingredient

from cat’s claw, a plant whose

extract seems to inhibit betaamyloid formation, examined

potential immunotherapeutics,

and tested compounds from

marine microbes for plaqueinhibiting activity.

■ Pilot trials give investigators funding to conduct smallerscale clinical trials to test drug

responses and generate the data

necessary to apply for funding 

for a full-scale trial. Examples 

of some of the pilot trials that NIA

is funding include a trial of pioglitazone (Actos), a drug used to

treat diabetes, which has antiinflammatory effects; a trial that

includes three anti-inflammatory

drugs, including the antibiotic

dapsone; and a trial of fish oil and

alpha-lipoic acid. Epidemiologic

studies have shown that people

who eat certain types of fish, 

such as salmon, weekly, have a

lower risk of dementia (Morris et

al., 2003).

■ Add-on components to

ongoing clinical trials are an efficient way to conduct research. In

this strategy, a funding agency

adds a cognitive or dementia

component onto an ongoing trial

that may be investigating a different topic. The PREADVISE

trial described on p.50 and the

NHLBI cardiovascular studies

described on p.40 and 42-43 

are good examples of the use of

this funding mechanism for clinical trials and for epidemiology

and long-term (longitudinal)

studies, respectively. 

With this idea in mind, investigators

are working to develop an array of

options from which clinicians can

choose. For example, developing new

and better drugs and broadening the

range of non-drug therapeutic approaches are critically important for those who

already have AD because of the longterm nature of the disease and the high

emotional and physical toll that AD

exacts. Slowing the progress of the disease and alleviating psychiatric and

behavioral problems could do much to

delay or prevent institutionalization,

maintain the dignity of people with 

AD, reduce physical and emotional 

stress on caregivers, and reduce the

financial costs associated with the 

disease. Finding ways to prevent the 

disease altogether is an increasingly

urgent priority because of the enormous current and future impact of 

AD on our society. 

Scientists use clinical trials to reach

this goal. Clinical trials that compare a

potential new strategy with a standard

strategy or with a placebo are the only

way to determine whether a drug, other

compound, or non-drug approach is safe

and effective. Clinical trials also tell

researchers which treatments are more

effective than others. Trials take place at

specialized AD research centers, medical

centers, teaching hospitals, private

research facilities, and doctors’ offices.

These complex and expensive studies

involve hundreds or even thousands of

people and are often conducted over a

long period of time. Because of the cost,

time, and effort involved, only the most
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 47

promising few compounds or treatment

strategies are tested in full-scale clinical

trials. However, funding agencies have

developed several additional mechanisms

for funding clinical trials, including pilot

trials and add-on components (see 

the box on p.46 for more on these 

mechanisms).

Some clinical trials are focused on

treatment strategies—helping people

with AD preserve cognitive function 

for as long as possible, for example, or

helping alleviate behavioral or psychiatric problems associated with AD. 

Other clinical trials are focused on 

prevention strategies—using specific

compounds to help people reduce the

risk of developing AD in the future, 

for example. The sections that follow

provide highlights from a number of

treatment and prevention clinical trials.

Recruitment is ongoing for several 

of these trials. For more information 

about the clinical trials described here

and other trials, visit NIA’s ADEAR 

website at www.alzheimers.org/trials. 

Treatment Trials

NIA is currently supporting 19 clinical trials that are or will be investigating

treatments for people who already have

AD. Here are highlights of just a few of

these trials.

■ Divalproex sodium and agitation.

Two clinical trials of divalproex sodium

(Valproate) are examining its effect on

agitation and psychosis. The first trial,

conducted among 150 nursing home residents, was designed to see whether this

medication could ease agitation among

individuals with severe AD. This study

has ended and results are being analyzed. The second trial has recently

begun and is designed to examine

whether divalproex sodium can delay 

or prevent agitation and psychosis from

developing in individuals with mild to

moderate AD. Researchers are also interested in seeing whether its possible neuroprotective properties have any effect on

slowing the rate of cognitive decline. 

■ Simvastatin and AD progression.

This 18-month trial, which began in

2003, is testing whether simvastatin

(Zocor), a commonly prescribed 

cholesterol-lowering drug, can safely 

For more information about AD clinical trials, 

contact the ADEAR Center at www.alzheimers.org/trials 

or 1-800-438-4380.
48 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

Estrogen is a hormone produced by a woman’s

ovaries during her childbearing years. Over the past

25 years, laboratory and animal studies, as well as

observational studies in women, have suggested

that estrogen has some positive effects on brain

activity. These findings have created scientific interest in the relationship among estrogen, memory, 

and cognitive function.

To test this relationship, researchers conducted

clinical trials of estrogen in postmenopausal women

who already had mild to moderate AD to see

whether the hormone helps. These trials did not find

estrogen beneficial. However, epidemiological and

other studies suggested that even if estrogen did 

not slow the progression of the disease in women

already affected with AD, perhaps menopausal hormone therapy (formerly known as hormone replacement therapy, or HRT) might in some way affect 

age-related cognitive decline or protect a woman

from developing AD. 

Two types of such therapies have been investigated—the use of estrogen alone in women who have

had a hysterectomy, and the use of estrogen plus

progestin in women who still have a uterus. 

In 1992, the NIH began the Women’s Health

Initiative (WHI), a very large study with 27,000 

participants that was designed to evaluate whether

hormonal therapy protected women from heart 

disease, as epidemiologic studies had indicated. 

The WHI included a randomized clinical trial to 

determine the benefits and risks of using

menopausal hormone therapy. 

A substudy of the WHI, called the Women’s Health

Initiative Memory Study (WHIMS) began in 1995.

This substudy was designed to assess whether

menopausal hormone therapy would keep older

women from developing dementia.

In July 2002, the part of the WHI involving estrogen plus progestin treatment was stopped early

when scientists found that women taking this combination were at increased risk for certain health problems, including heart attacks, breast cancer, strokes,

and blood clots (Rossouw et al., 2002). This combination also was beneficial in some ways—fewer hip

fractures and less chance of colorectal cancer. Even

so, the scientists believed the risks were greater than

the benefits. In 2004, scientists stopped the estrogenalone portion of the WHI because of an excess risk 

of stroke and no indications that estrogen would be

helpful for heart disease.

Scientists evaluating WHIMS data reported that, 

in women 65 and older, neither the combination 

of estrogen and progestin nor estrogen alone prevented dementia or slowed its progression over 

time (Espeland et al., 2004; Shumaker et al., 2003;

Shumaker et al., 2004). The older women taking the

estrogen plus progestin were at twice the risk of

developing dementia as those taking a placebo. This

combination also did not prevent general cognitive

decline (Rapp et al., 2003). Results for those taking

estrogen alone were similar. The scientists recommended that women not take menopausal hormone

therapy to prevent dementia or to preserve their

mental abilities.

In view of the risks documented in the WHI and

WHIMS, the NIA stopped a prevention clinical trial

designed to evaluate whether hormone therapy prevents or delays development of AD in cognitively

normal older women who are at increased risk of

AD, because of their family history. These women

will continue to be followed, as will the women in

WHIMS, to evaluate how their years of hormonal

treatment affect their risk of cognitive decline.

Though these recent clinical trials have answered

some questions about estrogen and cognitive function, others remain. Would giving a different estrogen or progestin agent change the result? Would

starting therapy around the age of 50, rather than 

65, be more beneficial or more harmful? The timing

of hormonal therapy is important, for example, in

decreasing osteoporosis risk, with positive effects

most marked if treatment begins as menopause

begins. Evidence that the timing and duration of hormone treatment may be important for dementia risk

comes from an ongoing epidemiologic study being

conducted in Cache Country, Utah (Zandi et al.,

2002b). Researchers from Johns Hopkins University

found that prior use of hormones was associated

with a decreased risk of AD, although use had to

have been longer than 10 years before the onset of

dementia. Use of early hormone treatment for more

than 10 years was associated with a 2.5-fold lower

incidence of dementia. More research is clearly

needed on this complex matter.

Estrogen and Cognitive Function: 

An Update on the Research
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 49

and effectively slow the rate of disease

progression in people with mild to moderate AD. Data from epidemiologic and

animal studies indicate that high cholesterol levels increase the risk of AD, and

that statin drugs specifically may help to

reduce this risk. The trial, which is being

conducted in about 40 sites around the

country, will enroll 400 participants.

Some participants will receive 20 milligrams of simvastatin for 6 weeks and then

40 milligrams of the statin for the rest of

the study period or a placebo for the

entire study. Clinical trial staff will track

changes in participants’ cognitive health

by measuring a number of indicators,

including mental status, functional

ability, behavioral disturbances, and

quality of life.

■ Huperzine A and cognitive function.

This trial is evaluating whether

huperzine A, a natural cholinesterase

inhibitor derived from the Chinese herb,

Huperzia serrata, can slow the progression

of cognitive decline in people with mild

to moderate AD. A number of small, randomized controlled trials in China have

indicated that people with AD who were

treated with huperzine performed better

on memory tests than patients on placebo. Investigators also are interested in

huperzine because it has antioxidant and

neuroprotective properties that suggest it

may be useful in treating AD. The study,

which will enroll 150 participants, is taking place in about 20 sites nationwide.

Participants will be randomly assigned 

to three equal groups—two groups will

receive varying amounts of huperzine A

every day and the third group will

receive a placebo. All participants will

receive huperzine A during the last 

8 weeks of the 24-week trial.

■ Supplements to reduce homocysteine and slow the rate of cognitive

decline. High homocysteine levels 

are associated with increased AD risk

(Seshadri et al., 2002). Levels of this

amino acid can be reduced by high-dose

supplements of folate and vitamins B6 and

B12. This clinical trial, which began in

2003, is designed to determine whether

reduction of homocysteine levels with

high-dose supplements of folate, vitamin

B6, and vitamin B12 will slow the rate of

cognitive decline in older adults with 

AD. Participants in this 18-month clinical

trial are being divided into two groups: 

60 percent of participants will receive

daily high-dose supplements (5 mg of

folate, 25 mg of vitamin B6, 1 mg of 

vitamin B12) and 40 percent will receive 

a placebo. The research team plans to

enroll 400 participants. 

■ The TAP-DAP Study. Some people

with AD also suffer from the symptoms of

PD, such as rigid muscles, difficulty walking, and tremors. Some people with PD

also suffer from dementia and behavioral

problems. This poses a therapeutic

dilemma because the most frequently

used drugs to treat AD behavioral problems, neuroleptic antipsychotics, can

worsen parkinsonian symptoms and, in

some types of dementia, have been associated with severe movement difficulties.

The Treating Agitation/Psychosis in

Dementia/Parkinsonism (TAP-DAP)

study is a clinical trial designed to 

determine the safety and efficacy of 

quetiapine (Seroquel), an antipsychotic

medication, in the treatment of psychosis

and/or agitation. Participants include

those who have dementia and parkinsonian symptoms and those who have 
50 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

PD with dementia and episodes of agitation or psychosis. All participants are on

a stable dose of a cholinesterase inhibitor

and/or memantine. Each will participate

in the trial for 10 weeks, and the

research team will perform systematic

ratings of behavior, motor function, 

cognition, adverse events, and other outcomes at 6 and 10 weeks of treatment. 

Prevention Trials

NIA is currently conducting seven 

AD prevention clinical trials. Several of

these trials are assessing the preventive

potential of drugs and other compounds

that already have been tested as therapeutic agents in people with established

AD. Even when results from these trials

have indicated that the compounds may

not be the most effective treatment strategy, enough laboratory, animal, and epidemiologic evidence exists to suggest

that they may still have a potentially 

useful preventive function. Here are

highlights from a few of these AD 

prevention studies.

■ The Memory Impairment Study.

This 3-year study was designed to compare the effectiveness of vitamin E,

donepezil (Aricept), and placebo in

delaying the onset of AD in people with

MCI. The 769 participants were assigned

to three groups, with each group taking

one of the three compounds. This landmark trial, which took place in 69 sites

around the country and in Canada, represents a major advance in clinical trial

methodology designed to prevent AD

because it defined a new population for

study in clinical trials. Preliminary data

from this just-completed trial showed

that participants who took donepezil

were at reduced risk of progressing to

AD initially, but that the benefit disappeared after 18 months. In those who

progressed to AD, the difference in the

delay to a diagnosis of AD was about 

6 months in the donepezil group as 

compared to the placebo group. 

Vitamin E did not appear to slow the

progression to AD. The investigators 

are conducting additional analyses to

determine why donepezil’s effect

dropped off over time and to assess 

the practical and clinical implications 

of this complex study.

■ NSAIDS and inflammation.

Although a clinical trial showed that 

neither rofecoxib (Vioxx) nor naproxen

(includes drugs such as Aleve, Anaprox,

and Naprosyn) slowed the rate of 

cognitive decline in people with AD, 

a large, multi-center trial, called the

Alzheimer’s Disease Anti-Inflammatory

Prevention Trial (ADAPT), has been

launched to determine whether beginning treatment with NSAIDs earlier 

will prevent or delay the onset of AD 

in people who are cognitively normal

but have a family history of AD. The

approximately 2,400 participants in

this prevention trial will take either

naproxen, celecoxib (Celebrex, a 

COX-2 inhibitor), or a placebo for 

several years. Their cognitive function 

will be assessed regularly.

■ The Prevention of Alzheimer’s

Disease with Vitamin E and Selenium

(PREADVISE) trial. This trial is NIA’s

addition to NCI’s Selenium and Vitamin

E Cancer Prevention Trial (SELECT),

which is evaluating whether taking selenium and/or vitamin E supplements can

prevent prostate cancer in healthy men

older than 60. PREADVISE is evaluating
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 51

whether these agents can help to prevent

memory loss and dementia, such as that

found in AD. Studies show that increased

oxidative stress may damage brain cells

and is linked with AD. Animal and tissue

culture studies of vitamin E and selenium suggest that they can protect brain

cells from oxidative damage (see p.23 for

more on oxidative stress). 

■ Ginkgo biloba. Extracts of leaves

from the ginkgo tree are thought to

have beneficial effects on brain function,

especially those related to dementia and

AD. Evidence to date has pointed 

to a protective effect on neurons, but

the mechanisms of action are still

unknown. Recently, in a trio of studies

supported by the National Center for

Complementary and Alternative

Medicine (NCCAM), investigators at 

the University of Southern Mississippi

found that a standardized ginkgo extract

protects cells from oxidative stress and

programmed cell death (Luo et al., 2002;

Smith et al., 2002; Wu et al., 2002).

Several small clinical studies also have

indicated that ginkgo may be beneficial

in preventing the onset of dementia.

NIA is co-funding NCCAM’s prevention

trial comparing ginkgo to placebo in

more than 3,000 people older than 70

who are cognitively healthy at the beginning of the trial. The study’s results

should indicate whether ginkgo is helpful in preventing or delaying the onset 

of dementia.

Improving Support 

for Caregivers

Although much of NIH’s AD research

effort is focused on the causes, characteristics, diagnosis, and treatment of AD,

the Institutes never lose sight of the

enormous personal and emotional toll

exacted by AD on those with the disease

as well as their families, friends, and caregivers. An “insider’s” view of AD recently

published by an NINR-funded study

team from the University of Texas Health

Science Center highlighted some of

these emotions and concerns (Ostwald 

et al., 2002). In a series of interviews 

with study team members, individuals

with AD talked about the stress associated with losing the ability to think and

converse clearly. They also described the

aggravation of not being able to remember things and the fear of losing control 

over their lives. They expressed sadness,

frustration, and anger about their condition, worry about their families, and 

trepidation about their uncertain future.

The interviews showed that at least some

people with AD are acutely aware of their

cognitive losses and experience a significant amount of stress in their relationships with family and friends as a result.

Studies funded by several Institutes,

including the NIA, NINR, and NIMH,

have consistently found that caring 

for a person with AD is highly stressful

and can contribute to negative physical

and psychological health outcomes.

The Institutes never lose sight of the enormous personal 

and emotional toll exacted by AD.
52 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

Many researchers are exploring these

emotional, psychological, and physical

costs, and are investigating ways to ease

the caregiving burden. One recent focus

of this caregiving research has been 

the varying impact of caregiving on

diverse populations. Researchers from

the University of North Carolina at

Greensboro, for example, have found

that African American caregivers use

fewer formal in-home services and are

more reluctant to place their loved ones

with AD into institutional care settings

than are Caucasian caregivers (DilworthAnderson et al., 2002). This may be due

to a reluctance to use such services or 

to an expansive conceptualization of

family and support networks in African

American culture, as described by a

University of California at San Francisco

researcher (Johnson, 1999). Most of the

information we have about the varying

impact of caregiving on diverse populations comes from work with African

Americans. Clearly, more information is

needed about the impact of caregiving

among various groups of caregivers, 

such as other ethnic populations and

male caregivers.

Findings from a growing body of

research on ways to ease the caregiving

burden are pointing in some similar

directions. For example, investigators

are finding that interventions structured

for individuals are more effective than

are group-based interventions. They’ve

also found that interventions that focus

on a range of services and needs have 

a more significant impact on reducing

caregiving stresses, such as a sense 

of burden, depression, and physical

symptoms, than do “single-target”

interventions. Not surprisingly, regular,

moderate exercise also has been found

to be an important stress reliever for

caregivers. In several studies, investigators from the University of Miami

Medical School and from Stanford

Medical School used telephone and

computer prompts to encourage exercise among older caregiving women.

They found that this strategy reduced

blood pressure increases due to stress,

improved sleep quality, and reduced

psychological distress and depression

(Czaja and Rubert, 2002; King et al.,

2000). There is still much to be learned

about caregiver stress, however. Future

research will focus on developing a better understanding of issues such as the

transitions into and out of a caregiving

role, the interrelationships of coping

strategies and behaviors of caregiver

and care recipient, and the physiological and clinical manifestations of caregiver stress. Researchers also are interested in testing whether interventions
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 53

that work in the short term are successful over longer periods as well, and 

they would like to see whether and 

how knowledge gained about informal

caregiving can be applied to formal

caregiving settings, such as nursing

homes and assisted living facilities. 

A major focus of caregiver research 

at NIH is Resources for Enhancing

Alzheimer’s Caregiving Health (REACH),

a multi-site effort funded by NIA and

NINR. In the first phase, begun in 1995,

REACH funded six universities around

the country to develop interventions to

help family caregivers of people with AD

or related disorders. Each intervention

tested a different home- or communitybased intervention to support family

caregiving. These interventions focused

on a variety of issues, including the use

of advanced communication technology,

the design and management of the care

recipient’s physical environment, and

methods for dealing with problem 

behaviors and other challenges. Detailed

analyses of initial findings suggested that

certain components of these interventions might be particularly effective in

helping caregivers. In 2001, therefore,

REACH II was funded to develop and

test a single multi-component intervention among family caregivers. The overall

objectives of the REACH II intervention

are to reduce depression and burden

among Caucasian, African American,

and Hispanic family caregivers; enhance

the quality of care provided; and

enhance the well-being of caregivers.

Participants in this 6-month trial will be

divided into two equal groups, with one

group receiving an information-only

intervention and the other group the

multi-component REACH intervention,

which includes 10 home visits by trained

staff plus five computer/telephone 

contacts with the staff. These same 

two interventions will be carried out 

in five sites: Birmingham, Alabama;

Memphis, Tennessee; Miami, Florida;

Palo Alto, California; and Philadelphia,

Pennsylvania. Investigators hope that the

outcomes from this REACH intervention will be clinically meaningful enough

so that they can be used to develop guidance materials for use by a wide range of

community service agencies that work

with AD caregivers (Schulz et al., 2002).

More information about this exciting

intervention is available at the REACH

website, at www.edc.gsph.pitt.edu/reach. 

Another important venue for work 

to improve support for AD caregivers

occurs in the 30 NIA-funded Alzheimer’s

Disease Centers (ADCs) around the

country. These state-of-the-art Centers

conduct research, provide investigator

training and patient care, and support

the research process by developing a

number of innovative strategies to

improve participation of diverse populations in AD clinical trials.

Regular, moderate exercise is an important 

stress reliever for caregivers.
San Francisco ■

Dallas ■

Rock ■

■

Birmingham

■

St. Louis

Rochester, MN

■

■ ■

Chicago (2)

Indianapolis

■

■

■

Little

Ann Arbor

Cleveland

Lexington

■

■

Durham

Baltimore

■

■

Pittsburgh

■ Philadelphia

■■ New York (3) ■

■

■

Boston (2)

Phoenix

■ ■

■

■ ■

■

■

■

■ Seattle

Portland

Davis

Stanford

Los Angeles (2)

Irvine

San Diego

54 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

In addition to two Centers that

directly support caregiving-related

research, all ADCs are engaged in 

various aspects of caregiving support

through their education and information transfer activities. Increasing public

knowledge of behavioral and psychological symptoms associated with dementia,

ways to deal with difficult situations, and

manage caregiver burden is a key part of

this effort. Several Centers have teamed

up with local officials and Alzheimer

Association chapters to widen access to

diagnostic services as well as to provide

support groups geared to the needs of

people with AD and their caregivers. A

particular emphasis is reaching out to

groups who are less likely to receive

information because of language barriers, cultural beliefs, or difficulties accessing information or understanding 

written materials. Here are just a few

examples of the innovative ways in which

ADCs are supporting people with AD

and their caregivers.

■ Using Creative Ways to Disseminate

Information.

■ The Arizona ADC recently produced a picture story book (fotonovela)

aimed at helping the children and

NIA-SUPPORTED

ALZHEIMER’S DISEASE CENTERS
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 55

grandchildren of Hispanic immigrants

recognize early signs of AD.

■ The Cleveland ADC pioneered 

the use of theater as an information

medium by producing a one-act drama

called The Eighth Day of the Week, which 

addresses health care and social issues

surrounding dementia in the African

American community. The play has

been performed free in shopping malls

and other public places, and has been

adopted by other ADCs. 

■ The Duke University ADC has 

produced and distributed a brochure

entitled Wait a Minute, which provides

tips for handling situations in which

anger may occur and escalate rapidly.

This easy-to-read brochure fills a gap 

for dementia caregivers who may find

lengthy written materials hard to use. 

■ Many ADCs have expanded their

Internet-based community outreach to

make it even easier for caregivers to get

information, learn about resources, and

obtain support.

■ The Oregon ADC is working with

the Oregon Health Sciences University’s

Biomedical Engineering Department on

a project funded by Intel to investigate

the use of unobtrusive technology in the

home, such as motion sensing devices, to

keep people with AD safe in their homes,

prevent wandering, and alert caregivers

to the whereabouts of their loved ones.

■ Providing Support Groups for People

with AD and Their Caregivers.

■ In collaboration with the New 

York City Chapter of the Alzheimer’s

Association, the Mount Sinai ADC operates five support groups—two groups for

people with mild AD (one in English,

one in Spanish), one group for adult

children of people with dementia, one

for people with moderate to severe AD,

and one for Spanish-speaking caregivers.

■ The New York University ADC provides a comprehensive program of support, education, and information for

family caregivers of people with AD,

from their first contact with the ADC

through all stages of the person’s illness,

whether the person lives at home or in 

a nursing home. 

■ The University of Pennsylvania ADC

collaborates with the Delaware Valley

Alzheimer’s Association chapter to offer

an educational and support group that 

is designed to provide practical information and sharing for people in the early

stages of AD. The group also offers a

concurrent support group for family

members.

■ Conducting Research in Caregiver

Issues.

■ The New York University ADC is

conducting several research projects

aimed at lessening caregiver burden.

One of these studies is investigating

ways to reduce the incidence and magnitude of stress, anxiety, and depression

that adult child caregivers frequently

experience. Participants are educated

about AD and the typical needs, skills,

and limitations of people with moderate AD. Participants are then divided

into two groups, each of which receives 

a different package of services geared 

to helping them relate to their parents

so as to enhance the satisfaction of

both parties and improve or maintain

the functioning of the person with 

AD. The two packages of services will

be compared. A second project is

examining the role of sociocultural 
The success of research efforts to develop

treatments for AD rests on the effective enrollment of individuals with AD as research participants. However, this presents an ethical challenge to researchers because the participants’

cognitive impairments may make them unable

to provide informed consent to enroll. Studies

show that people with mild to moderate AD

have substantial variations in their ability 

to provide informed consent, and a number 

of research teams are investigating this 

important topic. 

A team of scientists at the University of

Pennsylvania has an active research program 

on ethical issues pertaining to participation in

research of people with AD and their caregivers.

Two recent studies have given them an opportunity to examine various aspects of “capacity”

and “competency” in people with AD. “Capacity”

refers to a person’s performance in various

aspects of decision-making, such as understanding information provided, appreciating

that the information applies to him or her,

being able to compare and describe personal

consequences of options, and choosing among

options. “Competency” refers to a judgment

that a person’s capacity is adequate to make 

a decision. These studies also have raised

important questions about the relationship

between people with AD and their caregivers

and the evolving roles of caregivers as the 

disease progresses.

In the first study, the researchers evaluated

the capacity, competency, and reasons for

enrolling in an early phase AD clinical trial of

people with AD and their caregivers (Karlawish

et al., 2002b). Interviews were conducted with

15 older adults with AD, 15 non-demented older

adults who were matched by age and level of

education, and 15 caregivers. Capacity was

measured using the Mini-Mental State

Examination (MMSE), a widely-used method 

to assess cognitive status in adults. The MMSE

helped the researchers assess the participants’

decision-making capacities. Results indicated

that the capacity to understand is a key factor

for study staff to use in determining competency. The researchers also concluded that some

people with mild and moderate AD are competent to consent. Thus, the diagnosis in and of

itself does not mean that a person with AD is

unable to make such a decision. This study also

points out the need for further work to examine

whether the ability of a person to participate in

a conversational exchange can be used to determine competency. These results have implications for the design and conduct of clinical trials, as they suggest that a necessary enrollment

criterion be that potential participants score at 

a certain level on the MMSE, and that this test

be supplemented by an interview that can 

evaluate comprehension.

In the second study, the University of

Pennsylvania team evaluated the relationship

between AD severity and participation in decisions about medical care (Karlawish, et al.,

2002a). Caregivers of 74 older adults with AD

were asked to rate the degree of their relative’s

participation in making decisions about his or

her medical care. Results indicated that, in general, caregivers have a key role in making these

decisions. Not surprisingly, greater caregiver

involvement in decision making was associated

with increasing severity of disease and increasing caregiving burden. Only in very mild stages

of AD does the person with AD have a greater

than 50 percent chance of having either a collaborative or a final role in decision making,

though there is considerable variability in 

decision-making roles even at this stage of 

the disease. In all other stages, the caregiver

makes the final decision. These findings clearly

point out the evolving nature of the caregiving

role and the importance of recognizing the caregiver’s influence on choices about treatment 

and tests. They also suggest the need to investigate more closely how caregivers practice collaborative decision making with their loved 

ones who are able to participate.

Ethics and AD Research: Protecting the 

Rights and Interests of Study Participants

56 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 57

factors, such as ethnicity, acculturation,

education, and income, in a spouse

caregiver’s perception of the initial

symptoms of AD. This project aims to

clarify how perceptions of symptoms

guide the ways in which Hispanic and

non-Hispanic spouse caregivers seek

help for their loved one with AD.

■ The University of Washington 

ADC received a Pioneer Award from the

Alzheimer’s Association for a dementiaspecific training program it developed

for staff of assisted living residences.

This STAR (Staff Training in Assistedliving Residences) program has now

been carried out in 12 residences

around the Seattle area and has 

been described at more than a dozen

national meetings. 

■ Training and Reaching Out to

Physicians.

■ The Oregon ADC provides dementia education for primary care providers,

including physicians. This project aims

to increase awareness of the need for

this type of education for providers and

to offer education on the best ways to

perform assessments and provide AD

care in a primary care practice setting.

■ Through its Clinical Partners

Program and Clinical Dementia 

Rating On-line Training System, the

Washington University ADC has reached

a growing number of rural health care

professionals and provided education

and information on how to assess and

counsel families about dementia.

■ Reaching Out to Diverse Populations.

■ The Stanford University ADC 

provides outreach to various ethnically

diverse groups, including Japanese,

Hispanic, and Chinese communities. 

A key component of this effort is working closely with community-based agencies and health care providers who 

specialize in working with families 

from these groups.

■ Providing information and education to ethnically diverse populations—

in their own languages—also is a 

priority for the University of California

at Irvine ADC. Working with local government agencies and Alzheimer’s

Association chapters, the ADC is able 

to successfully support people with AD,

family members, and caregivers in a

number of communities, including

Koreans, Hispanics, and Chinese.

2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 59

PART 4

Outlook for the Future

As this report demonstrates, research in AD continues to move forward

rapidly, bringing us ever closer to a full

understanding of the causes of this devastating disease and to truly effective prevention and treatment strategies. In the

past several years, the NIA, in partnership

with other NIH Institutes, the Alzheimer’s

Association, the Institute for the Study 

of Aging, and other organizations, has

launched several major initiatives to move

this process along. Updates on five of

these initiatives are provided here, and

they are bringing to life a number of key

themes described in this Progress Report:

■ The importance of learning more

about normal aging and the healthy

brain, in order to understand more fully

what triggers and facilitates the transformation from healthy aging to AD.

■ The need to continue developing

sophisticated and sensitive imaging,

biological, and cognitive assessment

techniques that can help researchers

understand the very early stages and

progression of AD, and that may someday help clinicians track the initiation 

of the disease and more accurately and

rapidly assess response to treatments.

■ The importance of supporting

research to expand our knowledge about

genetic links to AD. 

■ The long-term benefits of building

research infrastructures to promote

sharing and pooling of data, which can

leverage knowledge from a variety of

individual sources into a whole that is

greater than the sum of its parts.

Cognitive and Emotional 

Health Project

There are now about 45 million

Americans over age 60 and 117 million

over age 40. Current evidence indicates

that a large number of these Americans

are at substantial risk of cognitive impairments from many causes as they age.

Much is known and publicized about

maintaining a “healthy heart” but relatively little consensus exists about the

much more complex “healthy brain.”

To jump-start the process of building

such a consensus, the NIA, the NIMH,

and the NINDS partnered to launch the

Cognitive and Emotional Health Project

(the “Healthy Brain” Initiative) in 2001.

The goals of this program are to assess

the current state of knowledge about
60 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

predictors of cognitive and emotional

health with age and to accelerate the

pace of scientific advances in these fields.

The Project has completed a number of

activities that have laid the groundwork

for these efforts. Currently, investigators

are conducting an evaluation of existing

longitudinal and epidemiologic studies

that have assessed cognitive and emotional function. The evaluation will be used

to detail the findings and critically assess

the value of existing data. This exercise

will help Project staff decide whether 

a new, comprehensive study of factors

that can preserve or augment cognitive

and emotional health in adults needs

to be launched, or whether current 

data have yielded enough substantive

findings to warrant a smaller-scale effort

consist-ing of add-on studies to existing 

projects or secondary analyses of existing data. For detailed information about

past and current Cognitive and

Emotional Health Project activities, 

visit http://trans.nih.gov/CEHP/.

Neuroimaging Initiative

NIA also has launched a multi-year

neuroimaging and biomarker initiative

using serial MRI and PET scans to examine how brains change as MCI and AD

progress. The project will follow approximately 200 cognitively normal individuals

for 3 years, 400 people with MCI for 

3 years, and 200 people with early AD 

for 2 years. Using MRI and PET scans 
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 61

at regularly scheduled intervals, investigators hope to learn when and where 

in the brain degeneration occurs as 

memory problems develop. 

Scientists will correlate this imaging

information with clinical, neuropsychological, and biological markers from

blood, cerebrospinal fluid, and urine

samples. Potential markers include levels

of beta-amyloid and tau, indicators of

inflammation, and measures of oxidative

stress. NIA hopes this initiative will help

create rigorous imaging and biomarker

standards that will aid in early diagnosis

and provide the yardstick by which the

success of future drug treatments can 

be measured. This would substantially

increase the pace and decrease the 

cost of developing medications.

This initiative is a partnership among

the NIA, the National Institute of

Biomedical Imaging and Bioengineering,

university investigators, the pharmaceutical and imaging equipment industries,

the FDA, and the Foundation for NIH,

with participation from the Alzheimer’s

Association and the Institute for the

Study of Aging. An important aspect of

this initiative is that the clinical, imaging,

and biological data collected will be

made available to all qualified scientific

investigators for further analysis.

The scans and other data and biological samples for the Neuroimaging

Initiative will be collected at approximately 50 clinical sites based in universities

throughout the country. Funding began

in September 2004, with participant

recruitment scheduled for April 2005.

The sharing of knowledge and resources

among academic, industry, and government institutions, as exemplified by this

initiative, can serve as a model for future

scientific partnerships in facilitating

biomarker and drug development. This

initiative is the most comprehensive

effort to date to find neuroimaging and

other biomarkers for the cognitive

changes associated with MCI and AD.

Genetics Initiative 

In the more than 10 years since 

APOE-4 was identified as a risk factor

gene, scientists have made great progress

in narrowing the search for other risk factor genes that may have links to late-onset

AD. They have drawn significantly closer

to identifying at least four regions of

chromosomes where other risk factor

genes might be. As this research has

intensified, however, it has become

increasingly clear that scientists need

many more samples of genetic material if

they are to continue making progress and

identify the missing risk factor genes.

In early 2002, NIA invited a group 

of leading scientists to plan a new AD

Genetics Initiative that would significantly expand the collection of blood samples from individuals with AD and their

family members. These blood samples

will allow investigators to create and

maintain “immortalized” cell lines—cells

NIA has launched a multi-year neuroimaging

and biomarker initiative. 
62 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

that are continuously regenerated in the

laboratory. These cell lines are crucial 

for the exhaustive DNA analysis studies

needed to identify risk factor genes. 

NIA hopes to gather between 1,000

and 2,000 samples from people with 

AD and their family members, and has

provided supplemental funding to 18

ADCs so they can recruit new individuals

for genetics research and encourage these

individuals to provide blood samples for

the Initiative. With the resources of the

ADEAR Center, NIA is collaborating with

the Alzheimer’s Association to develop

media and community outreach programs to foster participation in the

Initiative among families who have 

two or more living members with 

late-onset AD.

The National Cell Repository for AD

(NCRAD), located at Indiana University,

serves as the centralized repository for 

the Initiative. NCRAD was established 

to provide genetic researchers with cell

lines and/or DNA samples from people

with well-documented family histories of

AD. Since 1989, the Repository has been

banking DNA and cells and building a

database of rare and unique DNA information, family histories, and medical

records. Many researchers working to

identify genetic defects associated with

AD have used genetic material stored in

the Repository. For more information

about NCRAD, visit http://ncrad.iu.edu.

Future plans of the Initiative include

creating a national case-control sample

set, in which the genes of individuals with

AD (cases) will be compared to those 

who have no symptoms of the disease

(controls). Creating such a sample set will

give investigators additional opportunities

Steps in the National

Institute on Aging

Genetics Initiative

Researchers are looking for families with at least 

three members who can donate blood, including:

■ Two siblings (brothers or sisters) who developed

AD after age 60, and

■ Another family member over 50 who may have

memory loss or a family member over 60 who

does not have any memory loss.

Participants can live anywhere in the U.S. and 

can be of any racial or ethnic background.

Who Can Participate?

Identify families

▼

Obtain family member informed consent

▼

Conduct interviews and draw blood samples

▼

Send coded data and samples to NCRAD

▼

Distribute coded samples and data to geneticists

▼

Conduct research to find genes

▼

Share research data with other scientists
to evaluate potential candidates for risk

factor genes for late-onset AD. Finding

the missing risk factor genes for lateonset AD will give us important additional clues about pathways leading to AD. It

also will help identify more accurately

persons at high risk of developing AD

and aid in individual counseling and in

initiating prevention strategies, when

they are known. In addition, knowing the

risk factor genes will help in recruiting

susceptible individuals into clinical trials,

which would reduce the number of participants necessary and the cost and complexity of the trials.

Prevention Instrument Project

Through the Alzheimer’s Disease

Cooperative Study clinical trials consortium, another NIA initiative is focused

on a critical “nuts and bolts” aspect of

prevention clinical trials—developing

sensitive and more effective methods 

for evaluating change over time in cognitively healthy elderly. Investigators

involved in this project are focused on

designing, developing, and testing questionnaires and other instruments that

can be used to test individuals in a number of areas, such as overall cognitive

functioning, memory, ability to carry

out activities of daily life, and quality of

life. This study will compare the results

of evaluation instruments filled out by

participants at home versus those done

in the clinic to determine whether the

home evaluations are equivalent to 

the clinic evaluations. If they are, then

this approach could potentially reduce

the cost of prevention trials and also 

the burden on participants.

National Alzheimer’s

Coordinating Center

As research on AD and other neurodegenerative diseases has evolved, it has

become increasingly clear that AD is

genetically heterogeneous. At the same

time, researchers have gradually come 

to appreciate that the dementias of 

aging are a family of diseases with a 

variety of overlapping clinical and pathological characteristics. For example, 

vascular dementia, Lewy body disease,

hippocampal sclerosis, Parkinson’s

dementia, frontotemporal dementia, and

other less common neurodegenerative

diseases can, to a greater or lesser

degree, mimic the symptoms and 

pathology of AD. 

During the late 1990s, the NIA and

ADC directors decided to develop a

mechanism whereby data on patients

from all of the ADCs could be pooled

and shared. In 1999, following 2 years of

funding for an interim data coordinating

center, NIA awarded a grant to the

2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 63

The dementias of aging are a family

of diseases with a variety of overlapping clinical and 

pathological characteristics.
64 2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE

University of Washington in Seattle to

establish the National Alzheimer’s

Coordinating Center (NACC). Since

then, the NACC has made major

progress in setting up operating 

systems and data collection and 

sharing policies, funding a number of

cooperative studies, and making data

available to researchers through the

NACC website. Having this pooled data

resource also has catalyzed efforts to

standardize data collection procedures

across the ADCs to facilitate complex

analyses of data from multiple sites. 

For more information about the NACC,

visit www.alz.washington.edu. 

Benefits of the NACC are already

evident. For example, access to larger

datasets is beginning to allow investigators

to characterize rarer neurodegenerative

diseases and identify genetic and ethnic

differences. This would not be possible

with the smaller numbers of study 

participants available from individual

centers. Studies also are in progress on

normal aging using cognitively healthy

volunteers followed by each ADC and

also on the transition from normal aging

to MCI to AD. During 2002, NACC funded three new collaborative projects. The

first project, led by a research team 

at the University of Texas Southwestern
2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 65

and conducted at seven ADCs, will collaborate with an ongoing NIA-funded

statin clinical trial. In this study, older

adults with AD will take simvastatin (a

cholesterol-lowering statin drug) or a

placebo for 18 months. The investigators

will compare changes in levels of APP 

in blood and cognitive changes in 

the two groups to determine potential

beneficial effects from the statin. In the

second project, investigators from the

University of California at Los Angeles

ADC will collaborate with investigators

from two other ADCs to systematically

examine after-death tissue samples from

multiple brain regions and perform

simultaneous quantitative analyses using a variety of probes

and immunoreagents. The investigators hope that this method

will help them define brain

abnormalities that may contribute to cognitive impairment.

In the third project, researchers

from the University of Pittsburgh

ADC and from four other ADCs

will conduct genome scans of a

group of individuals with lateonset AD who also suffer from

psychotic symptoms. About half

of those with AD suffer from

these symptoms, and this combination is associated with more

rapid cognitive and functional deterioration. The investigators hope that these

genome scans will reveal chromosomal

regions that might contain genes that 

are linked to this form of AD. 

The future builds upon the events 

and experience of the past and present.

That’s certainly true for AD research. 

The explosion of knowledge that has

occurred during the past 25 years—and

that continues today—has set the stage

for a hopeful future in which, one day,

we may be able to cure or even prevent

this terrible disease, which robs our

loved ones of their most precious 

faculty—their minds.

The explosion of knowledge that has occurred 

during the past 25 years—and that continues today—has set

the stage for a hopeful future.

2003 PROGRESS REPORT ON ALZHEIMER ’ S DISEASE 67

PART 5

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Credits

Writer

Anne Brown Rodgers

Medical Illustrator

Christy Krames, MA, CMI

Pages 6, 9, 22

Animation Frames

Stacy Jannis and Rebekah Fredenburg

Page 8, Figures 1-3

Editors

Patricia D. Lynch and Karen M. Pocinki

Office of Communications and Public Liaison

National Institute on Aging

Design

Kristin Deuel Duffy, Jeffrey Dever

Dever Designs

Project Coordinator

David M. Burton

Johnson, Bassin & Shaw Inc.

Special thanks to:

The staff of the Neuroscience and

Neuropsychology of Aging Program, and the

staff of the Intramural Research Program of the

Gerontology Research Center, National

Institute on Aging

Photography 

Cover, left; back cover, bottom right – Creatas

Cover, right; inside front cover, right; inside

back cover, right; back cover, top right; pages i,

26 – courtesy of Dr. David Teplow, Harvard

Medical School

Back cover, left; pages iv, 4, 11, 12, 20, 39, 47,

52, 64 – Marty Katz

Inside front cover, bottom left; page ii, top left

– Digital Vision

Inside back cover, left; pages 24, 35, 42, 66 –

PhotoDisc

Pages ii-iii, center; page 35 – Stockbyte

Inside front cover, top left; pages 2, 16, 45, 62 –

Rick Brady

Page 14 – Max Hirshfeld

Page 29 – Courtesy of Dr. Carol Barnes,

University of Arizona

Page 33 – image100

Page 35 – Brand X Pictures

Page 58 – Digital Vision

Page 60 – Corbis

Page 65 – Comstock

For more information about the 

National Institute on Aging please 

visit www.nia.nih.gov
For additional copies of this report or 

further information about Alzheimer’s 

disease, please contact:

Alzheimer’s Disease Education 

and Referral (ADEAR) Center

P.O. Box 8250

Silver Spring, Maryland 20907-8250

Phone: 1- 800- 438- 4380

Fax: 301- 495-3334

e-mail: adear@alzheimers.org

Web: www.alzheimers.org
U.S. Department of Health and Human Services

National Institutes of Health

National Institute on Aging

NIH Publication Number: 04-5570

October 2004