National Institute on Aging

National Institutes of Health

Alzheimer’s Disease

Progress Report

2001-2002
The National Institute on Aging (NIA), part

of the Federal Government’s National

Institutes of Health (NIH), has primary

responsibility for research aimed at finding

ways to prevent, treat, and cure Alzheimer’s

disease (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 2001-

2002 Progress Report on Alzheimer’s Disease

summarizes recent AD research conducted or

supported by NIA and other components of

NIH, including:

● National Institute of Neurological 

Disorders and Stroke (pages 21, 27)

● National Institute of Mental Health 

(pages 10, 12, 15, 21, 30, 31, 39, 40)

● National Center for Research Resources

(pages 11, 29, 38)

● National Human Genome Research 

Institute (pages 30, 31)

● National Institute of Environmental 

Health Sciences (pages 16, 19)

● National Institute of Child Health and 

Human Development (pages 21, 26)

Modest AD research efforts also are supported

by the National Cancer Institute, National

Institute of Nursing Research, National

Institute of Arthritis and Musculoskeletal and

Skin Diseases, National Institute on Alcohol

Abuse and Alcoholism, National Institute 

on Deafness and Other Communication

Disorders, National Center for Complementary

and Alternative Medicine, National Center

on Minority Health and Health Disparities,

and the John E. Fogarty International Center. 
Table of Contents

Part1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2

The Impact of Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2

Alzheimer’s Disease: An Urgent National Health and Research Priority . . . . . . . . . . . . . . . . . .5

Part2 2001-2002 Research Advances: 

Opening Doors to New Discoveries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

What Causes the Transformation from Healthy Aging to Alzheimer’s Disease? . . . . . . . . . . . . .6

Mild Cognitive Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8

Neuropsychology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9

Neuroimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

Biological Markers and Oxidative Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14

Beta-Amyloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

Can Certain Factors Increase the Risk of or Protect Against AD? . . . . . . . . . . . . . . . . . . . . . .23

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24

Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26

Lifestyle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31

Cholesterol and Homocysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34

What Can Be Done to Halt AD, Slow Its Progress, or Lessen its Effects? . . . . . . . . . . . . . . . .36

Research to Help Families and Caregivers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .40

Part3 Outlook for the Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45
2 2001-2002 Progress Report on Alzheimer’s Disease

Part1

Introduction

lzheimer’s disease (AD) is an agerelated and irreversible brain 

disorder that develops gradually 

and results in memory loss, behavior and

personality changes, and a decline in thinking abilities. These losses are related to the

breakdown of the connections between

nerve cells in the brain and the eventual

death of many of these cells. 

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 

Alzheimer’s Disease

D 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 up to 4 million people currently

have the disease, and the prevalence (the

number of people with the disease at any one

time) doubles every 5 years beyond age 65. 

These numbers are significant now and will

become even more so in the future because

of dramatic increases in life expectancies

since the turn of the century. Furthermore,

the group over 85 – the group with the highest risk of AD – is the fastest growing group

in the population. Researchers estimate that

by 2050, 14 million Americans will have

Alzheimer’s disease if current population

trends continue and no preventive treatments become available (Hebert et al.,

2001).

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 AD patients are

estimated to be as much as $100 billion

(Ernst and Hay, 1994; Ernst et al., 1997;

Huang et al., 1988).

A

A

4 2001-2002 Progress Report on Alzheimer’s Disease

GIVEN OUR AGING POPULATION, THE 

MAGNITUDE OF AD AS A NATIONAL HEALTH 

PROBLEM IS STEADILY INCREASING.
Alzheimer’s Disease:

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 reduce the number of people with the disease. This in turn would ease

the personal and financial costs associated

with caring for them. 

AD research supported by the Federal

Government is divided into three broad, 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

element of scientific efforts to discover what

causes AD.

Many researchers also are looking for better

ways to diagnose AD in the early stages and to

identify the earliest brain changes that eventually result in AD. Investigators are striving to

identify markers of dementia, improve ways to

test patient function, determine causes and

assess risk factors, and improve case-finding

and sampling methods for population studies.

Other researchers are working hard to discover and develop drugs that may help treat

symptoms or slow the progress of the disease,

and eventually delay the onset of and prevent

AD. Many of these drugs are now being tested

in clinical trials. Finally, scientists and many

health care professionals are seeking better

ways to help patients and caregivers cope with

the decline in mental and physical abilities

and the problem behaviors that accompany

the disease and to support those who care for

people with AD. 

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 National Institute on Aging

(NIA) has recently revised and updated its

booklet Alzheimer’s Disease: Unraveling the

Mystery, which uses illustrations and text to

explain Alzheimer’s disease. Designed for a lay

audience, Unraveling also describes ongoing

research in the cause, diagnosis, and treatment

of AD and in ways to support caregivers of

people with AD. This booklet is available

from NIA’s Alzheimer’s Disease Education 

and Referral (ADEAR) Center

(www.alzheimers.org or 1-800-438-4380). The

ADEAR Center provides a variety of information materials on AD, including booklets on

caregiving, fact sheets, and reports on research

findings (many of which were developed by

NIA-funded investigators). ADEAR also

maintains a database of AD clinical trials and

studies, develops recommended reading lists,

and provides referrals to local AD resources. 

2001-2002 Progress Report on Alzheimer’s Disease 5
6 2001-2002 Progress Report on Alzheimer’s Disease

Part2

2001-2002 Research 

Advances: Opening Doors 

to New Discoveries

During the last year, scientists supported by NIA and other NIH Institutes made advances

in a number of areas important to Alzheimer’s disease. This report focuses on new

research that is attempting to answer three key questions:

● What happens in the brain to cause the transformation from healthy aging to Alzheimer’s disease?

● 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 get to the heart of this complex disease – what happens during the very first steps of the disease process, what might we be able to do to prevent AD,

and what can be done once the disease takes hold. They can be asked only because of the knowledge that has accumulated through research over the last 25 years. The answers are slowly emerging, and they hold the key to future prevention, treatment, and caregiving strategies.

What Causes the

Transformation from

Healthy Aging to

Alzheimer’s Disease?

s a person gets older, changes occur 

in all parts of the body, including 

the brain:

● Some neurons shrink, especially large ones

in areas important to learning, memory, planning, and other complex mental activities.

In certain brain regions, chemical and electrical changes occur in neurons and their connections to lower their efficiency and ability

to communicate with other cells. These

changes may make neurons more vulnerable

to damage.

● Neurofibrillary tangles develop in neurons

and beta-amyloid plaques develop in surrounding areas, though in much smaller numbers than in AD. 

● Damage by free radicals increases (a free

radical is a kind of molecule that reacts easily

with other molecules; too many of these molecules can damage neurons).

● Inflammation (the complex process that

occurs when the body responds to an injury

or abnormal situation) also increases.

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8 2001-2002 Progress Report on Alzheimer’s Disease

Many investigators are now focused on

understanding more fully these changes in normal aging and their effects on memory and

thinking. For example, scientists have examined whether older adults differ from younger

adults in the types of information they use to

make decisions and their actual decisionmaking processes. NIA intramural scientists

found that older adults’ memory and decision

accuracy improved when they perceived the

task to be personally relevant or when they

were held accountable for their performance

(Hess et al., 2001). Other studies comparing

the performance of older and younger adults

on memory tasks also showed that when older

adults were given materials that engaged their

emotional interest, their performance on memory tests equaled that of young adults (Rahhal

et al., 2001). Other work shows that older

adults perform better on most memory tasks at

their optimal time of day. This time is determined by a biological clock that appears to

shift toward the morning as a person ages

(West et al., 2002). These results further reinforce the growing understanding that many

factors besides age influence memory and

cognitive ability. 

By identifying the changes that occur in normal aging, investigators hope to be able to

understand the transformation from healthy

aging to Alzheimer’s disease. In addition,

learning more about the very earliest stages of

the disease process may open doors to treatments that may delay the onset of the disease

or prevent its progression. In the past year,

scientists have examined this early stage from

several perspectives: mild cognitive impairment, biological markers and oxidative stress,

and beta-amyloid.

Mild Cognitive Impairment

As they get older, some people 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 personality

changes or difficulties in making decisions

experienced by those with AD. These people

are thought to have mild cognitive impairment

(MCI) with memory loss. In certain studies,

about 40 percent of these individuals develop

AD within 3 years. Other people with MCI,

however, have not progressed to AD, even

after 8 years.

Some scientists think MCI with memory loss

is often a very early stage of AD. One recent

study provided some support for this notion

(Morris et al., 2001). In this study, researchers

at the Washington University School of

Medicine in St. Louis, Missouri, examined

404 people who had either mild memory loss

AS THEY GET OLDER, SOME PEOPLE DEVELOP 

MEMORY PROBLEMS GREATER THAN 

THOSE EXPECTED FOR THEIR AGE.
(classified as MCI) or no memory problems.

These participants agreed to have annual

memory assessments, and 42 agreed to donate

their brains to the study after death. The 227

people with MCI were placed into one of three

categories that reflected the researchers’ degree

of confidence that the subtle signs of memory

loss might indicate the onset of AD. The categories were: “fairly confident” of dementia,

“suspicious” of dementia, and “uncertain” of

dementia. The volunteers were reassessed

annually for up to 91⁄2 years. After 5 years, AD

symptoms had developed in 7 percent of the

healthy volunteers, 20 percent of the individuals in the “uncertain” group, 36 percent of

those in the “suspicious” group, and 60 percent

of those in the “fairly confident” group. By 91⁄2

years, all the volunteers with the most severe

form of MCI had developed the clinical symptoms of AD. In studying the donated brain tissue of those who died, investigators also found

that 21 of the 25 volunteers who originally

were diagnosed with MCI had damage to

brain tissue that was characteristic of AD.

The investigators

interpreted these

findings to mean

that MCI is an

early stage of AD. 

It must be noted

that most of the

participants in the

MCI studies done

thus far have been

recruited from

clinics that specialize in memory

problems. The

diagnosis of MCI

in general populations may be less

predictive of the

development of AD. However, because it

appears that many more of those with MCI

develop AD than do cognitively healthy individuals, many scientists are intensely interested in this clinical state, and they are studying

it using a number of approaches.

Neuropsychology

Several research teams have hypothesized that

performance on specific cognitive tests might

predict whether an individual will develop

AD. For example, in one recent study, Boston

University investigators gave 1,076 participants in the ongoing Framingham Heart Study

a series of cognitive tests every 2 years for up

to 22 years (Elias et al., 2000). At the time of

the first tests, participants were at least 65

years old. None had had a stroke or dementia.

The investigators found that lower scores in a

number of areas – learning new things, recall,

retention, and abstract reasoning – obtained

during any time period that a participant did

not have dementia were associated with the

2001-2002 Progress Report on Alzheimer’s Disease 9
10 2001-2002 Progress Report on Alzheimer’s Disease

later development of AD. The study team also

found that a detectable lowering of cognitive

functioning preceded the appearance of AD by

many years. Changes in abstract reasoning

ability and capacity to retain verbal information were the strongest predictors of AD when

there was a long interval between the initial

assessment and development of AD. 

A smaller study of cognitively normal elders

and people with mild memory difficulty, conducted by investigators at Massachusetts

General Hospital and Harvard Medical

School, also showed that neuropsychological

tests can predict the development of AD to

some extent (Albert et al., 2001). Of the 20

neuropsychological measures used in the initial

tests given in this study, four were useful in discriminating those who converted to a diagnosis of probable AD from those who did not.

Tests of memory and executive functions (such

as the ability to reason and make decisions)

had the most power to discriminate between

those who were likely to develop AD and

those who were not. 

Although scientists know that a majority of

people with dementia experience neuropsychiatric symptoms, such as depression, apathy, and

irritability, it has not been clear whether those

with MCI also suffer the same symptoms.

Depression and other neuropsychiatric symptoms are a major source of added disability for

patients and caregivers and contribute to the

costs of care. Johns Hopkins University

researchers supported by the National Institute

of Mental Health (NIMH) and the NIA analyzed more than 10 years’ worth of data from

the Cardiovascular Health Study (CHS)

Cognition Study, which was designed to evaluate the prevalence of neuropsychiatric symptoms

in dementia and MCI (Lyketsos et al., 2002). 

A total of 824 study participants completed the

Neuropsychiatric Inventory (NPI), a state-ofthe-art rating of neuropsychiatric symptoms

in dementia. Of these, 362 were classified

with dementia and 320 with MCI. Fortythree percent of MCI participants exhibited

neuropsychiatric symptoms in the previous

month, with depression, apathy, and irritability

being most common. These are the first population-based estimates for neuropsychiatric

symptoms in MCI, indicating a high prevalence associated with this condition. The

research team concluded that these types of

symptoms should be asked about and treated as

necessary, and called for further studies of possible treatments. Study of the causes of neuropsychiatric symptoms will not only help those

with dementia and MCI, but will also improve

our understanding of brain-behavior relationships and the development of neurodegenerative

diseases like AD.

Based on the results of these and similar

neuropsychological studies, the Quality

Standards Subcommittee of the American

Academy of Neurology has developed clinical

practice guidelines for clinicians who work

with patients with memory complaints

(Petersen et al., 2001). The guidelines recommend that clinicians use general cognitive

screening instruments, such as the MiniMental State Examination, and neuropsychological tests to evaluate and monitor patients

with MCI. These tests may help clinicians

assess the degree of cognitive impairment and

help them detect signs that might indicate the

development of dementia. In addition, the

Subcommittee suggested that clinicians consider using structured interviews of caregivers

or relatives when screening patients for cognitive impairment. The investigators also recommended a number of avenues for future

research, including better definition of the
course of cognitive function in normal aging,

and studies to identify which screening instruments might be most practical and useful in

busy clinical practices.

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 those people who

are at risk of AD before they develop the

symptoms of the disease. Over the past year,

results from a number of promising longitudinal neuroimaging studies have been published.

These studies have expanded our understanding of the potential usefulness of imaging techniques for research and diagnostic purposes as

well as increased our knowledge about early

AD changes in the brain. 

For example, it is well known that the hippocampus, a region of the brain important for

learning and short-term memory, is affected

early in the course of AD. Using a series of

MRI scans, researchers at the Mayo Clinic

documented for the first time the rate of hippocampal atrophy (shrinkage resulting in loss

of function) in patients with MCI (Jack et al.,

2000). In this study, the investigators grouped

participants into those who were cognitively

healthy, those who had MCI, and those who

had probable AD. Each participant had an

MRI at the beginning of the study and another

one later during the course of the study. The

percent change in hippocampal volume was

measured for each participant. Within the

cognitively healthy and MCI groups, those

who declined clinically over time had a significantly greater volume loss than those who

remained clinically stable. These results 

correlated the rate of change in hippocampal

volume and change in cognitive status. The

data also suggest that it should be possible to

distinguish stable from declining members of a

group, both in persons showing early symptoms

and in those who have not yet shown symptoms. The research team concluded from this

study that serial hippocampal volume measurements may be a useful tool to monitor the

efficacy of therapeutic interventions in clinical

trials for both progression and prevention of

AD, and that they may also be a way to identify

people with MCI who will not progress to AD.

Neuropathological studies have shown that

neurons die in the entorhinal cortex (EC),

another brain region involved in memory

function, even earlier than in the hippocampus (Kordower et al., 2001; Price et al., 2001).

Several studies using MRI have shown that

2001-2002 Progress Report on Alzheimer’s Disease 11

Improvements in the Not-So-Simple Matter

of Identifying Brain Structures

As particular areas of the brain are especially affected

by AD atrophy over time, neuroimaging studies of

brain volume are becoming an increasingly important

research tool. In these brain volume studies, a trained

anatomist or technician manually outlines brain structures shown on an MRI scan. This procedure is

tedious and time-consuming. National Center for

Research Resources (NCRR)-supported scientists at

the Massachusetts General Hospital have now developed an automated procedure that is as accurate as

the manual procedure and takes about 30 minutes on

computer workstations. This improved technique

enables scientists to process thousands of images per

day (Fischl et al., 2002).
12 2001-2002 Progress Report on Alzheimer’s Disease

patients with AD and MCI also have reduced

EC volumes as compared with cognitively

normal older adults. Some researchers have

found that changes in EC volume are better

than hippocampal volume for distinguishing

individuals with AD from those with MCI

(Du et al., 2001). Others have found that

conversion to dementia from MCI is better

predicted by volume of the EC, as opposed to

the hippocampus (Dickerson et al., 2001).

Further study of the time course of change in

the hippocampus, EC, and other structures

will help delineate which brain regions are

best for diagnosing AD early and following its

progression.

A research team from the New York

University School of Medicine has recently

published the first longitudinal PET imaging

study of cognitively healthy elderly declining

to MCI (deLeon et al., 2001). Unlike MRI,

which uses powerful electromagnets to create

the signals that are converted by computers

into detailed images, PET scanning uses shortlived radio-labeled water or glucose to measure

blood flow and glucose metabolism throughout

the brain. The investigators in this study

found that decreased glucose metabolism in

the EC at baseline was the most accurate 

predictor of conversion from normal cognition

to MCI. That is, changes in the EC were seen

before cognitive decline and before changes

in metabolism in other parts of the brain.

Reduced glucose metabolism in the EC accurately predicted declining cognitive function

in 83 percent of study participants who got

worse, and accurately predicted non-decline in

85 percent of participants who remained cognitively healthy after 3 years. At the followup PET evaluation in those who had progressed to MCI, reduced glucose metabolism

was also seen in the hippocampus and temporal neocortex, a development also seen in AD.

In addition, those who experienced cognitive

decline and were carriers of the APOE-ε4

allele (a genetic risk factor for AD) showed

especially marked reductions over time in glucose metabolism in the temporal neocortex

(see p. 26 for more on genetics and AD). This

finding is consistent with earlier reports by

other investigators that showed reductions in

temporal cortex metabolism of APOE-ε4 carriers compared to persons without APOE-ε4.

In another study, supported by the NIMH,

NIA, and other funders, Arizona State

University researchers also investigated the

potential of using PET in longitudinal studies.

PET Scan of Normal Brain PET Scan of Alzheimer’s Disease Brain
2001-2002 Progress Report on Alzheimer’s Disease 13

Magnetic resonance imaging (MRI) is a technique used

to image internal structures of the body. Images are

very clear and are particularly good for soft tissue, brain

and spinal cord, joints, and the abdomen.

Functional magnetic resonance imaging (fMRI) is a

variant of MRI that measures changes in the oxygenation

level of the blood. This level depends on blood flow and

is correlated with changes in the activity of nerve cells.

Since its development in the early 1990s, nearly all

studies using fMRI have focused on the changes in

blood flow that occur while a person is performing an

“activation” task, such as taking a memory test or looking at pictures. This presents a difficulty, however.

Because individuals must perform an activation task,

patients with moderate to severe dementia, who cannot

understand the experimental instructions, cannot be

scanned. Activation tasks also cannot be performed in

small animals because they must be anesthetized to

prevent them from moving while the scan is being

conducted.

fMRI also has another important limitation: The

images generated have a spatial resolution of a few millimeters, which is insufficient for evaluating many small

brain structures such as the subregions of the hippocampus. The cells of the hippocampal subregions

have unique patterns of gene expression that are reflected in their electrical properties and chemical profiles.

These differences may account for the fact that cells of

the different subregions are selectively vulnerable to different pathological processes. Thus, evaluating the hippocampus globally does not do full justice to its cellular

complexity.

To overcome these limitations and enhance the resolution of the images, investigators needed a highly sensitive approach that was applicable to both mice and

humans and that was based on fMRIs taken while the

person or animal was not being asked to do anything.

Because most causes of brain dysfunction produce

changes not only in the active but also in the resting

function of neurons, investigators reasoned that signals

that could be obtained at rest might also indicate brain

damage.

Investigators from Columbia University are in the

process of developing such a method (Small et al., 2000).

Using this technique, the investigators found that signals

from the hippocampus were significantly lower in elderly

people with memory decline than in cognitively healthy

elderly individuals. They also found that different people

showed dysfunction in different subregions of the hippocampus. Among healthy elders, signal intensity from

one subregion called the subiculum was correlated

selectively with memory performance. In tests with

mice, the investigators found that the fMRI signal was

sensitive enough to detect functional changes in hippocampal neurons even in the absence of underlying

anatomical changes in animals with memory deficits.

The new techniques introduced in this study are

beginning to make it possible for researchers to conduct

subregional analyses of the hippocampus, which eventually might allow precise mapping of existing dysfunction

and a greatly enriched understanding of the earliest

changes in the Alzheimer’s disease process.

Using Neuroimaging Techniques to See Deep Inside the Brain

MRI Scan Showing Atrophy (Wasting) due to AD
14 2001-2002 Progress Report on Alzheimer’s Disease

In this study, the research team used PET to

track changes in brain activity that precede

the onset of memory and thinking problems

in a group of individuals of late middle-age

(Reiman et al., 2001). The group was divided

into those who were APOE-ε4 carriers and

those who were not. The scientists found that

the cognitively normal APOE-ε4 carriers had

significant declines in regional brain activity

over a 2-year period, and that these declines

were significantly greater than those found in

non-APOE-ε4 carriers. Findings from this

study suggest that PET could be a useful future

tool to test, in a relatively small number of

people (APOE-ε4 carriers), the potential of

AD prevention and treatment strategies that

might benefit many thousands. 

It is important to note that using PET to

identify persons at risk of developing MCI and

AD is still at the experimental stage, and a

number of longitudinal studies will need to be

completed and analyzed before its potential

can be usefully evaluated.

Biological Markers and

Oxidative Stress

Scientists are also trying to discover whether

biological markers exist that could indicate

early changes in the brain associated with AD.

Understanding more about these markers –

what they are, how they function, and how

and when their levels change – will help

investigators answer questions about the cause

and development of AD and may lead one day

to 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 pathogenesis of neurodegenerative 

disorders such as Alzheimer’s, Parkinson’s, and

Huntington’s diseases and amyotrophic lateral

sclerosis. In the AD brain, in particular, such

Oxidative Damage from Free Radicals

Free Radicals

Mitochondrion

Phospholipid

Cell Membrane

Protein
damage has been observed, especially in the

late stages, when both beta-amyloid plaques

and neurofibrillary tangles (the two main neuropathological features of AD) are present.

However, scientists do not know whether the

oxidative stress causes or results from the

process of beta-amyloid plaque formation. 

A number of markers of oxidative stress have

been measured in the cerebrospinal fluid

(CSF) of people with AD, but for most of

these markers, the amounts found in those

with AD and in cognitively healthy individuals overlap substantially. 

Scientists have suggested that the extent to

which lipids in the central nervous system

have been affected by free radical oxidative

stress can be assessed by measuring body levels

of a newly described class of lipids – the isoprostanes (iP). Isoprostanes are formed by the

addition of oxygen to particular lipids. In a

new study, researchers at the University of

Pennsylvania School of Medicine worked with

transgenic mice (mice that have been specially

bred to develop beta-amyloid plaques in the

brain) to see whether iP accumulation might

be a useful biomarker of plaque pathology

(Praticò et al., 2001). Over 14 months, these

investigators compared the amount of a particular iP in urine, blood, CSF, and brain from

transgenic mice and a control group of mice at

different ages. Results showed that after the

age of 6 months, the amounts of iP in the two

groups began to diverge, and differences in all

the fluids and tissues increased in parallel with

age. The levels of iP began to increase just

before a surge in beta-amyloid levels in the

transgenic mice and well before the appearance of amyloid plaques at 8-12 months. High

iP levels in the transgenic mice were observed

only in the cortex and hippocampus, brain

regions that are heavily affected by plaque

accumulation. Results from this study suggest

that oxidative stress in the brains of these

transgenic mice is a very early event, occurring

just before the rise in amyloid peptide levels

and before amyloid plaque deposition.

Because iP is chemically stable and can be

measured in plasma, urine, or CSF, it may have

utility as a diagnostic tool and to monitor

development of pathology in AD or other neurodegenerative diseases in which oxidative stress

has been implicated. 

Cornell University investigators supported

by NIMH also used CSF to hunt for biological

markers of AD. These researchers used stateof-the-art protein analysis tools to identify

changes in the composition of CSF that correlate with Alzheimer’s disease (Choe et al.,

2002). Using this approach, the investigators

identified a panel of nine proteins that demonstrate altered expression in patients with

Alzheimer’s disease. When taken together,

these proteins suggest the clinical state of

Alzheimer’s disease. This study is one of the

2001-2002 Progress Report on Alzheimer’s Disease 15

OXIDATIVE STRESS MAY PLAY A 

ROLE IN THE PATHOGENESIS OF 

NEURODEGENERATIVE DISORDERS. 
16 2001-2002 Progress Report on Alzheimer’s Disease

first to use a multiple-marker assay for the

presence of Alzheimer’s disease based on

changes in CSF composition. In the future, a

biomarker assay like this may help to improve

the accuracy of AD diagnosis.

A study from a research team at the

University of Kentucky Sanders-Brown Center

on Aging examined the possibility that a

marker of oxidative stress in DNA may identify persons with neurodegenerative disorders

such as Alzheimer’s disease (Lovell and

Markesbery, 2001). This marker of DNA

oxidative stress is called 8-hydroxy-2’-

deoxyguanosine (8-OHG). It is formed by

oxidation of one of the four building blocks

(bases) that make up DNA strands. In normal

cells, not very much oxidation of this base

takes place, and the cell is able to repair the

DNA by removing the 8-OHG. The 8-OHG

is then found free in the cell. In AD, two

changes to this process seem to take place.

First, a high level of oxidative stress causes

more of the 8-OHG to be formed in the DNA.

Second, the repair process is much less efficient, so less of the oxidized base is removed

from the DNA and found free in the cell.

After comparing people with AD and cognitively healthy individuals, the University of

Kentucky investigators found that the ratio of

DNA-bound 8-OHG to free 8-OHG increased

100-fold in the patients with AD. The investigators suggest that this marker of DNA oxidation mirrors brain degeneration and might

be a useful indicator of disease progression.

A University of Wisconsin research team

funded by the National Institute of

Environmental Health Sciences (NIEHS)

studied the relationship between free radicals,

oxidative stress, and programmed cell death.

Programmed cell death, a process that occurs

naturally in all cells, appears to be accelerated

in Alzheimer’s disease, perhaps because of

increased oxidative stress caused by the accumulation of beta-amyloid. These researchers

focused on ways to increase defense mechanisms in the brain by activating multiple

antioxidant defense genes simultaneously, a

process they refer to as programmed cell life

(Li et al., 2002a). A small molecule, tertbutylhydroquinone (tBHQ) is known to activate the antioxidant response element and

protect against cell death induced by oxidative

stress. The researchers used tBHQ and cell

culture models as a simple system to help them

understand the genetic regulation of antioxidant defenses (Lee et al., 2001). Their work

led recently to the identification of a factor

that binds to the antioxidant response element

and helps activate a number of antioxidantrelated genes. Scientists hope that these and

other similar studies may help elucidate the

complex regulation of the many programmed

cell life genes and may lead to improved drug

targets and strategies in the future.

Beta-Amyloid

The study of beta-amyloid, the primary component of AD plaques, continues to be a vitally important part of the quest to discover what

happens in the brain to cause the transformation from healthy aging to AD. Investigators

continue to work intensely to understand the

process by which amyloid precursor protein

(APP) is cleaved by enzymes to release betaamyloid fragments, how the fragments accumulate in the brain to form plaques, and

whether the plaques themselves cause AD 

or whether they are a by-product of the production of beta-amyloid fragments. In 

studies during the past year, investigators

examined several different issues related to

beta-amyloid.
Scientists know that cleavage of APP by

two kinds of enzymes – beta-secretases and

gamma-secretases – generates the toxic betaamyloid fragments. Two very similar beta-secretases, BACE1 and BACE2, can generate

beta-amyloid. Previous studies demonstrated

that the BACE1 enzyme is likely responsible

for cleaving one end of the beta-amyloid fragment from APP. However, investigators

thought that BACE2 might also be involved.

A new study was designed to determine which

of the beta-secretases is more important for the

production of the toxic beta-amyloid (Cai et

al., 2001). In this study, investigators at the

Johns Hopkins University School of Medicine

developed a transgenic “knockout” mouse in

which the gene for the BACE1 enzyme was

eliminated. This allowed the team to see

whether removing the enzyme would interfere

with the production of beta-amyloid. With

the enzyme eliminated, beta-amyloid protein

fragments no longer were produced in neuronal cultures from the knockout mice. These

results suggested that BACE1 was involved in

the amyloid-producing activity, and that

BACE2 appeared to play a much smaller role

2001-2002 Progress Report on Alzheimer’s Disease 17

Beta-amyloid and Neurofibrillary Tangles: the Hallmarks of AD

The brains of people with AD have an abundance

of two abnormal structures – beta-amyloid plaques

and neurofibrillary tangles. This is especially true

in certain regions of the brain that are important in

memory.

● Plaques are dense, mostly insoluble deposits of

protein and cellular material outside and around

the neurons. They are made partly of a protein

called beta-amyloid, which is a fragment snipped

from a larger protein called amyloid precursor protein (APP). We don’t yet know whether plaques

themselves cause AD or are a by-product of the

disease process.

● Tangles are insoluble clumps of twisted fibers

that build up inside neurons. These fibers are made

of a protein called tau, which helps to stabilize the

neuron’s internal support structure. In AD, tau is

changed chemically, causing it to pair with other

threads of tau and become tangled up. This may

result in malfunctions in communications between

neurons and later in the death of the cells.

An AD Plaque

Tangled Clumps of Tau Proteins
18 2001-2002 Progress Report on Alzheimer’s Disease

Immunization is a common practice that protects people

against a wide variety of diseases. Scientists questioned

whether this might be a useful strategy for AD as well,

and the results of their intense work over the last several

years illustrate both the promise and the difficulties of

this type of research.

In early studies conducted at Elan Pharmaceuticals,

scientists worked with transgenic mice that gradually

develop beta-amyloid

plaques in the brain,

injecting them with a vaccine composed of very

small amounts of the

beta-amyloid peptide, or

protein fragment, mixed

with another substance

known to stimulate the

immune system (Schenk

et al., 1999). They found that the injections resulted in

much less beta-amyloid being deposited in the brains 

of the mice and better performance on memory tests.

The success of these studies in mice led to preliminary trials in humans, conducted by Elan investigators

and teams supported by NIH and other funders. These

trials tested the vaccine’s safety and assessed its effectiveness. In both trials, investigators also measured the

immune response in those who received the vaccine.

These human trials were halted prematurely in early

2002 because inflammation developed in the brains of

some of the participants. The researchers’ disappointment was tempered by the fact that the study still provided a wealth of important clinical and pathology data

on hundreds of participants and by the recognition that

cutting-edge research like this can suffer setbacks.

Simultaneously, other teams of investigators made

additional progress in this area by continuing work

with several strains of transgenic mice. One research

team, from Washington University School of Medicine

in St. Louis, used a strain of transgenic mice that carries

a mutation for the APP gene. These mice develop betaamyloid plaques as they get older. The scientists found

that passively immunizing these mice (administering an

antibody itself rather than stimulating the host’s immune

system to make an antibody) decreased the deposition of

beta-amyloid in the brain and reduced the overall number

of plaques (DeMattos, et al., 2001). In other studies, they

also found that prolonged administration of anti-betaamyloid antibody decreased the accumulation of betaamyloid in plaques and rapidly increased the amount of

beta-amyloid in the blood, effectively removing it from

the brain (DeMattos et al., 2002a; DeMattos et al.,

2002b). This is an important finding because it suggests

that there may be ways to remove beta-amyloid from the

brain without producing adverse side effects.

In conjunction with the researchers at Washington

University, scientists with Lilly Research Laboratories in

Indianapolis, showed that the antibody therapy rapidly

reversed the impairment shown by the transgenic mice in

certain learning and memory tasks (Dodart et al., 2002).

A group of Johns Hopkins University School of

Medicine investigators replicated these results in another strain of transgenic mice that carries a human presenilin gene mutation as well as the APP mutation (Vehmas

et al., 2001). This replication is significant because the

AD-related damage in the brain of the double mutant

occurs sooner and the amount of beta-amyloid deposited is greater than in mice with either mutation alone.

As with the Washington University studies, this research

suggests that binding antibodies to beta-amyloid clears

it from the brain and deposits it into the blood where it

can be degraded further.

Although scientists still have much to learn, this exciting research is helping them understand more fully the

steps involved in the metabolism of APP and beta-amyloid, and how beta-amyloid is distributed among body

compartments – including blood, cerebrospinal fluid, and

brain. This improved understanding may prove central to

more effective AD diagnosis and treatment in the future.

Update: Progress on the Immunization Front
in the cleavage of APP in neurons. To further

support this conclusion, the investigators also

compared the roles of BACE1 and alpha secretase, an enzyme involved in normal, nonpathological processing of APP into soluble

products. They found that the two enzymes

appear to compete with each other in the processing of APP, further demonstrating that

BACE1 is the primary enzyme in the

production of beta-amyloid. Many

scientists believe that interfering

with the deposition of beta-amyloid

may prevent AD or slow its progression. Because they play key roles in

the processing of APP and the

resulting deposition of beta-amyloid,

both beta- and gamma-secretase

activities represent potential targets

for drug therapies. The finding that

BACE1 is the principal beta-secretase in neurons suggests that scientists might want to focus on the

design of therapeutics to inhibit

BACE1 activity. 

In other studies, intramural

NIEHS researchers found that betaamyloid blocks the function of the nicotinic

acetylcholine receptor, a key nerve cell signaling receptor in the hippocampus (Pettit et al.,

2001). These results suggest that beta-amyloid

may exert its effects independently of plaque

formation, and they may provide an explanation for early cognitive problems experienced

by those with AD long before plaques begin to

form. Potentially, better drug therapies could

result from finding compounds that can prevent beta-amyloid from interacting with this

receptor, thus maintaining communication

between nerve cells in the brain.

In other work on beta-amyloid, scientists at

NIA followed up on earlier research showing

that, contrary to previous belief, the adult brain

can form new neurons. These investigators

wanted to see whether beta-amyloid had any

effect on the formation of these new neurons

(Haughey et al., 2002). They discovered that

the ability of new nerve cells to form from stem

cells is impaired in the brains of transgenic AD

mice. They further showed that beta-amyloid

has a direct adverse effect on neural stem cells,

inhibiting their ability to form nerve cells.

These findings suggest that an impaired ability

of stem cells to form nerve cells may occur in

AD, and might contribute to the progressive

depletion of nerve cells and cognitive impairment in this disease. Taken together with

other studies that have shown that dietary factors and nerve cell growth factors can stimulate

the production of new neurons from stem cells,

the present findings suggest that it might be

possible to increase formation of stem cells in

persons with AD, perhaps preventing or slowing down the depletion of neurons that causes

the memory impairment.

2001-2002 Progress Report on Alzheimer’s Disease 19

From APP to Beta-Amyloid

Nerve

Cell

Beta-Amyloid

Cell

Membrane

Enzymes

APP

Molecule
20 2001-2002 Progress Report on Alzheimer’s Disease

Other research in this area has looked to

vascular diseases, such as stroke, to provide

clues about the formation of beta-amyloid and

the pathogenesis of both early- and late-onset

forms of AD. AD and vascular diseases share

common risk factors, and stroke may be a risk

factor for AD; this has increased the interest in

the possible relationship of cerebrovascular

pathology, neurodegeneration, and dementia

(see p. 22 for a description of epidemiological

research examining possible links between vascular diseases and AD). We know that production of transforming growth factor-beta1

(TGF- beta1), a protein that is part of the

inflammatory response to injury, is increased

immediately following brain injury. Previous

work has shown that high levels of this protein

increase the deposition of beta-amyloid in

cerebral blood vessels. In this study, scientists

at the Gladstone Institute of Neurological

Disease at the University of California, 

San Francisco, developed a double transgenic

mouse by mating mice carrying the gene for a

mutated form of APP responsible for one

form of early-onset AD with other mice 

carrying the gene for an active form of TGFbeta1 (Wyss-Coray et al., 2001). This transgenic mouse allowed the researchers to examine

directly the effect of TGF-beta1 on deposition

of human beta-amyloid plaques in the brain

and its blood vessels. The study showed that

TGF-beta1 significantly influenced the extent

and localization of the beta-amyloid plaque

deposition in the mice. Cerebral blood 

vessels showed a significant accumulation of

beta-amyloid plaques while, at the same time,

the formation of neuritic plaques in brain 

tissue was dramatically reduced. Overall 

levels of brain beta-amyloid also were

markedly reduced in the double transgenics.

This reduction was associated with activation

of microglial cells and an increase in inflammatory molecules. In contrast to results from

epidemiologic and other studies that suggest

that an increase in brain inflammation might

increase the risk of developing AD, this

study’s findings suggest that particular components of the inflammatory response in the

brain might act to reduce, not elevate, plaque

levels in brain tissue.

Additional work in beta-amyloid has built

on earlier studies indicating that the amount

of copper and zinc is increased in the cortex of

brains from individuals who have died of AD.

These metals are concentrated in beta-amyloid

plaques. Although controversial, some scientists believe that beta-amyloid possesses binding sites for copper and zinc that enhance the

resistance of beta-amyloid to breakdown by

enzymes and encourage its tendency to clump

together to form plaques. In a new study,

investigators in Australia, Sweden, Germany,

and the U.S., led by scientists at the

Massachusetts General Hospital, treated

AD AND VASCULAR DISEASE

SHARE COMMON RISK FACTORS.
12-month-old transgenic mice with orally

administered clioquinol for 12 weeks (Cherny

et al., 2001). Clioquinol is a chemical that

binds metals such as copper and zinc and

removes them from body tissues. The team

found that treatment with clioquinol reversed

the deposition of beta-amyloid in the brain of

the transgenic mice with AD. The amyloid

plaque surface area was significantly reduced

and membrane-associated (sedimentable) betaamyloid in brain tissue decreased by 65 percent. In fact, two of the six animals treated

with clioquinol had no sedimentable betaamyloid, and no beta-amyloid could be detected using very specific and sensitive immunological techniques. Twenty older transgenic

mice (21 months of age) treated at a higher

dose for just 9 weeks also were examined.

After this treatment, sedimentable brain betaamyloid decreased by 49 percent and the study

team found an overall clearance of beta-amyloid from the brain. Clioquinol did not cause

decreased levels of APP nor did it result in

decreased levels of a protein involved in neuron-neuron communication, suggesting that it

was not toxic to brain tissue. Despite these

encouraging findings, safety issues in this therapy still need to be addressed in human studies, as small amounts of these metals are necessary for many chemical reactions in the body.

Other researchers are working to deepen

our understanding of the relationship

between beta-amyloid plaques and neurofibrillary tangles. Scientists at the Mayo Clinic

in Jacksonville, Florida, have made an important contribution to this work by developing

an animal model that exhibits both amyloid

plaques and neurofibrillary tangles (Lewis et

al., 2001). Many of the previous animal

models of AD developed plaques only. This

research team, supported by NIA, NINDS, and

2001-2002 Progress Report on Alzheimer’s Disease 21

Down Syndrome Research May Shed

Light on Alzheimer’s Disease

Many older adults with Down syndrome develop

dementia similar to that seen in Alzheimer’s disease,

and results from several recent studies in Down syndrome may contribute to a better understanding of

AD. For example, University of Colorado School of

Medicine scientists funded by the National Institute

of Child Health and Human Development (NICHD),

NIMH, and NIA have found that a particular strain

of transgenic mice have learning deficits that may

be related to problems with nerve fibers that send

impulses to the hippocampus (Hyde et al., 2001).

These mice are helping scientists understand

Down syndrome, but because the hippocampus is a

critical brain region that is damaged in AD, these

mice provide a potentially useful animal model for

researchers interested in examining changing 

patterns of cognitive function in AD.

In another study, a University of Connecticut Health

Sciences Center research team funded by NICHD, the

National Institute of Neurological Disorders and

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

examined whether mitochondrial dysfunction associated with Down syndrome affects APP and beta-amyloid plaque formation (Busciglio et al., 2002).

Mitochondria are structures inside a cell that provide

energy to the cell and play a role in synthesizing

some cellular proteins. The researchers found that

the mitochondrial problems not only disrupted the

normal functions of the APP, but also contributed to

the rapid accumulation of plaques.

Other research has indicated that vitamin E may be

protective against AD because of its antioxidant properties. The NIA is currently funding a study of vitamin

E treatment in people with Down syndrome, to

explore whether treatment may slow progression to

dementia. Results may offer insights into how some

of the damage to nerve cells occurs in both illnesses.
22 2001-2002 Progress Report on Alzheimer’s Disease

In 1965, NIH’s National Heart, Lung, and Blood Institute

(NHLBI) began the Honolulu Heart Program, a prospective epidemiological study of environmental and 

biological causes of cardiovascular disease among

Japanese-Americans living in Hawaii. This study gave

researchers an opportunity to investigate how heart disease prevalence rates, pathologic findings, and risk 

factors might be related in this population and to compare this population with other groups, especially

Japanese men living in Japan and in other parts of the

U.S. Initially, the study team examined 8,006 JapaneseAmerican men living on the island of Oahu, Hawaii, who

were born between 1900 and 1919. Over the next 25

years, investigators examined this group four additional

times, and their findings have contributed enormously to

our knowledge of heart disease and its risk factors.

From 1991 to 1996, NIA intramural investigators

worked with approximately 3,700 survivors of this same

group of Japanese-Americans to explore possible relationships between vascular factors – such as blood

pressure, blood cholesterol, and inflammation – and the

later development of dementias such as AD. This study,

called the Honolulu-Asia Aging Study, built on newly

emerging evidence suggesting that vascular factors

might contribute to neurodegeneration, lead to coexisting illnesses that increase the severity of dementia,

or somehow influence different stages of the dementia

process.

As they did for heart disease, this group of JapaneseAmerican men has made a valuable contribution to our

understanding of dementia and AD through their participation in the Honolulu-Asia Aging Study. More recently,

extramural grants have been awarded so that data collection and analysis can continue. Highlights of recent

findings from these grants have shed light on the complex interrelationships among genetics, lifestyle and

environmental factors, vascular diseases, and dementia:

● Investigators examined the association of total cholesterol, high-density lipoprotein (HDL), and low-density

lipoprotein (LDL) with brain plaques and tangles in

deceased study participants (Launer et al., 2001).

Cholesterol levels for all participants were measured

during late life; for some participants, levels were

measured 20 years earlier, when they were middle

aged. The investigators found a strong correlation

between increases in late-life and mid-life HDL levels

and increases in the number of plaques and tangles.

● An examination of the joint effect of the APOE-ε4

allele and midlife systolic blood pressure on the risk of

poor cognitive function in late life showed that midlife

high blood pressure had a stronger adverse effect on

cognitive function in those who carried the APOE-ε4

allele than in those without it (Peila et al., 2001).

However, the investigators speculate that this effect

might be modified by antihypertension medication.

● Investigators also explored the relationship between

Type 2 diabetes, alone or in combination with the

APOE-ε4 allele, and various types of dementia, including

AD and vascular dementia (Peila et al., 2002). They

found that study participants with both Type 2 diabetes

and the APOE-ε4 allele had a higher risk of AD than did

individuals with neither risk factor. They also found that

The Honolulu-Asia Aging Study: A Rich Source of Clues about Vascular and Other Risk Factors for AD 
others, crossed strains of transgenic mice that

harbored either a mutation in the amyloid

precursor protein or the tau protein. The offspring expressed abnormal forms of both molecules. By comparing the cellular changes in

these animals to those observed in the

parental strains, the investigators found that

the combination of these two mutations led to

increases in tangles in several regions of the

brain affected in AD. In addition, the animals also exhibited movement abnormalities.

These results suggest that the same type of

interactions may occur in the human brain as

AD develops. Because these animals exhibit

both plaques and tangles, they may serve as a

superior model for AD. In addition, the

movement abnormalities exhibited in these

animals will allow for the testing of potential

therapeutic agents at the behavioral level.

Can Certain Factors

Increase the Risk of or

Protect Against AD?

Scientists have known for some time that

both genetic and non-genetic factors can

increase the risk of developing AD. More

recently, evidence from some studies suggests

that certain protective factors may reduce the

chances of developing AD. Developing a

clearer understanding of possible risk and protective factors is important because it may provide clues to therapy and also suggest ways in

which people might be able to change their

lifestyles or environments to reduce AD risk.

Investigators have examined these issues in

several different ways and results in the past

year have shed light on differences in the rates

of new AD cases (incidence) across populations, genetic links to the development of AD,

and the implications of lifestyle issues for the

development of AD.

2001-2002 Progress Report on Alzheimer’s Disease 23

participants with both factors had more plaques and

tangles in their brains and had a higher risk of cerebral amyloid angiopathy (CAA), a condition in which

amyloid is deposited in the walls of the arteries that

supply the brain, resulting in an increased risk of

dementia and cerebral hemorrhage.

● In a study of brain tissue after death among 211

participants in the study, investigators evaluated the

relationship among CAA, dementia, and cognitive

function (Pfeifer et al., 2002). The researchers

found that 44 percent of these participants had CAA

in at least one brain region. The presence of CAA

was associated with higher numbers of plaques and

tangles and having the APOE-ε4 allele. Scores on

cognitive function tests that the participants took

before they died were lower for those individuals

who were later found to have AD and CAA than for

those with AD and no CAA and those with no AD or

CAA. The investigators concluded that by interacting with other neuronal pathologic processes, CAA

may lead to more severe cognitive impairment.

● Using specimens collected in 1968 during the

second examination of Honolulu Heart Program participants, Honolulu-Asia Aging Study investigators

measured blood levels of C-reactive protein, a nonspecific marker of inflammation, in 1,050 men

(Schmidt et al., 2002). This sample was divided into

four groups based on their levels of high-sensitivity

C-reactive protein. Compared with men in the

group with the lowest level of the protein, men in

the other three groups had a 3-fold increased risk of

all dementias, AD, and vascular dementia. This

relationship was independent of cardiovascular risk

factors or cardiovascular disease. The investigators

concluded that inflammatory markers may reflect

disease mechanisms related to dementia and that

these markers can be measured long before clinical

symptoms appear.
24 2001-2002 Progress Report on Alzheimer’s Disease

Epidemiology 

Comparing AD incidence and prevalence in

different populations may provide some clues

to genetic, environmental, and lifestyle factors

that may predispose or protect individuals. If

populations can be identified that have a significantly lower or higher incidence of AD,

this will greatly facilitate the search for both

genetic and non-genetic risk factors for the

disease. For example, over a 5-year period, an

Indiana University Medical School research

team followed 2,147 African-Americans in

Indianapolis and 2,459 Yoruba in Ibadan,

Nigeria, to see whether they developed

dementia and AD (Hendrie et al., 2001). All

the study participants were aged 65 and older.

In both communities, two-thirds were female.

To screen participants for AD, the study team

used the Community Screening Interview for

Dementia, a test developed by this group

specifically for use in comparative epidemiological

studies of dementia in 

culturally disparate, nonliterate and literate populations. All clinically

assessed participants at

both sites received the

same examination, which

included a structured interview, neuropsychological

testing, and examination

by a physician. Some also

received laboratory and

imaging studies. The

investigators took great care

to ensure that diagnostic

consistency was maintained

within and between sites.

Results indicated that in

the U.S. group, 3.24 percent per year developed

dementia, including 2.52

percent per year who developed AD. In the Nigerian

group, 1.35 percent per 

year developed dementia,

including 1.15 percent per

year who developed AD. 

This study provides one

of the first reports of 
incidence rate differences for dementia and

AD in studies of two populations from nonindustrialized and industrialized countries using

identical methods of evaluation and the same

group of investigators in both sites. Further

studies of these two populations will focus on

identifying genetic factors and potentially

modifiable non-genetic factors, such as heart

disease, diabetes, high cholesterol, and lifestyle

and environmental factors. For example, the

Yoruba have a much lower prevalence of vascular risk factors than do African-Americans.

These factors include high cholesterol levels

and body mass index, hypertension, and diabetes. The lower rates of these risk factors may

partially account for the reported difference in

AD.

A second large epidemiologic study examined the incidence of dementia in a rural population living in Ballabgarh, India, south of

New Delhi, and had analogous results to the

Indianapolis-Ibadan study (Chandra et al.,

2001). This 2-year prospective study of people

aged 55 and older, conducted by researchers

from the University of Pittsburgh, used repeated cognitive and functional ability screening

measures followed by standardized clinical

evaluation of dementia and AD. All the evaluation instruments had been developed and

validated in light of the cultural and linguistic

characteristics of this population. The investigators took the Indian incidence rates, standardized them against the age distribution of

the 1990 U.S. Census, and then compared the

rates against those of a population from the

Monongahela Valley in Pennsylvania studied

by the same researchers. The researchers calculated an overall incidence rate for those

more than 65 years old of 4.7 per 1,000 person-years, much lower than the rate of 17.5

per 1,000 person-years in the Monongahela

Valley population. The reason(s) for this difference is not known, but may include genetic

differences as well as a variety of medical and

demographic variables, such as those being

analyzed in the Indianapolis-Ibadan study. 

A third epidemiologic study took a slightly

different tack by comparing AD incidence

rates of different racial and ethnic populations

living in one country. This study focused on

cognitive abilities and dementia in a population of Caucasians, African-Americans, and

Caribbean Hispanics in northern Manhattan

(Tang et al., 2001). In this study, investigators from Columbia University studied 1,799

residents of the Washington Heights and

Inwood communities of New York City for 7

years, with interviews every 2 years. Results

indicated that probable or possible AD

occurred more frequently among AfricanAmericans (10.5 percent) and Hispanics (9.8

percent) than among Caucasians (5.4 percent). This differential risk did not seem to

depend on diabetes, hypertension, heart disease, or stroke. It also appeared that the differences in incidence could not be attributed

to differences in years of education or to frequency of illiteracy. It is important to note,

though, that many factors may be responsible

for these estimates, because populations vary

in many respects. Differences in socioeconomic status, health care, education, events occurring prenatally 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

may play a role in determining whether a person is diagnosed with AD. Clearly, further

careful investigation is needed to examine the

role that ethnic and racial differences may play

in determining risk of AD.

2001-2002 Progress Report on Alzheimer’s Disease 25
26 2001-2002 Progress Report on Alzheimer’s Disease

Genetics

Scientists have made enormous strides in the

past two decades in unraveling the genetic

components of AD and related dementias. For

example, we now know that mutations of particular genes on three chromosomes (1, 14,

and 21) virtually always lead to early-onset

AD. In addition, mutations in the tau gene on

chromosome 17 cause frontotemporal dementia and related diseases. These discoveries are

helping to broaden our understanding of how

mutations in particular genes cause changes in

cellular pathways that eventually cause different kinds of dementia. For example, in a

recent study funded by NICHD, investigators

at the University of Connecticut Health

Sciences Center examined the ways in which a

mutation in the presenilin-1 gene found on

chromosomes 14 might affect the cellular

structure of neurons during development.

They found that mutated presenilin-1 interferes with the ability of brain cells to regulate

and stabilize growing neurons by promoting

the formation of neurofibrillary tangles, and

interfering with brain receptors that help

determine the fate of cells during development

(Pigino et al., 2001). In other studies, NIA

investigators have found that the spectrum of

the dementias caused by mutations in the presenilin-1 and APP genes is much wider than

had been suspected. These investigators have

found that some presenilin-1 mutations can

cause a variant of Alzheimer’s disease characterized by a spinal disorder resulting in lower

body weakness or paralysis (Houlden et al.,

2000; Verkkoniemi et al., 2001). 

In other genetics and AD research, a team of

Columbia University investigators conducted a

family-based study series to identify mutations

in genes related to familial, early-onset AD

among Caribbean Hispanics, a rapidly growing

population in the United States (Athan et

al., 2001). The study was carried out in an

Alzheimer’s Disease Research Center in

northern Manhattan and in clinics in the

Dominican Republic and Puerto Rico.

Participants were drawn from 206 Caribbean

Hispanic families with two or more living

members with AD. Nineteen families and several individuals had developed AD before they

were 55 years old. To identify possible genetic

mutations, the investigators sequenced the

entire coding region of the presenilin-1 gene

from these 19 families and their living relatives. Based on these analyses, the study team

found a nucleotide change resulting in an

amino acid substitution in presenilin-1 that

had not been previously described. This same

mutation was observed in 23 people from eight

of the 19 families. A Caribbean Hispanic with

the mutation and early-onset familial AD was

also found by sequencing 319 unrelated 

Human

Chromosomes
individuals in northern Manhattan. This

mutation was later found in five people from

four Hispanic families with AD who had been

referred for genetic testing. Members from

another five Hispanic families have also been

identified with this mutation. None of the

families was related to one another and they

came from different places, yet all 18 carriers

of the new mutation shared a variant allele

indicating a common ancestor. This genetic

change probably accounts for a high percentage of early-onset familial AD in the Hispanic

population. The researchers also sequenced

the parts of the APP gene where mutations are

known to cause AD, but found no mutations.

A recent study funded by NINDS, NIA, and

other organizations provided further evidence

on the genetic basis of AD. This research

team identified a new mutation in a Swedish

family with a history of the disorder (Nilsberth

et al., 2001). Affected individuals have a

mutation in a unique location within APP,

which leads to early-onset AD. Information

collected from the family with this variation 

as well as from test tube studies suggests that 

a novel beta-amyloid processing mechanism

may be involved, specifically one in which the

formation of protofibrils (a very small betaamyloid toxic precursor to a plaque) is an initial event in the degeneration of neurons. 

The location of the mutations appears to have

a direct effect on the nature of beta-amyloid

plaque formation in affected individuals. In

turn, this may affect the clinical features of

their particular disease. The suggestion that a

novel form of beta-amyloid processing may be

occurring in individuals with this mutation

may help researchers better understand the

cellular mechanisms that contribute to the

development of AD.

We also know that slightly different forms of

the APOE gene on chromosome 19 can influence a person’s risk of developing late-onset

AD. However, the APOE-ε4 allele of this

gene may explain only about 10 to 15 percent

of the genetic risk of late-onset AD, and it is

likely that other major risk factor genes also

are involved. The roles that genetic changes

play in increasing or decreasing a person’s

chances of developing late-onset AD are under

intense scrutiny by many scientists. 

2001-2002 Progress Report on Alzheimer’s Disease 27
28 2001-2002 Progress Report on Alzheimer’s Disease

In the 10 years since APOE-ε4 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.

In the spring of 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 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 10 Alzheimer’s

Disease Centers (ADCs) so that they can recruit new

people for genetics research and encourage these people to provide blood samples for the Initiative. (The

ADCs conduct research, provide investigator training and

patient care, and support the research process by developing centralized databases and research tools.) NIA

also is collaborating with the Alzheimer’s Association to

develop community outreach programs to foster participation in the Initiative, especially among families that

have two or more members with late-onset AD.

The National Cell Repository for AD (NCRAD), located

at Indiana University, will serve 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. To enhance the diversity of

analysis and promote innovative research, NIA will

provide access to the Repository to AD genetics

researchers and encourage them to share data.

Future plans of the Initiative include creating a national case-control sample set, in which the genes of people

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 to evaluate potential candidates for risk factor

genes for late-onset AD.

The NIA’s AD Genetics Initiative: Accelerating the Pace of Research

DNA Strand

Chemical Bases

Chromosome

Genes
Three teams of investigators studying lateonset AD published papers recently reporting

results of studies investigating one particularly

intriguing chromosome – chromosome 10. In

the first study, investigators at the Mayo Clinic

in Jacksonville, Florida, confirmed a linkage

between high levels of beta-amyloid in blood

and a region on the long arm of chromosome

10 (Ertekin-Taner et al., 2001). Because betaamyloid is intimately associated with the

neuropathology of AD, the investigators think

that genes that elevate these beta-amyloid levels could be risk factor genes for AD. A second team, located at the Washington

University School of Medicine, conducted a

study on pairs of siblings who had definite or

probable AD. They also found a suggestive

linkage to AD in the same region of the long

arm of chromosome 10 (Myers et al., 2000).

In a third analysis, a Harvard Medical School

research team focused upon a specific gene

called the insulin degrading enzyme (IDE)

gene (Bertram et al., 2000). IDE is found in

neurons and another type of brain cell called

glia, and it acts to degrade beta-amyloid.

These investigators found a linkage between

one form of IDE, present in a region on the

long arm of chromosome 10, with AD. These

studies indicate that there may be more than

one late-onset AD gene on the long arm of

chromosome 10 that affects the risk of developing AD. 

Chromosome 10 is of interest for another

reason as well. Little is currently known about

genes that might influence the age at which

AD begins (“age of onset”). Because AD and

Parkinson’s disease (PD) share some common

characteristics, including dementia, Duke

University Medical Center investigators supported by NCRR and NIA performed a

genomic screen in the families of 449 AD and

174 PD families to see whether one or more

genes controlled age at onset for both diseases.

Results showed that this characteristic is highly heritable and that a specific region on chromosome 10 affects age of onset for both diseases (Li et al., 2002b).

Chromosomes 9 and 12 are also stirring

interest as possible sites of genes that might

affect AD risk. In collaboration with

researchers at Washington University School

of Medicine and Cardiff University, scientists

at NIA have used genetic analysis strategies to

find potentially promising regions on these two

chromosomes. They are now conducting

sequence analyses to pinpoint the locations

more exactly (Myers et al. 2002). These

investigators also are sequencing genes that

might be involved in oxidative stress and lipid

metabolism, two other factors thought to be

involved in the development of AD.

Scientist at NIA and investigators from

Duke University also have recently completed

a study designed to examine whether cognitive

decline associated with the APOE-ε4 allele is

different in older African-Americans than in

Caucasians (Fillenbaum et al., 2001). The

study involved more than 4,000 residents of

2001-2002 Progress Report on Alzheimer’s Disease 29
30 2001-2002 Progress Report on Alzheimer’s Disease

five adjacent counties in the Piedmont area of

North Carolina. Participants were given a brief

cognitive function test at the beginning of the

study and again 3 years later. The investigators

found that participants who had the APOE-ε4

allele scored lower on the first test than did

those without APOE-ε4, and that having the

allele increased by 59 percent the odds of cognitive decline. However, age and race were not

related to performance on the tests.

Other research is demonstrating that finding

genes that are involved in protecting cognitive

health in the elderly is as important as finding

risk factor genes for cognitive decline and AD.

University of Pittsburgh scientists supported by

NIMH recently began a systematic genome survey to identify the locations of particular

genes that might affect the

likelihood of reaching age 90

with preserved cognitive

abilities (Zubenko et al.,

2002). Participants included

100 young adults, aged 18-25

and 100 elders (94 nonagenarians and 6 centenarians).

All of the elderly participants were cognitively normal, as reflected by clinical

and psychometric assessments and “good” average

capacity to carry out their

activities of daily living.

The majority were living

independently despite multiple medical conditions.

None had a history of mental disorders in early

or middle adulthood, only one was a current

smoker, and 80 percent consumed alcohol less

than once each month. The genome survey

method revealed an elevated frequency of the

APOE-ε2 allele (the relatively rare APOE

form that is thought to provide some protection against AD), and a reduced frequency in

the APOE-ε4 allele among the elders compared to the young adults. These results suggest that several behavioral and genetic 

factors may contribute to the likelihood of

achieving exceptional longevity with 

preserved cognition.

Increasing knowledge about the genetics of

Alzheimer’s disease has led to an urgent need

for accurate information and materials to educate families, health care providers, and the

public about the challenges they may face and

to provide models for genetics education in

other, equally complex diseases. The National

Human Genome Research Institute (NHGRI)

has funded a group of researchers at the

Massachusetts General Hospital/Harvard

Medical School and the University of
Alabama to address the ethical, legal, and

social implications of the genetics of AD from

the critical perspective of a group at high risk

of the disease: currently unaffected relatives of

people with AD (Tanzi and Blacker, 2001).

The researchers have been working together

since 1990 as part of the NIMH Genetics

Initiative to identify families with Alzheimer's

disease for genetic linkage studies. Nearly 350

such families, predominantly affected sibling

pairs and over 300 of their unaffected siblings,

have been identified. The researchers will use

a variety of approaches to study knowledge,

attitudes, and behavior related to genetic studies and genetic testing in the unaffected people

in these AD families and their primary care

physicians, and will develop and pilot educational materials designed to address their needs

for genetic information. 

A second study, funded by NHGRI and conducted by Boston University School of Medicine

investigators, has estimated risk of AD among

adult children of persons with AD to determine

who chooses to obtain genetic susceptibility testing for AD and to assess the risks and benefits of

providing such information (Green et al., 2002).

Study investigators hope that their results can

inform the development of guidelines for clinicians for genetic testing, risk assessment, and

appropriate counseling scenarios.

Lifestyle

Another area that is capturing an increasing

amount of attention and interest is the possible influence of education, leisure, physical,

and intellectually stimulating activities on the

risk of developing AD. The interaction of

genetic and lifestyle factors is also of interest.

A number of studies over the past few years

have provided intriguing hints that these

activities may be linked to a reduced risk of

AD, and they are consistent with what we

know about other health benefits of lifelong

physical and intellectual activity. 

Several studies in the past year have

revealed some clues about the effect of these

potentially protective activities. The first

study, conducted by a research team at Case

Western Reserve University School of

Medicine, explored the longstanding notion

that high levels of education and occupation

are correlated with protection against development of AD (Friedland et al., 2001). Some

researchers have speculated that such protective effects occur because these activities may

build up brain reserves that delay or buffer

against cognitive decline. Others have argued

that the protective effect of education is related to its complex associations with economic,

medical, and occupational factors. This study

attempted to differentiate between these two

2001-2002 Progress Report on Alzheimer’s Disease 31

THE INTERACTION OF GENETIC AND 

LIFESTYLE FACTORS MAY BE LINKED 

TO A REDUCED RISK OF AD.
32 2001-2002 Progress Report on Alzheimer’s Disease

explanations by investigating the potential

protective effects of three general categories 

of recreational activities. These categories

included passive (e.g., watching television),

intellectual (e.g., playing chess, solving crossword puzzles), and physical (e.g., bowling,

skating) activities. Patients with AD were

found to have been much less active than

healthy control persons of similar background

in terms of both diversity and intensity of

recreational activities engaged in during early

and middle adulthood. These differences were

not explained by differing educational or

income levels, age, or gender. People who

were relatively inactive in midlife had a 250

percent increased risk of developing AD.

Differences were greatest for intellectual activities, but were significant for passive and physical activities as well. This study suggests that

engaging in physical and intellectual activities

may buffer against cognitive decline and that

underactivity is related to increased risk of

AD. Although these results are provocative,

the study authors suggest that they be interpreted with caution because it was not possible

to evaluate whether AD could be the cause

rather than the consequence of underactivity.

The disease may develop several decades

before the onset of symptoms and very early

deficits might adversely affect participation in

recreational activities.

In a similar study, investigators with the

Religious Orders Study, an ongoing examination of aging among older Catholic nuns,

priests, and brothers across the U.S., tested the

hypothesis that frequent participation in intellectually stimulating activities is associated

with a reduced risk of AD (Wilson et al.,

2002a). About 800 Religious Order Study participants were rated at the beginning of the

study for frequency of participation in such

cognitive activities as reading a newspaper. 

A 5-point cognitive activity score was derived

from these data, with the highest score given

to daily or almost daily participation and the

lowest score given to participation less than

once a year. Investigators also gathered information on time spent in physical activities.

For up to 7 years, participants underwent annual evaluations that included detailed cognitive

function testing to determine whether they had

developed AD. During an average of 4.5 years

of follow-up, 111 people

developed AD. In an analytic model that controlled

for age, sex, and education,

each 1-point increase in the

cognitive activity score was

associated with a 33 percent

reduction in risk of AD.

Results were comparable

when those with memory

impairment were excluded

at the beginning of the

study and when the presence of the APOE-ε4 allele

and medical conditions were
factored in. In other analytic models that

controlled for age, sex, education, and

beginning level of cognitive function, a 

1-point increase in cognitive activity was

associated with reduced decline in global cognition (by 47 percent), working memory (by

60 percent), and perceptual speed (by 30 percent). Participation in physical activity was

unrelated to risk of disease or rate of cognitive

decline. The results suggest that more frequent participation in intellectually stimulating activities is associated with reduced risk 

of AD.

Another research project with the Religious

Orders Study participants examined individual

differences in the rates of change in cognitive

abilities (Wilson et al., 2002b). Participants,

who were aged 65 years and older and free of

clinical evidence of AD at the beginning of

the study, underwent annual clinical evaluations for up to 6 years. Cognitive function

was assessed at each evaluation with a battery

of tests, from which summary measures of performance in seven cognitive areas, or domains,

were derived. On average, decline occurred in

each domain and was more rapid in older persons than in younger persons. However, wide

individual differences were evident at all ages.

The rate of change in a given domain was not

strongly related to the beginning level of function in that domain, but was moderately associated with rates of change in other cognitive

domains. The results suggest that change in

cognitive function in old age primarily reflects

person-specific factors rather than an inevitable

developmental process.

A recent study by scientists at the University

of Washington in Seattle explored how environmental risk may interact with the APOE genotype to clarify the possible relationships between

early life environment and the development of

AD (Moceri et al., 2001). The researchers

used information from Census data to index

socioeconomic risk through measures of the

father’s occupation, parental age, household

size, number of siblings, and birth order. They

found that the risk of AD increased among

individuals whose fathers were unskilled manual workers or laborers compared to those whose

fathers had nonmanual occupations, but this

increased risk was significant only among individuals who carried the APOE-ε4 allele.

Therefore, compared to those with neither risk

factor, the risk for Alzheimer’s disease was

greatly elevated when both the genetic and

the environmental risk factors were present.

These findings highlight some intriguing clues

about the possibility that the APOE-ε4 allele

may modify any relationship between early-life

environmental factors and the development of

Alzheimer’s disease.

2001-2002 Progress Report on Alzheimer’s Disease 33
34 2001-2002 Progress Report on Alzheimer’s Disease

Cholesterol and

Homocysteine

A third exciting area of research is providing

data about factors that may protect against or

increase the risk of AD. In recent years, a

number of studies have suggested a connection

between AD and cholesterol in the blood. For

example, the APOE-ε4 allele is a variant of

the APOE gene, which codes apolipoprotein

E, a protein that helps to carry cholesterol in

the blood. Test tube studies also have shown

that blood cholesterol increases production of

beta-amyloid from its APP precursor, and animal studies show a relationship between blood

cholesterol and brain plaque levels in transgenic mice. Epidemiologic studies linking vascular risk factors to dementia have lent further

support to this relationship (see the p. 22 sidebar on the Honolulu-Asia Aging Study for

more on findings from these studies). Many

questions remain about the relationship

between blood cholesterol and AD, but these

intriguing findings have spurred new research

and led scientists to hypothesize that drugs

that lower blood cholesterol might also lower

risk of developing dementia and AD.

Two recent observational studies examined

changes in AD risk with prescription of

statins, the most commonly prescribed cholesterol-lowering drugs. Both studies have stirred

considerable interest because they showed a

significant reduction in dementia risk correlated with individuals who take these drugs. In

the first study, a research team at the Boston

University School of Medicine, the University

of Massachusetts Medical School, and Harvard

School of Public Health analyzed data on more

than 1,300 people in the United Kingdom

(Jick et al., 2000). They found that people

with high cholesterol who were prescribed

statins had a risk of dementia 70 percent lower

than those who did not have high cholesterol

(or hyperlipidemia) or who were not on lipidlowering treatment. The effect was similar

regardless of the specific statin prescribed.

People with high cholesterol who were prescribed a non-statin drug or those who

remained untreated did not have reduced risk

for dementia, suggesting that the effect was

not due to lowering lipid levels per se. 

Investigators at Loyola University Medical

School in Maywood, IL, conducted a second

study, which involved cases listed in a threehospital database in the U.S. This study

showed a relationship between either lovastatin or pravastatin prescription and a 60 to 

73 percent lowered risk of developing AD

(Wolozin et al., 2000). This relationship was

not found with non-statin medications for

hypertension or cardiovascular disease.

Although epidemiologic studies do not

prove causality, the implications of this

research could be considerable. The authors

of these studies speculate that AD risk may be
2001-2002 Progress Report on Alzheimer’s Disease 35

To thoroughly understand the factors that might

increase the risk of AD or protect against it and to

develop effective treatment strategies, researchers need

to study people who come from a variety of locations,

racial and ethnic groups, and demographic backgrounds. For some years, NIH has made a concerted

effort to improve the diversity of its research participants and to reach out to groups who traditionally have

not participated in clinical studies. Increasing the numbers of non-Caucasians who are over 65 and therefore

at higher risk of AD, has been an important priority for

Alzheimer’s disease researchers.

As part of this effort, in 1990, the NIA began a program of Satellite Diagnostic and Treatment Clinics

through its existing Alzheimer’s Disease Centers (ADCs)

Program. The satellite clinic program was significantly

expanded in following years; currently 25 clinics are

operating across 18 ADCs.

Many satellite clinics are located in areas where staff

can reach out to minority, rural, or underserved populations. The clinics are primarily focused on providing

diagnostic and treatment services to people with AD and

their families, but through their connection with the

ADCs, they can offer families opportunities to participate

in research protocols and clinical drug trials.

Before NIA established the satellite clinic program,

minority enrollment in the ADCs was approximately 4

percent. Since 1990, the overall ADC rate of minority

enrollment has increased significantly, ranging between

10 and 14 percent for African-Americans and 4 to 7

percent for Hispanics. The satellite clinics have had

similar success in enrolling Native Americans. For

example, the University of Texas Southwestern ADC in

Dallas has developed close ties with the Choctaw

Nation, with a subsequent enrollment of 146 subjects,

representing 6.6 percent of the Center enrollment. This

effort comes almost exclusively from their satellite clinic. American Indian/Alaskan Natives represent 18.7 percent of the registry from the University of Washington

ADC. Almost all of these study participants come from

their satellite clinic.

ADCs are also using other strategies to promote diversity in clinical trial enrollment, such as active community

outreach and education activities. Memory screening at

health fairs, mass mailing of brochures, educational presentations, and high visibility research projects have all

helped to promote enrollment. For example, the Indiana

ADC was highly successful in recruiting AfricanAmerican participants because of its association with

the Indianapolis-Ibadan Dementia Project (see p. 24 for

more on this study). The Rush-Presbyterian-St. Luke’s

ADC in Chicago has established a successful working

relationship with the president of the National Black

Sisters Conference and the National Black Catholic

Clergy Caucus and this has led to increased enrollment

of African-American nuns, priests, and brothers in the

Religious Orders Study. Efforts to cement the relationship with the African-American Catholic Communities

continue with the formation of an Advisory Panel of

African-American Catholic religious leaders to gain a

better appreciation of potential barriers to participation

of individual nuns, priests, and brothers.

Improving Clinical Research and Care by Improving Outreach
36 2001-2002 Progress Report on Alzheimer’s Disease

reduced because onset of dementia is delayed

or because age-related changes that result in

cognitive impairment are delayed, and they

suggest that the use of statins could substantially reduce the risk for dementia in older

people. The only way to determine whether

statins delay onset of AD is to perform a clinical trial.

A recent epidemiologic study from investigators at Boston University, based on data from

the Framingham Heart Study, also found that

elevated levels of an amino acid called homocysteine, a risk factor for heart disease, are

associated with an increased risk of developing

AD (Seshadri et al., 2002). Investigators at

NIA have shown in transgenic mice that high

homocysteine levels make neurons vulnerable

to dysfunction and death (Kruman et al.,

2002). The relationship between AD and

homocysteine is particularly interesting

because blood levels of homocysteine can be

reduced by increasing intake of folic acid and

vitamins B6 and B12. These findings have led

the NIA to fund a multicenter, randomized,

placebo-controlled clinical trial, currently

underway, to determine whether reducing

homocysteine levels through high-dose supplements of folate and vitamins B6 and B12 will

slow the rate of decline in people with AD.

What Can Be Done to

Halt AD, Slow Its

Progress, or Lessen

its Effects?

s the earlier sections of this report have 

shown, recent advances in genetics and

molecular biology have vastly increased our

understanding of the brain – how it works normally and what happens when something goes

wrong. Improvements in this understanding

have opened the doors to a number of 

potential therapeutic targets for AD. NIA,

other NIH Institutes, and private industry are

conducting studies on an estimated 30 compounds that may be active against AD. These

studies focus on four issues: 

● helping people with AD maintain 

cognitive function over the short-term;

● slowing the progress of the disease; 

● treating AD-associated behavioral 

problems; and

● preventing AD.

The remainder of this section provides highlights of several ongoing clinical trials.

● The Memory Impairment Study –

Launched in March 1999, this study has completed enrollment with 769 participants in 68

sites in the Alzheimer’s Disease Cooperative

Study (ADCS) network. The ADCS is a

study in which many Alzheimer’s Disease

Centers and other clinical sites cooperate to

investigate promising drugs for AD and develop and improve tests for evaluating AD

patients in clinical trials. The purpose of the

A
Memory Impairment Study is to determine

whether daily doses of vitamin E or donepezil

(Aricept) given over a 3-year period can delay

or prevent the onset of AD in people who

have MCI. A major challenge for this trial

was screening and recruiting enough people

with MCI and retaining them for the long

study period. The design of the trial and the

success of the recruitment phase represent a

major advance in AD clinical trial methodology, and this protocol has been widely copied by

the pharmaceutical industry, which has now

used this study design to set up several independent trials of various agents using volunteers with MCI. Results of this trial are

expected in mid-2004.

● Estrogen and cognitive function – Over the

past 25 years, animal studies have suggested

that estrogen has some positive effects on the

brain and memory function. Some human epidemiological studies have supported this

notion. These findings have created scientific

interest in the relationship among estrogen,

memory, and cognitive function. Although

scientists still don’t know whether normally

aging women who take estrogen alone will be

protected from developing AD, women aged

65 and older taking a combination of estrogen/progestin (Prempro) in a recent clinical

trial were found to have a significantly

increased risk of developing dementia

(Shumaker et al., 2003). Another part of this

same study, the Women’s Health Initiative,

previously showed that combined estrogen/

progestin therapy also increases risk of heart

disease, stroke, blood clots, and breast cancer, while decreasing the risk for hip fracture

and colon cancer. The NIA continues to

explore potential benefits of estrogen alone

in an ongoing clinical trial on cognitively

normal older women with a family history of

dementia. Safety monitoring boards that

include expert physicians and scientists are

carefully monitoring the side effects of treatment for women participating in this study.

Clearly, more research is needed on this complex issue.

● Simvastatin and AD progression – This

study, which is actively recruiting, is testing

whether simvastatin (Zocor), a commonly 

prescribed cholesterol-lowering drug, can slow

the rate of disease progression in people with

AD. Results of this trial are expected in late

2005.

● NSAIDs and inflammation – One of the

hallmarks of AD is inflammation in the brain,

but whether it is a cause or an effect of the disease is not yet known. Epidemiologic evidence suggests that anti-inflammatory agents,

2001-2002 Progress Report on Alzheimer’s Disease 37
38 2001-2002 Progress Report on Alzheimer’s Disease

such as non-steroidal anti-inflammatory drugs

(NSAIDs), including ibuprofen, naproxen, and

indomethacin are associated with a decreased

risk of AD. One clinical trial designed to

determine whether naproxen or rofecoxib 

(a new selective cyclooxygenase, or COX-2,

inhibitor) found that neither NSAID slowed

the rate of cognitive deterioration in people

with mild to moderate AD. Researchers hope

that prevention trials underway will prove the

effectiveness of NSAIDs in preventing AD in

people at risk, but not yet showing symptoms,

of the disease (Aisen et al., 2003).

● Nicotinic agents and cognitive function –

The mainstay of current AD treatment is drugs

that help to maintain levels of acetylcholine, a

neurotransmitter that is crucial in the formation of memories. These drugs have limited

effectiveness, however, so researchers also 

are exploring other therapeutic strategies.

Ongoing NCRR-supported investigations of

the molecular substructure of central nervous

system nicotinic receptors, their accompanying

pharmacology, and the effects of nicotinic

agents on cognitive function have suggested

the possibility that nicotinic cholinergic receptor stimulation may have beneficial effects in

AD and other neuropsychiatric disorders.

Results from recent NCRR-supported pilot

clinical trials with nicotine and novel nicotinic agents suggest that acute nicotinic stimulation in AD patients can transiently improve

the acquisition and retention of verbal and

visual information and decrease errors in cognitive tasks, as well as improve accuracy and

response time (Newhouse et al., 2001). 

● Drug treatments for psychiatric and behavioral problems in AD – Many people with AD

have periods of restless or irritable behavior

and become easily agitated. Agitation may be

an expression of pain, anger, anxiety, or

depression, or it may be a still unexplained

part of the disease. Whatever the cause, it is a

frequent and often difficult behavioral issue for

people with AD and their caregivers. An

ADCS research team is now conducting a

clinical trial among 120 nursing home residents with severe AD to see whether divalproex sodium (Valproate), an antiseizure medication, can help to ease agitation. 

Other psychiatric and behavioral problems,

such as delusions, mood changes, and aggression, also are common in patients with

Alzheimer’s disease and other dementias, and

are disturbing to the person and his or her

family. A range of medications and non-medication approaches are used to help treat these

symptoms, but many questions remain about

which treatments to use for which symptoms

and how to balance positive treatment effects
2001-2002 Progress Report on Alzheimer’s Disease 39

against potential side effects. The NIMH and

NIA are supporting several clinical trials

examining the effectiveness of drugs used to

treat aggression, psychosis, depression, and

other common behavioral problems in persons

with AD (Pollock et al., 2002; Schneider et

al., 2001; Sultzer et al., 2001). Findings from

this research may lead to improved and more

precise therapies for the behavioral and psychotic disturbances associated with AD and

other forms of dementia. 

In addition to these ongoing or just completed trials, NIA is planning a number of other

innovative clinical trials over the next 5 years.

These studies, which will be conducted

through the ADCS and other clinical sites,

include:

● A project to develop sensitive and more

effective methods for evaluating change over

time in cognitively healthy elderly in a number of areas, such as overall cognitive functioning, memory, ability to carry out activities of

daily life, and quality of life. These improved

evaluation instruments will then be used in

AD prevention clinical trials to measure

changes that result from the interventions.

● A study to see whether low-doses of divalproex sodium (Valproate) can delay or prevent

agitation and psychosis from developing in

people with mild to moderate AD, and also

to see whether its possible neuroprotective

properties have any effect on slowing the rate

of cognitive decline. 

● A study to test the safety and tolerability of

indole-3-propionic acid (IPA), a highly potent,

naturally occurring antioxidant that also

inhibits fibril formation by beta-amyloid.

Investigators will measure levels of biological

markers related to oxidative damage and AD

to assess the biological activity of IPA and also

determine whether this antioxidant has any

beneficial short-term effects on AD.

RESEARCH MAY LEAD TO IMPROVED

THERAPIES FOR THE BEHAVIORAL 

DISTURBANCES ASSOCIATED WITH AD.
40 2001-2002 Progress Report on Alzheimer’s Disease

Research to Help Families

and Caregivers

Although much of NIH’s AD research effort is

focused on the basic science aspects of the

causes, characteristics, diagnosis, and treatment of AD, the Institutes have never lost

sight of the enormous personal toll exacted by

AD on the families, friends, and caregivers of

people with the disease. Investigators supported by several Institutes, including NIA, the

National Institute of Nursing Research

(NINR), and NIMH, are exploring the emotional, psychological, and physical costs of

caregiving, and they are investigating ways to

ease the burden. 

A number of studies are examining the factors that contribute to stress and depression in

family caregivers of people with AD. In one

study, Case Western Reserve University investigators explored the relationship between

depression in the care recipient and in the

caregiver (Neundorfer et al., 2001). They

found that the well-being of both people is

closely related – the more depressed the person

with AD was, the more depressed the caregiver

also was. Wives of men with AD and caregivers who were themselves in poor health

were at particular risk of depression. The

researchers concluded that interventions for

caregivers are needed early on in the family

member’s illness and that further research is

needed to understand what interventions will

sustain the quality of life and physical and

mental well-being of the person with AD as

well as the caregiver. 

A second study examined caregiving stress

from a somewhat different angle. We know

that the chronic stress resulting from continuously caring for a family member with dementia has been associated with depression, elevated stress hormones, and increased vulnerability

to influenza and poor wound healing in older

caregivers. However, only recently have the

long-term effects of this stressful period for

caregivers after the death of the demented

spouse been investigated. This study, funded

by NIA and NIMH and conducted by a

research group at the Houston Veterans Affairs

Medical Center, examined the psychological

state of spousal caregivers for up to 4 years following the death of the person with dementia

(Robinson-Whelen et al., 2001). The former

caregivers were compared to a group of caregivers who were still caring for their husbands

or wives throughout the study, as well as to a

group of non-caregiving age-matched control

participants. The investigators found that

although former caregivers experienced slight

decreases in stress and negative mood after

their spouses had died, their emotional state

and levels of depression and loneliness had not

returned to levels comparable to non-caregivers up to 3 years later. In fact, they

remained similar to those of current spousal

caregivers, suggesting that the consequences of

long-term caregiving may be long-term as well.

INTERVENTIONS FOR CAREGIVERS

ARE NEEDED EARLY ON IN THE 

FAMILY MEMBER’S ILLNESS. 
2001-2002 Progress Report on Alzheimer’s Disease 41

The investigators also found that social support after the death of the spouse helped more

to ensure a positive post-caregiving outcome

than support received during the caregiving

years. Not surprisingly, an inability to suppress

thoughts of the caregiving years was negatively

associated with psychological well-being.

Clearly, the needs of caregiving spouses must

receive long-term attention. Programs aimed

at providing social support and working

through the persistent traumatic and stressful

thoughts of the prior years of spousal caregiving have the potential to help former caregivers and boost their psychological and physical well-being. 

A third study looked at ways to help family

caregivers by building on previous research

showing that people who exercise benefit in

various ways, including reduced stress-induced

high blood pressure and improved quality of

sleep. This study, conducted by Stanford

University Medical School researchers, is the

first to examine the role that a regular 

moderate-intensity exercise program plays in

enhancing health and quality of life for women

caring for loved ones with dementia (King et

al., 2002). A group of 100 women caregivers,

aged 49 to 82 years old, received either homebased, telephone-supervised moderate-intensity exercise training or a nutrition education

program. Exercise consisted of brisk walking

for four 30- to 40-minute sessions per week.

Compared with the nutrition education group,

exercise participants showed significant

improvements in physical activity levels,

stress-induced blood pressure reactions, and

sleep quality. The nutrition group also benefited through reducing the percentage of total

calories from fats and saturated fats and consuming fewer fats, oils, sweets, and high-fat

snacks. Both groups reported significant

reductions in psychological distress, including

depressive symptoms and self-rated stress.

This research demonstrates that properly tailored health promotion programs can improve

the health and functioning of older women

family caregivers. A critical challenge

remains: How best to tailor programs to the

needs and preferences of other populations of

caregivers. 
42 2001-2002 Progress Report on Alzheimer’s Disease

15years ago, we did not know any

of the genes that could cause

AD, and we had only an inkling

of the biological pathways that were involved

in the development of brain pathology. 

Today, we know the 3 major genes for

early-onset disease and one of the major risk

factor genes for late-onset disease, and we are

rapidly expanding the research infrastructure

to identify the other major risk factor genes for

late-onset AD (see the description of NIA’s

Genetics Initiative on page 28). The known

genes have made major contributions to our

extensive knowledge of pathways leading to

the development of AD’s characteristic amyloid plaques in the brain. Identification of the

tau gene mutations causing frontotemporal

dementia with parkinsonism (FTDP-17),

another late-onset dementia, is providing clues

to ways in which the formation of the characteristic intracellular tangles in AD may be prevented.

10years ago, we could not model

Alzheimer’s disease in animals. 

Today, transgenic mice are an invaluable

resource for modeling amyloid plaque development in the brain and in testing possible therapies (for more on this work, see the betaamyloid section on page 16 and the immunization sidebar on page 18). Other animals also

are now being effectively used as models for

age-related and disease-related changes in

brain, as well as models for testing promising

interventions. 

Part3

Outlook for the Future

The future builds upon the events and experience of the past and present. That’s certainly true for Alzheimer’s disease research, for the explosion of knowledge during the past

25 years has set the stage for a hopeful future in which, one day, we may be able to prevent or even cure this terrible disease, which robs

our loved ones of their most precious faculty –

their minds.

Here are just a few ways in which past and present research findings are providing a foundation

for the future:

44 2001-2002 Progress Report on Alzheimer’s Disease

5years ago, we had no ways of identifying people at high risk for the disease

and did not have any prevention clinical trials funded.

Today, scientists are identifying people at

high risk of developing AD by brain imaging,

neuropsychological tests, and structured clinician interviews, leading to insights into the

preclinical phases of the disease, such as MCI

(see page 11 for more about advances in neuroimaging). We have eight ongoing prevention clinical trials, and 11 clinical trials that

are aimed at slowing the progression of AD or

alleviating distressing symptoms such as agitation (see page 36 for more information on

clinical trials). 

2years ago, we did not understand 

the mechanism by which plaques 

and tangles relate to each other. 

Today, as a result of developing the first

double transgenic mouse that produces both

plaques and tangles, we know that plaques in

the brain can influence the development of tangles in brain regions susceptible in AD (see page

20 for more on the double transgenic mouse).

Recent findings also suggest that a number of

neurodegenerative disorders have some common mechanisms of disease, and these findings

will further inform research in AD.

The challenge for the future is to predict the

specific pilot and full-scale clinical trials that

are most likely to yield effective strategies for

preventing and treating AD in different populations. To facilitate this, we need to develop

new strategies for moving compounds that show

promise in the laboratory into animal studies to

test for safety and efficacy and then into pilot

trials in people. The Alzheimer’s Disease

Prevention Initiative, a major effort by NIH in

collaboration with other Federal agencies and

the private sector, is providing a focus for AD

researchers to meet this challenge through support for current

research on

genetics, on the

basic cellular

biology of ADrelated pathways, and on the

changes taking

place in the brains of people with mild cognitive impairment and early AD. 

Results from animal model research and tantalizing hints of possible risk and protective factors from epidemiologic studies will contribute

further information. Other studies will also provide valuable clues about the possible impact of

diseases such as cardiovascular disease and diabetes on AD-related dementia in later life. The

ultimate goal of this research is to develop and

test a variety of types of interventions, be they

behavioral, dietary, or drug, to determine

whether they can ameliorate the cognitive and

behavioral symptoms of Alzheimer’s disease,

modify its course, or eventually delay the onset

of or prevent the disease entirely.
2001-2002 Progress Report on Alzheimer’s Disease 45

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Writer

Anne Brown Rodgers

Editors

Patricia D. Lynch and Karen M. Pocinki

National Institute on Aging

Design

Rodney C. Williams and Brian Taylor

RCW Communication Design Inc.

Project Coordinator

David Burton

Johnson, Bassin & Shaw Inc.

Medical Illustrator

Christy Krames, MA, CMI

(Front-Back Cover, 2, 14, 17, 19, 28) 

Photography 

Front Cover (top), 30 – Comstock.com

Front Cover (bottom), Back Cover (top), 3, 6, 22,

34, 37, 39, 42 (inset) – Getty Images

Back Cover (bottom), 27, 29, 32, 38 – Marty Katz 

Page 2 – Corbis Images 

Page 4, 6 (fade), 7, 13, 18, 26-27, 36, 42 (fade), 44

(top left) – SPL/Photoresearchers, Inc.

Page 5, 9, 24, 43, 44 (right) – Max Hirshfield

Page 12 – Courtesy of Dr. Gary Small, 

University of California at Los Angeles

Page 17 (left) – Courtesy of Dr. William

Markesbery, University of Kentucky

Page 33 – Courtesy of Dr. David Bennett, Rush

Presbyterian-St. Luke’s Medical Center, and the

Benedictine Monks, Collegeville, MN

Page 35, 41 – Rick Brady

Special thanks to:

The staff of the Neuroscience and Neuropsychology

of Aging Program, National Institute on Aging

For additional copies of this report or further information about Alzheimer’s disease, please contact:

Alzheimer’s Disease Education and Referral

(ADEAR) Center

PO Box 8250

Silver Spring, MD 20907-8250

Phone: 1-800-438-4380

E-mail: adear@alzheimers.org

Web site: www.alzheimers.org

Credits
U.S. Department of Health and Human Services

National Institutes of Health

NIH Publication Number: 03-5333

July 2003