Alzheimer's Disease: Unraveling the Mystery

Alzheimer's Disease: Unraveling the Mystery

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Description: “Never have I loved my husband of 41 years more than I do today....Though he may not know I’m his wife, he does know that my presence means his favorite foods and drinks are near at hand....I wonder why I can sit daily by his side as I play tapes, relate bits and pieces of news, hold his hand, tell him I love him. Yet I am content when I am with him, though I grieve for the loss of his smile, the sound of my name on his lips.” This excerpt from Lessons Learned: Shared Experiences in Coping, by participants of the Duke University Alzheimer Support Groups, gives a glimpse into what a person with Alzheimer’s disease (AD) and a family caregiver might experience as the disease progresses. The gradual slipping away of mind and memory is frightening and frustrating, both for the person with the disease and for family and friends, and can elicit strong feelings of love, grief, anger, and exhaustion.

 
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Contents:
ALZHEIMERS

DISEASE
Unraveling the Mystery
National Institute
on Aging

ALZHEIMERS

DISEASE
Unraveling the Mystery

Preface

O

ver the past few
decades, Alzheimer’s
disease (AD) has
emerged from
obscurity. Once considered a
rare disorder, it is now seen as
a major public health problem
that has a severe impact on
millions of older Americans
and their families. The National
Institute on Aging (NIA) is the

lead agency for AD research at
the National Institutes of Health
(NIH). NIA launched its AD
program in 1978, and since
then, the study of this disease
has become one of NIA’s top
priorities. Several other NIH institutes also conduct and sponsor
studies on AD.
Thanks to the work of NIH
institutes, other research orga-

nizations around the world, and
many private-sector research,
education, and advocacy groups,
the study of AD is moving
ahead rapidly. This book explains
what AD is, describes the main
areas in which researchers are
working, and highlights new
approaches for helping families
and friends care for people
with AD.

TO GET THE MOST OUT OF THIS BOOK

Learn the Basics of the Healthy Brain
I
I
I

The parts of the brain (pages 10-13)
How neurons work (pages 14-16)
The changing brain in healthy aging
(pages 17-19)

Explore Cutting-Edge AD Research
I
I
I

Looking for causes (pages 36-47)
Diagnosing AD (pages 48-53)
Searching for treatments (pages 54-61)

Discover What Happens
to the Brain in AD
I
I

The hallmarks of AD (pages 21-26)
The changing brain in AD (pages 27-33)

Learn about Caregiver Support
I
I

I

Who are AD caregivers? (page 63)
Reducing the personal costs of caregiving
(pages 64-67)
Taking care of mom or dad from a distance
(page 68)

TO LEARN EVEN MORE

Visit NIA’s Alzheimer’s Disease Education and Referral Center website at www.nia.nih.gov/alzheimers.
There, you will find resources to accompany this book, such as downloadable versions of the illustrations
and an animation that shows what happens to the changing brain in AD. And while you are there,
explore the ADEAR Center’s many other offerings. These include free publications about AD and AD
caregiving, clinical trials information, and a list of NIA-funded Alzheimer’s Disease Centers.

2

A L ZHE IME R’S DI S EAS E

Unraveling the Mystery

Table of Contents
4

INTRODUCTION

4 AD: A Growing National Problem
5 About This Book

    1
8

THE BASICS OF THE HEALTHY BRAIN

10
10
12
12

Inside the Human Brain
The Main Players
Other Crucial Parts
The Brain in Action

14
14
16
16

Neurons and Their Jobs
Communication
Metabolism
Repair

17 The Changing Brain in Healthy
Aging

    2
20

WHAT HAPPENS TO THE BRAIN IN AD

21
21
25
26

The Hallmarks of AD
Amyloid Plaques
Neurofibrillary Tangles
Loss of Connection Between
Cells and Cell Death

27
27
28
30
31
31

The Changing Brain in AD
Preclinical AD
Very Early Signs and Symptoms
Mild AD
Moderate AD
Severe AD

    3
34

AD RESEARCH: BETTER QUESTIONS,
NEW ANSWERS

36 Looking for the Causes of AD
36 Genetic Factors at Work in AD
40 Other Factors at Work in AD
48 New Techniques Help in Diagnosing AD
50 Exciting New Developments in
AD Diagnosis
54 The Search for New Treatments
55 Helping People with AD Maintain Their
Mental Functioning
56 Managing Symptoms
57 Slowing, Delaying, or Preventing AD

    4
62

IMPROVING SUPPORT FOR
FAMILIES AND OTHER CAREGIVERS

64 Research Findings Benefit Caregivers
66 Early-Stage AD Support Groups:
A Vital Source of Help
69

CONCLUSION

70

GLOSSARY

74

FOR MORE INFORMATION

74
75
76
76

Information and Support Resources
Caregiving Support and Services
Research and Clinical Trials
Recommended Reading

AL Z H EIMER’ S D IS EAS E

Unraveling the Mystery

3

Introduction
“Never have I loved my husband of 41 years more than I do today....Though he may not know I’m his wife,
he does know that my presence means his favorite foods and drinks are near at hand....I wonder why I can
sit daily by his side as I play tapes, relate bits and pieces of news, hold his hand, tell him I love him. Yet I am
content when I am with him, though I grieve for the loss of his smile, the sound of my name on his lips.”

T

his excerpt from Lessons Learned: Shared
Experiences in Coping, by participants
of the Duke University Alzheimer
Support Groups, gives a glimpse into
what a person with Alzheimer’s disease (AD) and
a family caregiver might experience as the disease
progresses. The gradual slipping away of mind
and memory is frightening and frustrating, both
for the person with the disease and for family and
friends, and can elicit strong feelings of love, grief,
anger, and exhaustion.
AD is an irreversible, progressive brain disease
that slowly destroys memory and thinking skills,
eventually even the ability to carry out the simplest
tasks. In most people with AD, symptoms first
appear after age 60. AD is caused by a disease that
affects the brain. In the absence of disease, the
human brain often can function well into the
10th decade of life.
Not so long ago, we were not able to do
much for people with AD. Today, that situation
is changing. Thousands of scientists, voluntary
organizations, and health care professionals are

studying AD so that they can find ways to manage,
treat, and one day prevent this terrible disease.
AD: A GROWING NATIONAL PROBLEM

For many older adults and their families, AD
stands in the way of the “Golden Years.” It also
presents a major problem for our health care system
and society as a whole. AD is the most common
cause of dementia among older people. Recent
estimates of how many people in the United States
currently have AD differ, with numbers ranging
from 2.4 million to 4.5 million, depending on how
AD is measured. But scientists agree that unless
the disease can be effectively treated or prevented,
the numbers will increase significantly if current
population trends continue.
Our aging society makes AD an especially critical issue. A 2005 Census Bureau report on aging
in the United States notes that the population
age 65 and older is expected to double in size to
about 72 million people within the next 25 years.
Moreover, the 85 and older age group is now the
fastest growing segment of the population. This is
all the more important for a neurodegenerative
See the glossary on page 70 for
definitions of boldfaced terms.

4

A L ZHE IME R’S DI S EAS E

Unraveling the Mystery

disease like AD because the number of people
with the disease doubles for every 5-year age
interval beyond age 65.
AD not only affects the people with the disease,
of course. The number of AD caregivers—and
their needs—can be expected to rise rapidly as
the population ages and as the number of people
with AD grows. During their years of AD caregiving, spouses, relatives, and friends experience
great emotional, physical, and financial challenges.
As the disease runs its course and the abilities of
people with AD steadily decline, family members
face difficult, and often costly, decisions about the
long-term care of their loved ones.
The growing number of people with AD and
the costs associated with the disease also put a
heavy economic burden on society. The national
direct and indirect costs of caring for people with
AD are estimated to be more than $100 billion a
year. A 2004 study provided an equally sobering
picture of the impact of AD. It is estimated that
if current AD trends continue, total Federal
Medicare spending to treat beneficiaries with the
disease will increase from $62 billion in 2000 to
$189 billion in 2015.
For these reasons, AD is an urgent research
priority. We need to find ways to manage and treat
AD because of its broad-reaching and devastating
impact. We now know that the disease process

begins many years, perhaps even decades,
before symptoms emerge. Discovering ways to
identify AD in the earliest stages and halt or slow
its progress will benefit individuals, families, and
the Nation as a whole.
ABOUT THIS BOOK

Thinking about AD leads to questions such as:
What causes it? What can be done to cure it or
prevent it? Will I get it? Scientists ask the same
types of questions, and this book describes their
search for answers. It is written for people with
AD, their family members and friends, caregivers,
and others interested in AD.
This book has four sections:
Part 1 gives readers some basics about the
healthy brain. Illustrations and text show what a
healthy brain looks like and how it works.
I Part 2 focuses on what happens in the brain
during AD.
I

Visit the National Institute on Aging (NIA)
Alzheimer’s Disease Education and Referral
(ADEAR) Center website at www.nia.nih.gov/
alzheimers/alzheimers-disease-video to view
an animation that helps this part of the book
come alive.

AL Z H EIMER’ S D IS EAS E

Unraveling the Mystery

5

Introduction
Part 3 talks about current research and the
advances that are bringing us closer to ways of
managing and eventually defeating AD.
I Part 4 focuses on issues important to AD
caregivers and families, including current research
that is finding ways to improve caregiver support.
I

The end of the book includes a list of publications and resources that people with AD, family
members, and caregivers may find useful as they
live day to day with the disease.

A book like this is possible only because of
the major progress that scientists throughout the
world have made. Not long ago, we knew very
little about AD other than some facts about its
major characteristics. Today, we are beginning
to understand more about what AD is and who
gets it, how and why it develops, and what course
it follows. We are learning about the complex
interface between AD and normal age-related
changes in the brain. We also are getting much

Then and Now: The Fast Pace of Developments in AD Research

A

s shown in this timeline, we have learned a lot since Dr. Alzheimer presented the case of his patient, Auguste D.
The pace of research continues to accelerate as new findings open more and more doors to discovery.
196Os

19O6
I

Dr. Alois Alzheimer, a German neurologist and
psychiatrist, describes the case of a 51-year-old
woman, Auguste D., who had been admitted to
a hospital 5 years earlier with a cluster of unusual
symptoms, including problems with comprehension
and memory, an inability to speak, disorientation,
behavioral problems, and hallucinations. After her
death, Dr. Alzheimer examined her brain tissue and
described two of the hallmarks of AD—numerous
globs of sticky proteins in the spaces between
neurons (beta-amyloid plaques) and a tangled
bundle of fibrils within neurons (neurofibrillary
tangles).

191Os – 194Os
I

I

197Os
I

I

I

Belief persists that “senile dementia” is a normal part
of aging.

I

6

I

Scientists study the biological structure of plaques
and tangles.

A L ZHE IME R’S DI S EAS E

Unraveling the Mystery

Scientists find that levels of acetylcholine, a
neurotransmitter important in memory formation,
falls sharply in people with AD. This discovery is
one of the first to link AD with biochemical changes
in the brain.
“Alzheimer’s disease” becomes a common term as
recognition of AD as a major public health problem
grows.
NIA is established.

198Os
I

195Os

Scientists discover a link between dementia and
the number of plaques present in the brain. AD is
recognized as a distinct disease, not a normal part
of aging.

I

Diagnostic criteria for AD are established.
Genetic links to early-onset AD begin to surface.
Congress mandates NIA as lead Federal agency
for AD research.

better at diagnosing it early and accurately. Most
important, we now have some promising leads on
possible treatments. Studies also are beginning
to focus on preventive strategies by examining
lifestyle factors that might influence a person’s
risk of developing AD.
Since the 1970s, research supported by
NIA and other organizations has deepened
our understanding of this devastating disease.
It also has expanded our knowledge of brain

I

I

Scientists start to unravel the biological pathways
that lead to the development of beta-amyloid
plaques in the brain.
Abnormal tau protein in tangles is identified.

199Os
I

I

I

I
I

I

The U.S. Food and Drug Administration (FDA)
approves tacrine (Cognex®), the first drug used to
treat AD. This drug has since been replaced by
other medications.
Genetic mutations linked to early-onset and
late-onset AD are discovered.
The first transgenic mouse model of AD is
created.
Additional diagnostic criteria are developed for AD.
Characteristics of mild cognitive impairment are
described and defined.
NIA launches the Alzheimer’s Disease Education
and Referral Center, AD Cooperative Study, and
other initiatives to conduct and support AD treatment
and prevention clinical trials.

function in healthy older people and identified
ways we might lessen normal age-related declines
in mental function. Most importantly, this accumulated research has increased our appreciation
for just how complex AD is. It is now clear that
many scientific and clinical disciplines need to
work together to untangle the genetic, biological,
and environmental factors that, over many
years, set a person on a course that ultimately
results in AD.

2OOOs

The FDA approves other AD drugs, including
rivastigmine (Exelon®), galantamine (Razadyne®),
donepezil (Aricept®), and memantine (Namenda®)
to treat symptoms of AD.
I Early work on an AD vaccine begins.
I Many new AD clinical trials, initiatives, and
studies are launched, looking at a broad array of
translational, treatment, and prevention issues.
I New transgenic mouse models, including one
that develops both plaques and tangles, are
developed.
I Pittsburgh Compound B (PiB) is developed, allowing
researchers to “see” beta-amyloid plaques in the
brains of living people.
I The growing sophistication of neuroimaging
techniques, genetics, memory and cognitive
tests, structured interviews, and other technologies
improve our ability to identify people at high
risk of AD.
I

AL Z H EIMER’ S D IS EAS E

Unraveling the Mystery

7

PART

1

Basics
of the
Healthy
Brain

The

T

o understand AD, it is important to
know a bit about the brain. This part of
Unraveling the Mystery gives an inside
view of the normal brain, how it works,
and what happens during aging.
The brain is a remarkable organ. Seemingly
without effort, it allows us to carry out every
element of our daily lives. It manages many body
functions, such as breathing, blood circulation,
and digestion, without our knowledge or
direction. It also directs all the functions we carry
out consciously. We can speak, hear, see, move,
remember, feel emotions, and make decisions
because of the complicated mix of chemical and
electrical processes that take place in our brains.
The brain is made of nerve cells and several
other cell types. Nerve cells also are called
neurons. The neurons of all animals function in
basically the same way, even though animals can
be very different from each other. Neurons survive
and function with the help and support of glial
cells, the other main type of cell in the brain. Glial
cells hold neurons in place, provide them with
nutrients, rid the brain of damaged cells and other
cellular debris, and provide insulation to neurons
in the brain and spinal cord. In fact, the brain
has many more glial cells than neurons—some
scientists estimate even 10 times as many.
Another essential feature of the brain is its
enormous network of blood vessels. Even though

The Brain’s
Vital Statistics
A D ULT W E I GH T

about 3 pounds
A D ULT S I Z E

a medium cauliflower
N UMBE R OF N E URON S

about 100,000,000,000 (100 billion)
N UMBE R OF S Y N A P S E S

(the gaps between neurons)
about 100,000,000,000,000 (100 trillion)
N UMBE R OF CA P I L L A RI E S

(tiny blood vessels)
about 400,000,000,000 (400 billion)

the brain is only about 2 percent of the body’s
weight, it receives 20 percent of the body’s blood
supply. Billions of tiny blood vessels, or capillaries,
carry oxygen, glucose (the brain’s principal source
of energy), nutrients, and hormones to brain cells
so they can do their work. Capillaries also carry
away waste products.

AL Z H EIMER’ S D IS EAS E

Unraveling the Mystery

9

P A R T

1

The Basics of the Healthy Brain

Inside the

Human Brain

T

he brain has many parts, each of which
is responsible for particular functions.
The following section describes a few
key structures and what they do.

The occipital lobe, which is at the back of the
brain, is concerned with vision.
The temporal lobe, which runs along the
side of the brain under the frontal and parietal lobes, deals with the senses of smell, taste,
and sound, and the formation and storage of
memories.
I

I

THE MAIN PLAYERS

Two cerebral hemispheres account for 85 percent of the brain’s weight. The billions of neurons
in the two hemispheres are connected by thick
bundles of nerve cell fibers called the corpus callosum. Scientists now think that the two hemispheres differ not so much in what they do (the
“logical versus artistic” notion), but in how they
process information. The left hemisphere appears
to focus on details (such as recognizing a particular
face in a crowd). The right hemisphere focuses on
broad background (such as understanding the relative position of objects in a space). The cerebral
hemispheres have an outer layer called the cerebral
cortex. This is where the brain processes sensory
information received from the outside world,
controls voluntary movement, and regulates
cognitive functions, such as thinking, learning,
speaking, remembering, and making decisions.
The hemispheres have four lobes, each of which
has different roles:
The frontal lobe, which is in the front of the
brain, controls “executive function” activities
like thinking, organizing, planning, and
problem solving, as well as memory, attention,
and movement.
The parietal lobe, which sits behind the
frontal lobe, deals with the perception and
integration of stimuli from the senses.

I

I

I

10 A L ZHE IME R’S DI S EAS E

Unraveling the Mystery

The cerebellum sits above the brain stem and
beneath the occipital lobe. It takes up a little more
than 10 percent of the brain. This part of the
brain plays roles in balance and coordination. The
cerebellum has two hemispheres, which receive
information from the eyes, ears, and muscles and

I

Front View of the Brain

Side View of the Brain
This illustration shows a three-dimensional side
view of one of two cerebral hemispheres of the brain.
To help visualize this, imagine looking at the cut side
of an avocado sliced long ways in half, with the
pit still in the fruit. In this illustration, the “pit” is
several key structures that lie deep within the brain
(the hypothalamus, amygdala, and hippocampus)
and the brain stem.

P A R T

1

The Basics of the Healthy Brain

joints about the body’s movements and position.
Once the cerebellum processes that information, it
sends instructions to the body through the rest of
the brain and spinal cord. The cerebellum’s work
allows us to move smoothly, maintain our balance,
and turn around without even thinking about it. It
also is involved with motor learning and remembering how to do things like drive a car or write
your name.
I The brain stem sits at the base of the brain. It
connects the spinal cord with the rest of the brain.
Even though it is the smallest of the three main
players, its functions are crucial to survival. The
brain stem controls the functions that happen
automatically to keep us alive—our heart rate,
blood pressure, and breathing. It also relays
information between the brain and the spinal
cord, which then sends out messages to the
muscles, skin, and other organs. Sleep and
dreaming are also controlled by the brain stem.
OTHER CRUCIAL PARTS

Several other essential parts of the brain lie deep
inside the cerebral hemispheres in a network of
structures called the limbic system. The limbic
system links the brain stem with the higher
reasoning elements of the cerebral cortex. It plays
a key role in developing and carrying out instinctive behaviors and emotions and also is important in perceiving smells and linking them with
memory, emotion, and instinctive behaviors. The
limbic system includes:
The amygdala, an almond-shaped structure
involved in processing and remembering strong
emotions such as fear. It is located in the temporal
lobe just in front of the hippocampus.

I

12 A L ZHE IME R’S DI S EAS E

Unraveling the Mystery

The hippocampus, which is buried in the
temporal lobe, is important for learning and
short-term memory. This part of the brain is
thought to be the site where short-term
memories are converted into long-term
memories for storage in other brain areas.
I The thalamus, located at the top of the brain
stem, receives sensory and limbic information,
processes it, and then sends it to the cerebral
cortex.
I The hypothalamus, a structure under
the thalamus, monitors activities such as body
temperature and food intake. It issues instructions
to correct any imbalances. The hypothalamus also
controls the body’s internal clock.
I

THE BRAIN IN ACTION

Sophisticated brain-imaging techniques allow
scientists to monitor brain function in living people and to see how various parts of the brain are
used for different kinds of tasks. This is
opening up worlds of knowledge about brain
function and how it changes with age or disease.
One of these imaging techniques is called
positron emission tomography, or PET
scanning. Some PET scans measure blood
flow and glucose metabolism throughout the
brain. (For more on metabolism, see page 16.)
During a PET scan, a small amount of a radioactive substance is attached to a compound, such
as glucose, and injected into the bloodstream.
This tracer substance eventually goes to the brain.
When nerve cells in a region of the brain become
active, blood flow and glucose metabolism in that
region increase. When colored to reflect metabolic activity, increases usually look red and yellow.
Shades of blue and black indicate decreased or no
activity within a brain region.

In essence, a PET scan produces a “map” of
the active brain.
Scientists can use PET scans to see what happens in the brain when a person is engaged in
a physical or mental activity, at rest, or even
while sleeping or dreaming. Certain tracers can
track the activity of brain chemicals, for example
neurotransmitters such as dopamine and

serotonin. (To learn about exciting developments
using one new tracer, see PiB and PET on page
28.) Some of these neurotransmitters are changed
with age, disease, and drug therapies.

AL Z H EIMER’ S D IS EAS E

Unraveling the Mystery

13

P A R T

1

The Basics of the Healthy Brain

Neurons
and Their

T

Jobs

he human brain is made up of billions
of neurons. Each has a cell body,
an axon, and many dendrites. The
cell body contains a nucleus, which
controls much of the cell’s activities. The cell
body also contains other structures, called
organelles, that perform specific tasks.
The axon, which is much narrower than the
width of a human hair, extends out from the cell
body. Axons transmit messages from neuron to
neuron. Sometimes, signal transmissions—like
those from head to toe—have to travel over very
long distances. Axons are covered with an insulating layer called myelin (also called white matter
because of its whitish color). Myelin, which is
made by a particular kind of glial cell, increases
the speed of nerve signal transmissions through
the brain.
Dendrites also branch out from the cell body.
They receive messages from the axons of other
neurons. Each neuron is connected to thousands
of other nerve cells through its axon and dendrites.
Groups of neurons in the brain have special
jobs. For example, some are involved with
thinking, learning, and memory. Others are
responsible for receiving information from the
sensory organs (such as the eyes and ears) or the
skin. Still others communicate with muscles,
stimulating them into action.
Several processes all have to work smoothly
together for neurons, and the whole organism,

14 A L ZHE IME R’S DI S EAS E

Unraveling the Mystery

to survive and stay healthy. These processes are
communication, metabolism, and repair.
COMMUNICATION

Imagine the many miles of fiber-optic cables that
run under our streets. Day and night, millions of
televised and telephonic messages flash at incredible
speeds, letting people strike deals, give instructions,
share a laugh, or learn some news. Miniaturize it,
multiply it many-fold, make it much more complex,
and you have the brain. Neurons are the great communicators, always in touch with their neighbors.
Neurons communicate with each other through
their axons and dendrites. When a dendrite receives an incoming signal (electrical or chemical),
an “action potential,” or nerve impulse, can be
generated in the cell body. The action potential
travels to the end of the axon and once there, the
passage of either electrical current or, more
typically, the release of chemical messengers,
called neurotransmitters, can be triggered. The
neurotransmitters are released from the axon
terminal and move across a tiny gap, or synapse,
to specific receptor sites on the receiving, or postsynaptic, end of dendrites of nearby neurons. A
typical neuron has thousands of synaptic connections, mostly on its many dendrites, with other
neurons. Cell bodies also have receptor sites for
neurotransmitters.

Neurons in the Brain

P A R T

1

The Basics of the Healthy Brain

Once the post-synaptic receptors are activated,
they open channels through the cell membrane
into the receiving nerve cell’s interior or start other
processes that determine what the receiving nerve
cell will do. Some neurotransmitters inhibit nerve
cell function (that is, they make it less likely that
the nerve cell will send an electrical signal down
its axon). Other neurotransmitters stimulate nerve
cells, priming the receiving cell to become active
or send an electrical signal down the axon to more
neurons in the pathway. A neuron receives signals
from many other neurons simultaneously, and the
sum of a neuron’s neurotransmitter inputs at any
one instant will determine whether it sends a signal down its axon to activate or inhibit the action
of other neighboring neurons.
During any one moment, millions of these signals are speeding through pathways in the brain,
allowing the brain to receive and process information, make adjustments, and send out instructions
to various parts of the body.

METABOLISM

All cells break down chemicals and nutrients to
generate energy and form building blocks that
make new cellular molecules such as proteins.
This process is called metabolism. To maintain
metabolism, the brain needs plenty of blood
constantly circulating through its billions of
capillaries to supply neurons and other brain
cells with oxygen and glucose. Without oxygen
and glucose, neurons will quickly die.
REPAIR

Nerve cells are formed during fetal life and for a
short time after birth. Unlike most cells, which
have a fairly short lifespan, neurons in the brain
live a long time. These cells can live for up to 100
years or longer. To stay healthy, living neurons
must constantly maintain and repair themselves.
In an adult, when neurons die because of disease
or injury, they are not usually replaced. Research,
however, shows that in a few brain regions, new
neurons can be generated, even in the old brain.

The

Changing Brain

I

in HealthyAging

n the past several decades, investigators have
learned much about what happens in the
brain when people have a neurodegenerative
disease such as Parkinson’s disease, AD, or
other dementias. Their findings also have revealed
much about what happens during healthy aging.
Researchers are investigating a number of changes related to healthy aging in hopes of learning
more about this process so they can fill gaps in our
knowledge about the early stages of AD.
As a person gets older, changes occur in all parts
of the body, including the brain:

Certain parts of the brain shrink, especially
the prefrontal cortex (an area at the front of the
frontal lobe) and the hippocampus. Both areas
are important to learning, memory, planning, and
other complex mental activities.
I Changes in neurons and neurotransmitters
affect communication between neurons. In certain
brain regions, communication between neurons
can be reduced because white matter (myelincovered axons) is degraded or lost.
I Changes in the brain’s blood vessels occur.
Blood flow can be reduced because arteries narrow
and less growth of new capillaries occurs.
I

In some people, structures called plaques and
tangles develop outside of and inside neurons,
respectively, although in much smaller amounts
than in AD (see The Hallmarks of AD on page 21
for more information on plaques and tangles).
I Damage by free radicals increases (free radicals
are a kind of molecule that reacts easily with other
molecules; see The Aging Process on page 42 for
more on these molecules).
I Inflammation increases (inflammation is the
complex process that occurs when the body
responds to an injury, disease, or abnormal
situation).
I

What effects does aging have on mental
function in healthy older people? Some people
may notice a modest decline in their ability to
learn new things and retrieve information, such
as remembering names. They may perform worse
on complex tasks of attention, learning, and
memory than would a younger person. However,
if given enough time to perform the task, the
scores of healthy people in their 70s and 80s are
often similar to those of young adults. In fact, as
they age, adults often improve in other cognitive
areas, such as vocabulary and other forms of verbal
knowledge.
It also appears that additional brain regions can
be activated in older adults during cognitive tasks,

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The Basics of the Healthy Brain

such as taking a memory test. Researchers do not
fully understand why this happens, but one idea is
that the brain engages mechanisms to compensate
for difficulties that certain regions may be having.
For example, the brain may recruit alternate brain
networks in order to perform a task. These findings have led many scientists to believe that major
declines in mental abilities are not inevitable as
people age. Growing evidence of the adaptive
(what scientists call “plastic”) capabilities of the
older brain provide hope that people may be able
to do things to sustain good brain function as
they age. A variety of interacting factors, such as
lifestyle, overall health, environment, and genetics
also may play a role.
Another question that scientists are asking
is why some people remain cognitively healthy
as they get older while others develop cognitive
impairment or dementia. The concept of
“cognitive reserve” may provide some insights.
Cognitive reserve refers to the brain’s ability to
operate effectively even when some function is
disrupted. It also refers to the amount of damage
that the brain can sustain before changes in
cognition are evident. People vary in the cognitive
reserve they have, and this variability may be
because of differences in genetics, education,
occupation, lifestyle, leisure activities, or other life
experiences. These factors could provide a certain
amount of tolerance and ability to adapt to change
and damage that occurs during aging. At some
point, depending on a person’s cognitive reserve

18 A L ZHE IME R’S DI S EAS E

Unraveling the Mystery

and unique mix of genetics, environment, and life
experiences, the balance may tip in favor of a disease process that will ultimately lead to dementia.
For another person, with a different reserve and
a different mix of genetics, environment, and life
experiences, the balance may result in no apparent
decline in cognitive function with age.
Scientists are increasingly interested in the
influence of all these factors on brain health, and
studies are revealing some clues about actions
people can take that may help preserve healthy
brain aging. Fortunately, these actions also benefit
a person’s overall health. They include:
I

I
I

I

Controlling risk factors for chronic disease,
such as heart disease and diabetes (for example,
keeping blood cholesterol and blood pressure at
healthy levels and maintaining a healthy weight)
Enjoying regular exercise and physical activity
Eating a healthy diet that includes plenty of
vegetables and fruits
Engaging in intellectually stimulating activities
and maintaining close social ties with family,
friends, and community

Vascular Disease on page 43 and Lifestyle
Factors on page 45 provide more information

about these issues and how they may influence the
risk of developing AD.

ACTIVE Study May Provide Clues to Help Older Adults Stay Mentally Sharp

T

he phrase “use it or lose it” may make you think
of your muscles, but scientists who study brain
health in older people have found that it may apply
to cognitive skills as well. In 2006, scientists funded
by NIA and the National Institute of Nursing Research
completed a study of cognitive training in older adults.
This study, the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study, was the first
randomized controlled trial to demonstrate long-lasting,
positive effects of brief cognitive training in older adults.
The ACTIVE study included 2,802 healthy adults
age 65 and older who were living independently.
Participants were randomly assigned to four groups.
Three groups took part in up to 10 computer-based
training sessions that targeted a specific cognitive
ability—memory, reasoning, and speed of processing
(in other words, how fast participants could respond
to prompts on a computer screen). The fourth group
(the control group) received no cognitive training. Sixty
percent of those who completed the initial training also
took part in 75-minute “booster” sessions 11 months
later. These sessions were designed to maintain
improvements gained from the initial training.
The investigators tested the participants at the
beginning of the study, after the initial training and booster
sessions, and once a year for 5 more years. They found
that the improvements from the training roughly counteracted the degree of decline in cognitive performance
that would be expected over a 7- to 14-year period
among older people without dementia:
I Immediately after the initial training, 87 percent
of the processing-speed group, 74 percent of
the reasoning group, and 26 percent of
the memory group showed improvement
in the skills taught.

After 5 years, people in each group performed
better on tests in their respective areas of training
than did people in the control group. The reasoning
and processing-speed groups who received booster
training had the greatest benefit.
The researchers also looked at the training’s effects
on participants’ everyday lives. After 5 years, all three
groups who recieved training reported less difficulty
than the control group in tasks such as preparing
meals, managing money, and doing housework.
However, these results were statistically significant for
only the group that had the reasoning training.
As they get older, many people worry about their
mental skills getting “rusty.” The ACTIVE study offers
hope that cognitive training may be useful because it
showed that relatively brief and targeted cognitive
exercises can produce lasting improvements in the
skills taught. Next steps for researchers are to determine ways to generalize the training benefits beyond
the specific skills taught in ACTIVE and to find out
whether cognitive training programs could prevent,
delay, or diminish the effects of AD.

I

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19

PART

What Happens
to the

2

Brain
AD

in

The

Hallmarks of AD

A

lzheimer’s disease disrupts critical metabolic
processes that keep neurons healthy. These
disruptions cause nerve cells in the brain
to stop working, lose connections with
other nerve cells, and finally die. The destruction
and death of nerve cells causes the memory failure,
personality changes, problems in carrying out
daily activities, and other features of the disease.
The brains of people with AD have an abundance
of two abnormal structures—amyloid plaques
and neurofibrillary tangles—that are made of
misfolded proteins (see Protein Misfolding on
page 41 for more information). This is especially
true in certain regions of the brain that are
important in memory.
The third main feature of AD is the loss of
connections between cells. This leads to diminished cell function and cell death.

AMYLOID PLAQUES

Amyloid plaques are found in the spaces between
the brain’s nerve cells. They were first described
by Dr. Alois Alzheimer in 1906. Plaques consist
of largely insoluble deposits of an apparently toxic
protein peptide, or fragment, called beta-amyloid.
We now know that some people develop
some plaques in their brain tissue as they age.
However, the AD brain has many more plaques
in particular brain regions. We still do not know
whether amyloid plaques themselves cause AD or
whether they are a by-product of the AD process.
We do know that genetic mutations can increase
production of beta-amyloid and can cause rare,
inherited forms of AD (see Genes and EarlyOnset Alzheimer’s Disease on page 38 for
more on inherited AD).
To view a video showing what happens to
the brain in AD, go to www.nia.nih.gov/
alzheimers/alzheimers-disease-video.

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What Happens to the Brain in AD

From APP to Beta-Amyloid Plaques

A

myloid precursor protein (APP), the starting
point for amyloid plaques, is one of many proteins
associated with the cell membrane, the barrier that
encloses the cell. As it is being made inside the cell,
APP becomes embedded in the membrane, like a toothpick stuck through the skin of an orange (Figure 1).
In a number of cell compartments, including the
outermost cell membrane,
specific enzymes snip, or
cleave, APP into discrete
fragments. In 1999 and
2000, scientists identified
Figure 1
the enzymes responsible for
cleaving APP. These enzymes are called alphasecretase, beta-secretase, and gamma-secretase.
In a major breakthrough, scientists then discovered
that, depending on which enzyme is involved and
the segment of APP where the cleaving occurs, APP
processing can follow one of two pathways that
have very different consequences for the cell.
In the benign pathway, alpha-secretase cleaves the
APP molecule within the portion that has the potential to
become beta-amyloid. This eliminates the production of
the beta-amyloid peptide and the potential for plaque
buildup. The cleavage releases from the neuron a fragment called sAPPα, which has beneficial properties,
such as promoting neuronal growth and survival. The
remaining APP fragment, still tethered in the neuron’s
membrane, is then cleaved by gamma-secretase at
the end of the beta-amyloid segment. The smaller of
the resulting fragments also is released into the space
outside the neuron, while
the larger fragment remains
within the neuron and
interacts with factors in the
nucleus (Figure 2).
In the harmful pathway,
beta-secretase first cleaves
Figure 2

22 A L ZHE IME R’S DI S EAS E

Unraveling the Mystery

the APP molecule at one
end of the beta-amyloid
peptide, releasing sAPPβ
from the cell (Figure 3).
Gamma-secretase then
cuts the resulting APP
fragment, still tethered in
Figure 3
the neuron’s membrane,
at the other end of the
beta-amyloid peptide.
Following the cleavages
at each end, the betaamyloid peptide is
released into the space
outside the neuron and
Figure 4
begins to stick to other
beta-amyloid peptides (Figure 4). These small,
soluble aggregates of two, three, four, or even
up to a dozen beta-amyloid peptides are called
oligomers. Specific sizes of oligomers may
be responsible for reacting with receptors on
neighboring cells and synapses, affecting their
ability to function.
It is likely that some oligomers are cleared from
the brain. Those that cannot be cleared clump
together with more beta-amyloid peptides. As the
process continues, oligomers grow larger, becoming
entities called protofibrils and fibrils. Eventually, other
proteins and cellular material are added, and these
increasingly insoluble entities combine to become the
well-known plaques that are characteristic of AD.
For many years, scientists thought that plaques
might cause all of the damage to neurons that is seen
in AD. However, that concept has evolved greatly
in the past few years. Many scientists now think that
oligomers may be a major culprit. Many scientists
also think that plaques actually may be a late-stage
attempt by the brain to get this harmful beta-amyloid
away from neurons.

From APP to Beta-Amyloid Plaque

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What Happens to the Brain in AD

Healthy and Diseased Neurons

24 A L ZHE IME R’S DI S EAS E
24

Unraveling the Mystery

Inside a
Healthy Neuron

Inside a Diseased Neuron

NEUROFIBRILLARY TANGLES

The second hallmark of AD, also described by
Dr. Alzheimer, is neurofibrillary tangles. Tangles
are abnormal collections of twisted protein
threads found inside nerve cells. The chief
component of tangles is a protein called tau.
Healthy neurons are internally supported
in part by structures called microtubules,
which help transport nutrients and other
cellular components, such as neurotransmittercontaining vesicles, from the cell body
down the axon.
Tau, which usually has a certain number of
phosphate molecules attached to it, binds to
microtubules and appears to stabilize them. In
AD, an abnormally large number of additional
phosphate molecules attach to tau. As a result
of this “hyperphosphorylation,” tau disengages
from the microtubules and begins to come
together with other tau threads. These tau
threads form structures called paired helical
filaments, which can become enmeshed
with one another, forming tangles
within the cell. The microtubules can
disintegrate in the process, collapsing the neuron’s internal transport
network. This collapse damages
the ability of neurons to communicate with each other.

Formation of Tau Tangles

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What Happens to the Brain in AD

LOSS OF CONNECTION BETWEEN
CELLS AND CELL DEATH

The third major feature of AD is the gradual
loss of connections between neurons. Neurons
live to communicate with each other, and this
vital function takes place at the synapse. Since
the 1980s, new knowledge about plaques and
tangles has provided important insights into
their possible damage to synapses and on the
development of AD.

The AD process not only inhibits communication between neurons but can also damage
neurons to the point that they cannot function
properly and eventually die. As neurons die
throughout the brain, affected regions begin to
shrink in a process called brain atrophy. By the
final stage of AD, damage is widespread, and
brain tissue has shrunk significantly.

Loss of Connection
Between Cells
This illustration shows
the damage caused by AD:
plaques, tangles, and the
loss of connection between
neurons.

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The

Changing Brain

AD

in

N

o one knows exactly what starts
the AD process or why some of the
normal changes associated with
aging become so much more extreme
and destructive in people with the disease. We
know a lot, however, about what happens in the
brain once AD takes hold and about the physical
and mental changes that occur over time. The
time from diagnosis to death varies—as little as
3 or 4 years if the person is older than 80 when
diagnosed to as long as 10 or more years if the
person is younger. Several other factors besides
age also affect how long a person will live with
AD. These factors include the person’s sex,
the presence of other health problems, and the
Preclinical AD

severity of cognitive problems at diagnosis.
Although the course of the disease is not the same
in every person with AD, symptoms seem to
develop over the same general stages.
PRECLINICAL AD

AD begins deep in the brain, in the entorhinal
cortex, a brain region that is near the hippocampus
and has direct connections to it. Healthy neurons
in this region begin to work less efficiently, lose
their ability to communicate, and ultimately die.
This process gradually spreads to the hippocampus, the brain region that plays a major role in
learning and is involved in converting short-term
memories to long-term memories. Affected
regions begin to atrophy. Ventricles, the fluidfilled spaces inside the brain, begin to enlarge
as the process continues.
Scientists believe that these brain changes
begin 10 to 20 years before any clinically
detectable signs or symptoms of forgetfulness appear. That’s why they are increasingly
interested in the very early stages of the disease
process. They hope to learn more about what
happens in the brain that sets a person on the
path to developing AD. By knowing more about
the early stages, they also hope to be able to

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What Happens to the Brain in AD

PiB and PET

I

magine being able to see deep inside the brain tissue of
a living person. If you could do that, you could find out
whether the AD process was happening many years before
symptoms were evident. This knowledge could have a
profound impact on improving early diagnosis, monitoring
disease progression, and tracking response to treatment.
Scientists have stepped closer to this possibility with the
development of a radiolabeled compound called Pittsburgh
Compound B (PiB). PiB binds to beta-amyloid plaques in the
brain and it can be imaged using PET scans. Initial studies
showed that people with AD take up more PiB in their brains
than do cognitively healthy older people. Since then, scientists have found high levels of PiB in some cognitively healthy
people, suggesting that the damage from beta-amyloid may
already be underway. The next step will be to follow these
cognitively healthy people who have high PiB levels to see
whether they do, in fact, develop AD over time.

develop drugs or other treatments that will
slow or stop the disease process before significant
impairment occurs (see The Search for New
Treatments on page 54 for more information).
VERY EARLY SIGNS AND SYMPTOMS

At some point, the damage occurring in the brain
begins to show itself in very early clinical signs and
symptoms. Much research is being done to identify
these early changes, which may be useful in
predicting dementia or AD. An important part of
this research effort is the development of increasingly sophisticated neuroimaging techniques (see
Exciting New Developments in AD Diagnosis

on page 50 for more on neuroimaging) and the use
of biomarkers. Biomarkers are indicators, such as
changes in sensory abilities, or substances that appear in body fluids, such as blood, cerebrospinal
fluid, or urine. Biomarkers can indicate exposure

28 A L ZHE IME R’S DI S EAS E

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In this PET scan, the red and yellow colors
indicate that PiB uptake is higher in the brain
of the person with AD than in the cognitively
healthy person.

to a substance, the presence of a disease, or the
progression over time of a disease. For example,
high blood cholesterol is a biomarker for risk of
heart disease. Such tools are critical to helping
scientists detect and understand the very early
signs and symptoms of AD.
Mild Cognitive Impairment
As some people grow older, they develop memory
problems greater than those expected for their age.
But they do not experience the personality changes
or other problems that are characteristic of AD.
These people may have a condition called mild
cognitive impairment (MCI). MCI has several
subtypes. The type most associated with memory
loss is called amnestic MCI. People with MCI are
a critically important group for research because

Charting the Course from Healthy Aging to AD

T

his chart shows current thinking about the
evolution from healthy aging
to AD. Researchers view it as
a series of events that occur
in the brain over many years.
This gradual process, which
results from the combination of
biological, genetic, environmental, and lifestyle factors,
eventually sets some people
on a course to MCI and
possibly AD. Other people,
whose genetic makeup may
be the same or different and
who experience a different
combination of factors over a
lifetime, continue on a course
of healthy cognitive aging.

Amnestic MCI:
memory problems;
other cognitive
functions OK;
brain compensates
for changes

AD brain
changes start
decades before
symptoms
show

Cognitive
decline
accelerates
after AD
diagnosis

Normal age-related
memory loss
Total loss of
independent
function

Birth

40

60
Life Course

Healthy Aging

a much higher percentage of them go on to develop AD than do people without these memory
problems. About 8 of every 10 people who fit the
definition of amnestic MCI go on to develop AD
within 7 years. In contrast, 1 to 3 percent of people older than 65 who have normal cognition will
develop AD in any one year.
However, researchers are not yet able to say
definitively why some people with amnestic MCI
do not progress to AD, nor can they say who
will or will not go on to develop AD. This raises
pressing questions, such as: In cases when MCI
progresses to AD, what was happening in the brain
that made that transition possible? Can MCI be
prevented or its progress to AD delayed?
Scientists also have found that genetic
factors may play a role in MCI, as they do in

80

Death

Amnestic MCI

Clinically Diagnosed AD

AD (see Genetic Factors at Work in AD on
page 36 for more information). And, they have
found that different brain regions appear to
be activated during certain mental activities in
cognitively healthy people and those with MCI.
These changes appear to be related to the early
stages of cognitive impairment.
Other Signs of Early AD Development
As scientists have sharpened their focus on the
early stages of AD, they have begun to see hints of
other changes that may signal a developing disease
process. For example, in the Religious Orders Study,
a large AD research effort that involves older nuns,
priests, and religious brothers, investigators have

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What Happens to the Brain in AD

explored whether changes in older adults’ ability to
move about and use their bodies might be a sign of
early AD. The researchers found that participants
with MCI had more movement difficulties than the
cognitively healthy participants but less than those
with AD. Moreover, those with MCI who had lots
of trouble moving their legs and feet were more
than twice as likely to develop AD as those with
good lower body function.
It is not yet clear why people with MCI might
have these motor function problems, but the
scientists who conducted the study speculate that
they may be a sign that damage to blood vessels in
the brain or damage from AD is accumulating in
areas of the brain responsible for motor function.
If further research shows that some people with
MCI do have motor function problems in addition to memory problems, the degree of difficulty,
especially with walking, may help identify those at
risk of progressing to AD.
Other scientists have focused on changes in
sensory abilities as possible indicators of early
cognitive problems. For example, in one study they
found associations between a decline in the ability
to detect odors and cognitive problems or dementia.
These findings are tentative, but they are
promising because they suggest that, some day, it
may be possible to develop ways to improve early
detection of MCI or AD. These tools also will help
scientists answer questions about causes and very
early development of AD, track changes in brain
and cognitive function over time, and ultimately
track a person’s response to treatment for AD.

Mild to Moderate AD

MILD AD

As AD spreads through the brain, the number of
plaques and tangles grows, shrinkage progresses,
and more and more of the cerebral cortex is
affected. Memory loss continues and changes
in other cognitive abilities begin to emerge. The
clinical diagnosis of AD is usually made during
this stage. Signs of mild AD can include:
I
I

I

I
I
I
I

Memory loss
Confusion about the location of familiar places
(getting lost begins to occur)
Taking longer than before to accomplish
normal daily tasks
Trouble handling money and paying bills
Poor judgment leading to bad decisions
Loss of spontaneity and sense of initiative
Mood and personality changes, increased
anxiety and/or aggression

In mild AD, a person may seem to be healthy
but is actually having more and more trouble
making sense of the world around him or her. The
realization that something is wrong often comes
gradually to the person and his or her family.

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Accepting these signs as something other than
normal and deciding to go for diagnostic tests can
be a big hurdle for people and families. Once this
hurdle is overcome, many families are relieved to
know what is causing the problems. They also can
take comfort in the fact that despite a diagnosis
of MCI or early AD, a person can still make
meaningful contributions to his or her family
and to society for a time.

I

I

I

Hallucinations, delusions, suspiciousness or
paranoia, irritability
Loss of impulse control (shown through
undressing at inappropriate times or places
or vulgar language)
An inability to carry out activities that involve
multiple steps in sequence, such as dressing,
making a pot of coffee, or setting the table

Behavior is the result of complex brain
processes, all of which take place in a fraction of
MODERATE AD
a second in the healthy brain. In AD, many of
By this stage, AD damage has spread to the areas
those processes are disturbed, and these disrupted
of the cerebral cortex that control language,
communications between neurons are the basis
reasoning, sensory processing, and conscious
for many distressing or inappropriate behaviors.
thought. Affected regions continue to shrink,
For example, a person may angrily refuse to take
ventricles enlarge, and signs and symptoms of the
a bath or get dressed because he does not underdisease become more pronounced and widespread.
stand what his caregiver has asked him to do. If
Behavioral problems, such as wandering and
he does understand, he may not remember how
agitation, can occur. More intensive supervision
to do it. The anger can be a mask for his conand care become necessary, which can be
fusion and anxiety. Or, a person with AD may
difficult for many spouses and families. The
constantly follow her husband or caregiver and
symptoms of this stage can include:
fret when the person is out of sight. To a person
I Increasing memory loss and confusion
who cannot remember the past or anticipate the
I Shortened attention span
future, the world can be strange and frightening.
I Inappropriate outbursts of anger
Sticking close to a trusted and familiar caregiver
I Problems recognizing friends and family members may be the only thing that makes sense and
I Difficulty with language and problems with
provides security.
reading, writing, and working with numbers
I Difficulty organizing thoughts and thinking
SEVERE AD
logically
In the last stage of AD, plaques and tangles are
I Inability to learn new things or to cope with
widespread throughout the brain, most areas of
new or unexpected situations
the brain have shrunk further, and ventricles have
I Restlessness, agitation, anxiety, tearfulness,
enlarged even more. People with AD cannot
wandering—especially in the late afternoon or
recognize family and loved ones or communicate
at night
in any way. They are completely dependent on
I Repetitive statements or movement, occasional
others for care. Other symptoms can include:
muscle twitches
I Weight loss
I Seizures
I Skin infections
I Difficulty swallowing

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I
I
I

2

What Happens to the Brain in AD

Groaning, moaning, or grunting
Increased sleeping
Lack of bladder and bowel control

Near the end, the person may be in bed much or
all of the time. The most frequent cause of death for
people with AD is aspiration pneumonia. This type
of pneumonia develops when a person is not able to
swallow properly and takes food or liquids into the
lungs instead of air.
Severe AD

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AD Spreads Through the Brain

The Buddy Program at Northwestern University

T

he medical school curriculum

The Buddy Program atspend
Northwestern University
demands that students
enormous amounts of time in the
classroom and clinic learning the
information and skills necessary
for a career in medicine. However, little or no time is set aside
for students to be with patients
outside the hospital or clinic
setting. As a result, it is hard for
medical students to get to know
the human side of the diseases
they are learning about.
The Buddy Program pairs medical students and people with AD
A program at Northwestern
to spend time with—and learn from—each other.
University’s Cognitive Neurology
and Alzheimer’s Disease Center
museums, exercising together, or
hands-on way to learn about AD
is adding just that element to its
even just sharing a coffee or a
and related dementias, and it
medical education. The Buddy
meal. The students also are able
helps him or her understand the
Program, begun in 1998,
to observe their buddies’ clinical
daily realities and issues involved
matches first-year medical
evaluations at the Center. Other
in caring for and supporting
students with people diagnosed
medical schools have started
people with AD and their
with AD or another form of
similar programs.
families. It also introduces them
dementia. About 10 to 15
The people with AD and
to the career path of research
medical students participate
their families are selected from
and clinical practice in AD and
every year. They first take a
Northwestern’s Alzheimer’s
related dementias. For the person
3-hour orientation course on AD, Disease Center and other
with AD, participation in the
family issues, and communication related programs at the university. program provides an opportunity
skills. Then, for the next year, they Families are contacted about
for friendship and socializing
spend at least 4 hours a month
participating, and the people
and an outlet for sharing their
with a person with dementia in
with AD are selected based on
experiences with a sympathetic
addition to monthly meetings
their ability to understand the
listener.
with the program coordinators.
nature of the program and their
For many of the students, the
Together with the person’s
willingness to spend time every
program is a transformative
caregiver and the program’s
month with the student buddy.
experience. They become very
professional staff, students and
The program has clear beneclose to their buddies and family
their “buddies” choose activities
fits for both the medical student
caregivers during their year
for their visits together. Activities
and the person with AD. For the
together, and continue the friendcan include shopping, visiting
medical student, it provides a
ship even after the year is over.

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33

PART

AD RESEARCH :

Better

3

Questions,
New
Answers

S

cientists have studied AD from many
angles. They have looked at populations
to see how many cases of AD occur
every year and whether there might
be links between the disease and lifestyles or
genetic backgrounds. They also have conducted
clinical studies with healthy older people and
those at various stages of AD. They have done
many studies with laboratory animals. They
have begun to look at neuronal circuits and
networks of cells to learn how AD pathology
develops and spreads. They even have examined
individual nerve cells to see how beta-amyloid,
tau, and other molecules affect the ability of
cells to function normally.
These studies have led to a fuller understanding of many aspects of the disease, improved
diagnostic tests, new ways to manage behavioral
aspects of AD, and a growing number of possible

drug treatments. Findings from current research
are pointing scientists in promising directions for
the future. They are also helping researchers to
ask better questions about the issues that are still
unclear.
Part 3 of Unraveling the Mystery describes what
scientists are learning from their search for:
I
I
I

The causes of AD
New techniques to help in diagnosis
New treatments

Results from this research will bring us closer
to the day when we will be able to delay the onset
of, prevent, or cure the devastating disease that
robs our older relatives and friends of their most
precious possession—their minds.

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Looking
for the Causes of AD

O

ne of the most important parts of
unraveling the AD mystery is
finding out what causes the disease.
What makes the disease process begin
in the first place? What makes it worse over time?
Why does the number of people with the disease
increase with age? Why does one person develop
AD while another remains healthy?
Some diseases, such as measles or pneumonia,
have clear-cut causes. They can be prevented with
vaccines or cured with antibiotics. Others, such as
diabetes or arthritis, develop when genetic, lifestyle,
and environmental factors work together to start
a disease process. The role that any or all of these
factors play may be different for each individual.
AD fits into the second group of diseases.
We do not yet fully understand what causes AD,
but we believe it develops because of a complex
series of events that take place in the brain over a
long period of time. Many studies are exploring
the factors involved in the cause and development of AD.
GENETIC FACTORS AT WORK IN AD

Genetic studies of complex neurodegenerative diseases such as AD focus on two main
issues—whether a gene might influence
a person’s overall risk of developing
a disease and whether a gene might
influence some particular aspect of a

person’s risk, such as the age at which the disease
begins. Slow and careful detective work by scientists
has paid off in discoveries of genetic links to the two
main types of AD.
One type is the rare, early-onset Alzheimer’s
disease. It usually affects people aged 30 to 60.
Some cases of early-onset disease are inherited and
are called familial AD (FAD). The other is
late-onset Alzheimer’s disease. It is by far the
more common form and occurs in those 60 and
older. Gaining insight into the genetic factors
associated with both forms of AD is important
because identifying genes that either cause the
disease or influence a person’s risk of developing it
improves our ability to understand how and why
the disease starts and progresses.

DNA, Chromosomes, and Genes: The Body’s Amazing Control Center

T

he nucleus of almost
every human cell contains
an encrypted “blueprint,” along
with the means to decipher it. This
blueprint, accumulated over eons
of genetic trial and error, carries all
the instructions a cell needs to do
its job. The blueprint is made up of
DNA, which exists as two long,
intertwined, thread-like strands
called chromosomes. Each cell
has 46 chromosomes in 23 pairs.
The DNA in chromosomes is made
up of four chemicals, or bases,
strung together in various sequence
patterns. The DNA in nearly all
cells of an individual is identical.
Each chromosome contains
many thousands of segments,
called genes. People inherit two
copies of each gene from their
parents, except for genes on the
X and Y chromosomes, which are
chromosomes that, among other
functions, determine a person’s sex.
Each person normally has one pair
of sex chromosomes (females are
XX and males are XY). The
sequence of bases in a gene tells
the cell how to make specific
proteins. Proteins in large part determine the different kinds of cells that
make up an organism and direct
almost every aspect of the cell’s

construction, operation, and repair.
Even though all genes are present
in most cells, the pattern in which
they are activated varies from cell
to cell, and gives each cell type
its distinctive character. Even slight
alterations in a gene can produce
an abnormal protein, which, in turn,
may lead to cell malfunction and,
eventually, to disease.
Any permanent change in the
sequence of bases in a gene’s

DNA that causes a disease is
called a mutation. Mutations
also can change the activation
of a particular gene. Other more
common (or frequent) changes in
a gene’s sequence of bases do not
automatically cause disease, but
they can increase the chances that
a person will develop a particular
disease. When this happens,
the changed gene is called a
genetic risk factor.

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Genes and Early-Onset
Alzheimer’s Disease
In the early days of AD genetics research, scientists
realized that some cases, particularly of the rare
early-onset AD, ran in families. This led them to
examine DNA samples from these families to see
whether they had some genetic trait in common.
Chromosomes 21, 14, and 1 became the focus of
attention. The scientists found that some families
have a mutation in selected genes on these chromosomes. On chromosome 21, the mutation causes an
abnormal amyloid precursor protein to be produced
(see page 22 for more on APP). On chromosome
14, the mutation causes an abnormal protein called
presenilin 1 to be produced. On chromosome 1,
the mutation causes another abnormal protein to be
produced. This protein, called presenilin 2, is very
similar to presenilin 1. Even if only one of these
genes that are inherited from a parent contains a
mutation, the person will almost inevitably develop
early-onset AD. This means that in these families,
children have about a 50-50 chance of developing
the disease if one of their parents has it.
Early-onset AD is very rare, and mutations in
these three genes do not play a role in the more
common late-onset AD. However, these findings
were crucial because they showed that genetics was
indeed a factor in AD, and they helped to identify
some key cell pathways involved in the AD disease
process. They showed that mutations in APP can
cause AD, highlighting the presumed key role of
beta-amyloid in the disease. Mutations in presenilin 1 and 2 also cause an increased amount of
the damaging beta-amyloid to be made in the brain.

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A Different Genetic Story in
Late-Onset Alzheimer’s Disease
While some scientists were studying the role of
chromosomes 21, 14, and 1 in early-onset AD,
others were looking elsewhere to see if they could
find genetic clues for the late-onset form. By 1992,
investigators had narrowed their search to a region
of chromosome 19. They found a gene on
chromosome 19 that they were able to link to
late-onset AD.
This gene, called APOE, produces a protein
called apolipoprotein E. APOE comes in several
forms, or alleles—ε2, ε3, and ε4:

The APOE ε2 allele is relatively rare and may
provide some protection against the disease. If AD
does occur in a person with this allele, it develops
later in life than in those with an APOE ε4 allele.
I APOE ε3 is the most common allele. Researchers think it plays a neutral role in AD.
I APOE ε4 occurs in about 40 percent of all
people who develop late-onset AD and is present
in about 25 to 30 percent of the population. People with AD are more likely to have an APOE ε4
allele than people who do not have AD. However,
at least one-third of people with AD do not have
an APOE ε4 allele. Dozens of studies have confirmed that the APOE ε4 allele increases the risk
of developing AD, but how that happens is not
yet understood. These studies also have helped to
explain some of the variation in the age at which
AD develops, as people who inherit one or two
APOE ε4 alleles tend to develop AD at an earlier
age than those who do not. However, inheriting
an APOE ε4 allele does not mean that a person
will definitely develop AD. Some people with one
or two APOE ε4 alleles never get the disease, and
others who do develop AD do not have any APOE
ε4 alleles.
I

The Hunt for New AD Genes

F

or some time, scientists have
suspected that, in addition
to APOE ε4, as many as half a
dozen other risk-factor genes exist
for late-onset AD, but they have
been unable to find them. In 2007,
scientists unveiled their discovery of
one new AD risk-factor gene.
This AD risk-factor gene is
called SORL1. It is involved in
recycling APP from the surface of
cells, and its association with AD
was identified and confirmed in
three separate studies. Researchers
found that when SORL1 is
expressed at low levels or in a
variant form, harmful beta-amyloid
levels increase, perhaps by
deflecting APP away from its
normal pathways and forcing it
into cellular compartments that
generate beta-amyloid.
As AD genetics research has
intensified, it has become increasingly clear that scientists need
many different samples of genetic
material if they are to continue
making progress in identifying new
risk-factor genes. Genetic material
is also essential for identifying
associated environmental factors
and understanding the interactions
of genes and the environment.
These advances ultimately will
allow investigators to identify people
at high risk of developing AD and
help them focus on new pathways
for prevention or treatment.

In 2003, NIA launched the
Alzheimer’s Disease Genetics
Study to identify at least 1,000
families with members who have
late-onset AD as well as members
who do not have the disease. All
of these family members provide
blood samples and other clinical
data for the initiative. The material
collected allows 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,
each of which may have relatively
small effects on AD development.
More than 4,000 new cell lines
are now available for researchers
to study risk-factor genes for
late-onset AD.
A new initiative, the Alzheimer’s
Disease Genetics Consortium,
was launched in 2007 to accelerate the application of genetics
technologies to late-onset AD
through collaborations among most
of the leading researchers in AD
genetics. The ultimate goal of this
effort is to obtain genetic material
from 10,000 people with AD and
10,000 cognitively healthy people
to comprehensively scan the whole
genome for the remaining AD
risk-factor genes, as well as those
for age-related cognitive decline.
Some of the genetic material will

be drawn from existing samples
of blood and tissue; other genetic
material will be collected from new
participants.
New AD genetics discoveries
are possible largely because
of close collaboration among
scientists, participation of volunteer
families, new genetics technologies, statistical and analytic
advances, and rapid data sharing.
For example, the SORL1 studies
involved 14 scientific institutions in
North America, Europe, and Asia
and the participation of more than
6,000 people who donated blood
and tissue for genetic typing. An
important part of NIA’s efforts to
promote and accelerate AD
genetics research is to make
biological samples and data
publicly available to approved
researchers.

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OTHER FACTORS AT WORK IN AD

Genetics explains some of what might cause AD,
but it does not explain everything. So, researchers
continue to investigate other possibilities that may
explain how the AD process starts and develops.
Beta-Amyloid
We now know a great deal about how betaamyloid is formed and the steps by which
beta-amyloid fragments stick together in small
aggregates (oligomers), and then gradually form
into plaques (see page 22 in The Hallmarks of
AD for more on this process). Armed with this
knowledge, investigators are intensely interested
in the toxic effects that beta-amyloid, oligomers,
and plaques have on neurons. This research is
possible in part because scientists have been able
to develop transgenic animal models of AD.
Transgenics are animals that have been specially
bred to develop AD-like features, such as
beta-amyloid plaques.
Beta-amyloid studies have moved forward to
the point that scientists are now carrying out
preliminary tests in humans of potential therapies
aimed at removing beta-amyloid, halting its
formation, or breaking down early forms before
they can become harmful.
For example, one line of research by a pharmaceutical company started with the observation that
injecting beta-amyloid into AD transgenic mice
caused them to form antibodies to the betaamyloid and reduced the number of amyloid
plaques in the brain. This exciting finding led to
other studies and ultimately to clinical trials in
which human participants were immunized with
beta-amyloid. These studies had to be stopped
because some of the participants developed
harmful side effects, but the investigators did
not give up hope. Rather, they went back to the
drawing board to rethink their strategy. More

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refined antibody approaches are now being tested
in clinical trials, and additional research on new
ways of harnessing the antibody response continues in the lab.
Another important area of research is how
beta-amyloid may disrupt cellular communication
well before plaques form. One recent study
described how beta-amyloid oligomers target
specific synaptic connections between neurons,
causing them to deteriorate. Other scientists are
studying other potentially toxic effects that plaques
have on neurons and in cellular communication.
Understanding more about these processes may
allow scientists to develop specific therapies to
block the toxic effects.
Tau
Tau, the chief component of neurofibrillary tangles
(see page 25 in The Hallmarks of AD for more
on tau), is generating new excitement as an area
of study. The recent focus on tau has been spurred
by the finding that a mutant form of the protein
is responsible for one form of frontotemporal
dementia, the third most common cause of late-life
dementia, after AD and vascular dementia. This
form is known as frontotemporal dementia with
parkinsonism linked to chromosome 17 (FTDP17). Finding this mutant protein was important
because it suggested that abnormalities in the tau
protein itself can cause dementia.
New transgenic mouse models of AD have
helped tau research make rapid progress. For
example, a recent model, the “triple transgenic”
mouse, forms plaques and tangles over time in
brain regions similar to those in human AD.
Another recent transgenic mouse model, which
contains only human tau, forms clumps of
damaging tau filaments also in a region-specific
fashion similar to AD in humans.
These studies of tau also have suggested a
mechanism for tau damage that is different from
that previously suspected. With these new insights,

scientists now speculate that one reason tau may
damage and kill neurons is because it upsets
the normal activity of the cell, in addition to
forming neurofibrillary tangles.
Other studies of mutant tau in mice suggest that
the accumulation of tau in tangles may not even be the
culprit in memory loss. Rather, as with beta-amyloid,
it may be that an earlier and more soluble abnormal
form of the protein causes the damage to neurons.

Protein Misfolding
Researchers have found that a number of devastating neurodegenerative diseases (for example, AD,
Parkinson’s disease, dementia with Lewy bodies,
frontotemporal lobar degeneration, Huntington’s
disease, and prion diseases) share a key
characteristic—protein misfolding.
When a protein is formed, it “folds” into a
unique three-dimensional shape that helps it

Researchers Explore Neurodegenerative “Cousins”

N

eurodegenerative diseases like AD, Parkinson’s
disease, amyotrophic lateral sclerosis (ALS),
and dementia with Lewy bodies share more than the
basic characteristic of misfolded proteins. They also
share clinical characteristics. For example, people
with AD have trouble moving, a characteristic of
Parkinson’s disease. Sleep-wake disorders, delusions,
psychiatric disturbances, and memory loss occur in
all of these diseases. These diseases also result from

Lifetime
Influences

Genes
Environment
Systemic
factors

Damaging Processes
Occurring Before
Symptoms Appear

Amyloid plaques
Tau tangles
Other abnormal
protein deposits
Reduced oxygen
flow to tissues
Toxic processes

a combination of genetic, lifestyle, and environmental
causes and they develop over many years.
This graphic shows one way of thinking about
how these diseases may be linked as well as what
makes them unique. By investigating the unique
characteristics of these diseases as well as the
characteristics they share, scientists hope to learn
even more than they would if they focused on each
disease by itself.

Neurodegenerative
Diseases*

Early Symptoms
Tremor
Memory loss
Executive function
problems
Movement problems
Gait and balance problems
Sleep-wake disorders
Hallucinations
Delusions
Rigidity

AD
VaD

ALS

AD/PD
PD
DLB
PDD
FTLD

*AD = Alzheimer’s disease, AD/PD = AD with parkinsonism, ALS = amyotrophic lateral sclerosis, DLB = dementia with Lewy bodies,
FTLD = frontotemporal lobar degeneration, VaD = vascular dementia (includes multi-infarct dementia), PD = Parkinson’s disease,
PDD = Parkinson’s disease with dementia
Adapted from an Emory University illustration

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perform its specific function. This crucial process
can go wrong for various reasons, and more
commonly does go wrong in aging cells. As a
result, the protein folds into an abnormal shape—
it is misfolded. In AD, the misfolded proteins are
beta-amyloid (the cleaved product of APP; see
From APP to Beta-Amyloid Plaques on page 22
for more on the formation of beta-amyloid)
and a cleaved product of tau.
Normally, cells repair or degrade misfolded
proteins, but if many of them are formed as part
of age-related changes, the body’s repair and
clearance process can be overwhelmed. Misfolded
proteins can begin to stick together with other
misfolded proteins to form insoluble aggregates.
As a result, these aggregates can build up, leading
to disruption of cellular communication, and
metabolism, and even to cell death. These
effects may predispose a person to AD or other
neurodegenerative diseases.

Scientists do not know exactly why or how
these processes occur, but research into the unique
characteristics and actions of various misfolded
proteins is helping investigators learn more about
the similarities and differences across age-related
neurodegenerative diseases. This knowledge may
someday lead to therapies.
The Aging Process
Another set of insights about the cause of AD
comes from the most basic of all risk factors—
aging itself. Age-related changes, such as inflammation, may make AD damage in the brain worse.
Because cells and compounds that are known to be
involved in inflammation are found in AD plaques,
some researchers think that components of the
inflammatory process may play a role in AD.
Other players in the aging process that may
be important in AD are free radicals, which are
oxygen or nitrogen molecules that combine easily
with other molecules (scientists
call them “highly reactive”). Free
radicals are generated
in mitochondria, which are
structures found in all cells,
including neurons.
Mitochondria are the cell’s
power plant, providing the
energy a cell needs to maintain
its structure, divide, and carry
Mitochondria and
Free Radicals
Any given cell has hundreds of
mitochondria. This illustration
shows two—a healthy mitochondrion and an oxidatively stressed
and damaged one. The arrows
indicate the movement of free
radicals, which can spread easily
from damaged mitochondria to
other parts of the cell.

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The Brain’s Vascular System
This image shows the complexity of the human brain’s
vascular system, particularly large and small arteries
that carry oxygen from the lungs to the brain. Although
many blood vessels are visible here, this image shows
fewer than half of the total number in the brain.

out its functions. Energy for the cell is produced
in an efficient metabolic process. In this process,
free radicals are produced. Free radicals can help
cells in certain ways, such as fighting infection.
However, because they are very active and combine
easily with other molecules, free radicals also can
damage the neuron’s cell membrane or its DNA.
The production of free radicals can set off a chain
reaction, releasing even more free radicals that
can further damage neurons (see illustration on
page 42). This kind of damage is called oxidative
damage. The brain’s unique characteristics, including its high rate of metabolism and its long-lived
cells, may make it especially vulnerable to oxidative damage over the lifespan. The discovery that
beta-amyloid generates free radicals in some AD
plaques is a potentially significant finding in the
quest for better understanding of AD as well as for
other neurodegenerative disorders and unhealthy
brain aging.
Researchers also are studying age-related
changes in the working ability of synapses in
certain areas of the brain. These changes may
reduce the ability of neurons to communicate
with each other, leading to increased neuronal
vulnerability in regions of the brain important
in AD. Age-related reductions in levels of
particular growth factors, such as nerve growth
factor and brain-derived neurotrophic factor,
also may cause important cell populations to be
compromised. Many studies are underway to tease
out the possible effects of the aging process on the
development of AD.

Vascular Disease
For some time now, hints have been emerging
that the body’s vast network of small and large
blood vessels—the vascular system—may make
an important contribution in the development of
dementia and the clinical symptoms of AD. Some
scientists are focusing on what happens with the
brain’s blood vessels in aging and AD. Others are
looking at the relationship between AD and vascular problems in other parts of the body.

AD and Vascular Problems in the Brain

The brain requires a constant and dependable flow
of oxygen and glucose to survive and flourish. The
brain’s blood vessels provide the highways to deliver
these vital elements to neurons and glial cells.
Aging brings changes in the brain’s blood
vessels—arteries can narrow and growth of new
capillaries slows down. In AD, whole areas of
nervous tissue, including the capillaries that supply

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and drain it, also are lost. Blood flow to and from
various parts of the brain can be affected, and the
brain may be less able to compensate for damage
that accumulates as the disease progresses.
For some time now, study of the brain’s blood
vessel system in AD has been a productive line of
inquiry. One important finding has been that the
brain’s ability to rid itself of toxic beta-amyloid by
sending it out into the body’s blood circulation
is lessened. Some scientists now think that poor
clearance of beta-amyloid from the brain, combined with a diminished ability to develop new
capillaries and abnormal aging of the brain’s blood
vessel system, can lead to chemical imbalances in
the brain and damage neurons’ ability to function
and communicate with each other. These findings
are exciting because they may help to explain part
of what happens in the brain during the development of AD. These findings also suggest several
new targets for potential AD therapies.

AD and Vascular Problems in
Other Parts of the Body

Research also has begun to tease out some
relationships between AD and other vascular
diseases, such as heart disease, stroke, and type 2
diabetes. It is important to sort out the various
effects on the brain of these diseases because they
are major causes of illness and death in the United
States today.
Much of this evidence comes from epidemiologic studies, which compare the lifestyles, behaviors, and characteristics of groups of people
(see Describing Scientific Findings: The Type of
Study Makes an Important Difference on page
47 for more information about epidemiologic

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studies). These studies have found, for example,
that heart disease and stroke may contribute to the
development of AD, the severity of AD, or the development of other types of dementia. Studies also
show that high blood pressure that develops during middle age is correlated with cognitive decline
and dementia in later life.
Another focus of AD vascular research is the
metabolic syndrome, a constellation of factors that
increases the risk of heart disease, stroke, and type
2 diabetes. Metabolic syndrome includes obesity
(especially around the waist), high triglyceride
levels, low HDL (“good cholesterol”) levels, high
blood pressure, and insulin resistance (a condition
in which insulin does not regulate blood sugar
levels very well). Evidence from epidemiologic
studies now suggests that people with the metabolic syndrome have increased risk of cognitive
impairment and accelerated cognitive decline.
Nearly one in five Americans older than age 60
has type 2 diabetes, and epidemiologic studies
suggest that people with this disease may be
at increased risk of cognitive problems, including
MCI and AD, as they age. The higher risk
associated with diabetes may be the result of high
levels of blood sugar, or it may be due to other
conditions associated with diabetes (obesity, high
blood pressure, abnormal blood cholesterol levels,
progressive atherosclerosis, or too much insulin
in the blood). These findings about diabetes
have spurred research on a number of fronts—
epidemiologic studies, test tube and animal
studies, and clinical trials. The objective of these
studies is to learn more about the relationship
between diabetes and cognitive problems and to
find out in clinical trials whether treating the disease
rigorously can positively affect cognitive health and
possibly slow or prevent the development of AD.

Lifestyle Factors
We know that physical activity and a nutritious diet
can help people stay healthy as they grow older. A
healthy diet and exercise can reduce obesity, lower
blood cholesterol and high blood pressure, and
improve insulin action. In addition, association
studies suggest that pursuing intellectually
stimulating activities and maintaining active
contacts with friends and family may contribute
to healthy aging. A growing body of evidence now
suggests that these lifestyle factors may be related
to cognitive decline and AD. Researchers who
are interested in discovering the causes of AD are
intensively studying these issues, too.

Physical Activity and Exercise

Exercise has many benefits. It strengthens muscles,
improves heart and lung function, helps prevent
osteoporosis, and improves mood and overall wellbeing. So it is not surprising that AD investigators
began to think that if exercise helps every part of
the body from the neck down, then it might help
the brain as well.
Epidemiologic studies, animal studies, and
human clinical trials are assessing the influence
of exercise on cognitive function. Here are a few
things these studies have found:
Animal studies have shown that exercise increases the number of capillaries that supply blood
to the brain and improves learning and memory in
older animals.

I

If you want to know more about the
benefits of exercise and physical activity
and learn ways to be active every day,
NIA has free information just for you!
Call 1-800-222-2225 or visit
www.nia.nih.gov/Go4Life.

Epidemiologic studies show that higher levels
of physical activity or exercise in older people are
associated with reduced risk of cognitive decline
and reduced risk of dementia. Even moderate
exercise, such as brisk walking, is associated with
reduced risk.
I Clinical trials show some evidence of short-term
positive effects of exercise on cognitive function,
especially executive function (cognitive abilities
involved in planning, organizing, and decision
making). One trial showed that older adults who
participated in a 6-month program of brisk
walking showed increased activity of neurons in
key parts of the brain.
More clinical trials are underway to expand
our knowledge about the relationship of exercise
to healthy brain aging, reduced risk of cognitive
decline, and development of AD. (See Participating in a Clinical Trial on page 59 for more
information).
I

Diet

Researchers have explored whether diet may help
preserve cognitive function or reduce AD risk,
with some intriguing findings. For example,
studies have examined specific foods that are rich
in antioxidants and anti-inflammatory properties
to find out whether those foods affect age-related

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changes in brain tissue. One laboratory study
found that curcumin, the main ingredient of
turmeric (a bright yellow spice used in curry),
can bind to beta-amyloid and prevent
oligomer formation. Another study in
mice found that diets high in DHA
(docosahexaenoic acid), a type of
healthy omega-3 fatty acid found
in fish, reduced beta-amyloid
and plaques in brain tissue.
Other studies have shown
that old dogs perform better on
learning tasks when they eat diets
rich in antioxidants, such as vitamin
E and other healthful compounds, while
living in an “enriched” environment (one in
which the dogs have many opportunities to play and
interact with people and other dogs).
Scientists also have examined the effects of
diet on cognitive function in people. A very large
epidemiologic study of nurses found an association
between participants who ate the most vegetables
(especially green leafy and cruciferous vegetables)
and a slower rate of cognitive decline compared
with nurses who ate the least amount of these
foods. An epidemiologic study of older adults
living in Chicago found the same association. The
researchers do not know the exact reason behind
this association, but speculate that the beneficial
effects may result from the high antioxidant and
folate content of the vegetables.
Dietary studies, such as the curcumin study in
mice or the vegetables study in nurses, generally
examine individual dietary components so that
scientists can pinpoint their specific effects on an
issue of interest. This approach has obvious
limitations because people do not eat just single
foods or nutrients. Several recent epidemiologic
studies have taken a different approach and looked
at an entire dietary pattern.

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In one of these studies, researchers worked
with older adults living in New York who ate the
“Mediterranean diet”—a diet with lots of fruits,
vegetables, and bread; low to moderate
amounts of dairy foods, fish, and
poultry; small amounts of red meat;
low to moderate amounts of wine;
and frequent use of olive oil. The
researchers found that sticking
to this type of diet was associated
with a reduced risk of AD and
that the association seemed to
be driven by the whole approach,
rather than by its individual dietary
components. A follow-up study found
that this pattern also was associated with
longer survival in people with AD.
All of these results are exciting and suggestive,
but they are not definitive. To confirm the results,
scientists are conducting clinical trials to examine the
relationship of various specific dietary components
and their effect on cognitive decline and AD.

Intellectually Stimulating
Activities and Social Engagement

Many older people love to read, do puzzles, play
games, and spend time with family and friends. All
these activities are fun and help people feel alert
and engaged in life. Researchers are beginning to
find other possible benefits as well, for some studies
have shown that keeping the brain active is associated with reduced AD risk. For example, over a
4-year period, one group of researchers tracked how
often a large group of older people did activities
that involved significant information processing,
such as listening to the radio, reading newspapers,
playing puzzle games, and going to museums. The
researchers then looked at how many of the participants developed AD. The researchers found that

the risk of developing AD was 47 percent lower in
The reasons for these findings are not entirely
the people who did them the most frequently
clear, but a number of explanations are possible.
compared with the people who did the activities
Among them:
least frequently. Another study supported the value
I Intellectually stimulating activities and social
of lifelong learning and mentally stimulating
engagement may protect the brain in some way,
activity by finding that, compared with older study
perhaps by establishing a cognitive reserve.
participants who may have had AD or who had
I These activities may help the brain become
AD, healthy older participants had engaged in more
more adaptable and flexible in some areas of
mentally stimulating activities and spent more time
mental function so that it can compensate for
at them during their early and middle adulthood.
declines in other areas.
Studies of animals, nursing home residents, and
I Less engagement with other people or in
people living in the community also have suggested
intellectually stimulating activities could be
a link between social engagement and cognitive
the result of very early effects of the disease
performance. Older adults who have a full social
rather than its cause.
network and participate in many social activities tend
I People who engage in stimulating activities may
to have less cognitive decline and a decreased risk of
have other lifestyle qualities that may protect
dementia than those who are not socially engaged.
them against developing AD.

Describing Scientific Findings:
The Type of Study Makes an Important Difference

T

hese days, the media are
full of stories about scientific
studies. It can be hard to know
what to conclude about their findings. Knowing how the study was
conducted can help put the results
into the right perspective.
One main type of research is
the epidemiologic study. These
studies are observational—they
gather information about people
who are going about their daily
lives. Study participants follow
many behaviors and practices. It
is difficult, therefore, to determine
the exact benefits or risks of one
particular behavior from among all
the healthy or harmful behaviors

followed by the participants. That
is why, in epidemiologic studies of
AD, scientists only say that a finding is “associated with” AD, or not.
The epidemiologic evidence linking
a behavior and AD is, at best, suggestive, but we do not know that
the behavior by itself actually helps
to cause or prevent AD.
Other types of research—test
tube studies and studies in animals—add to the findings from
epidemiologic studies. Scientists
use them to examine the same
issue but in ways in which the
various factors that might influence a result are controlled to
a greater degree. This element

of control allows scientists to be
more certain about why they get
the results they do. It also allows
them to be more definitive in the
words they use to describe their
results. Of course, showing a
cause-and-effect relationship in
tissue samples or even in animal
studies still does not mean that the
relationship will be the same in
humans. Clinical trials in humans
are the gold standard for deciding whether a behavior or a
specific therapeutic agent
actually prevents or delays AD
(see Participating in a Clinical
Trial on page 59 for more on
this kind of research).

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AD Research: Better Questions, New Answers

New Techniques
Help in Diagnosing
A man in his mid-60s begins to notice that his
memory isn’t as good as it used to be. More and more
often, a word will be on the tip of his tongue but
he just can’t remember it. He forgets appointments,
makes mistakes when paying his bills, and finds
that he’s often confused or anxious about the normal
hustle and bustle of life around him. One evening, he
suddenly finds himself walking in a neighborhood he
doesn’t recognize. He has no idea how he got there or
how to get home.

AD

mimic those of AD. Finding out early that the
observed changes in cognitive abilities are not AD
but something else is almost always a relief and
may be just the prod needed to seek appropriate
medical treatment (see Causes of Dementia on
page 50 for more information). For the small
percentage of dementias that are treatable or
even reversible, early diagnosis increases the
chances of successful treatment. Increasing early
diagnosis and improving treatment are among
NIA’s most important goals.
ot so long ago, this man’s condition
Even when the cause of a loved one’s dementia
would have been swept into a broad
turns out to be AD, it is best to find out sooner
catch-all category called “senile
rather than later. One benefit of knowing is medidementia” or “senility.” Although we
cal. The drugs now available to treat AD can help
now know that AD and other causes of dementia are some people maintain their mental abilities for
distinct diseases, in the early stages it is difficult to months to years, although they do not change the
differentiate between the onset of AD and other types underlying course of the disease (see Helping
of age-related cognitive decline. We have improved People with AD Maintain their Mental Functionour ability to diagnose AD correctly, and doctors
ing on page 55 for more about these drugs).
experienced in AD can diagnose the disease with up
Other benefits are practical. The sooner the perto 90 percent accuracy. A definitive diagnosis of AD, son with AD and the family have a firm diagnosis,
however, is still only possible after death, during an the more time they have to make future living
autopsy, and we are still far from the ultimate goal— arrangements, handle financial matters, establish
a reliable, valid, inexpensive, and early diagnostic
a durable power of attorney and advance direcmarker that can be used in any doctor’s office.
tives, deal with other legal issues, create a support
Early diagnosis has several advantages. For
example, many conditions cause symptoms that

N

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Current Tools for Diagnosing AD

W

ith the tools now available,
experienced physicians
can be reasonably confident about
making an accurate diagnosis of
AD in a living person. Here is
how they do it.
They take a detailed
patient history, including:
I A description of how and when
symptoms developed.
I A description of the person’s
and his or her family’s overall
medical condition and history.
I An assessment of the person’s
emotional state and living
environment.
They get information
from family members or
close friends:
I People close to the person can
provide valuable insights into

how behavior and personality
have changed; many times,
family and friends know something is wrong even before
changes are evident on tests.
They conduct physical and
neurological examinations
and laboratory tests:
I Blood and other medical tests
help determine neurological
functioning and identify possible
non-AD causes of dementia.
They conduct neuropsychological testing:
I Question-and-answer tests
or other tasks that measure
memory, language skills, ability
to do arithmetic, and other
abilities related to brain functioning help show what kind of
cognitive changes are occurring.

network, and even consider joining a clinical trial
or other research study. Being able to participate
for as long as possible in making personal decisions
is important to many people with AD.
Early diagnosis also gives families time to recognize that life does not stop with a diagnosis of
AD. The person is still able to participate in many
of the daily activities he or she has always enjoyed,
and families can encourage the person to continue

They may do a computed
tomography (CT) scan or a
magnetic resonance imaging
(MRI) test:
I CT and MRI scans can detect
strokes or tumors or can reveal
changes in the brain’s structure
that indicate early AD.
Exams and tests may be repeated
every so often to give physicians
information about how the person’s
memory and other symptoms are
changing over time.
Based on findings from these
exams and tests, experienced
physicians can diagnose or rule
out other causes of dementia, or
determine whether the person has
MCI, “possible AD” (the symptoms
may be due to another cause), or
“probable AD” (no other cause for
the symptoms can be found).

with them for as long as possible. Finally, early
diagnosis gives family caregivers the opportunity to
learn how to recognize and cope with changes over
time in their loved one as well as to develop strategies that support their own physical, emotional,
and financial health.

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Causes of Dementia

D

ementia is the loss of cognitive functioning—thinking, remembering, and reasoning—to such
an extent that it interferes with a person’s daily life and activities. It is not a disease itself, but a
group of symptoms that often accompanies a disease or condition. Some dementias are caused by
neurodegenerative diseases. Dementia also has other causes, some of which are treatable.

Neurodegenerative Diseases that Cause Dementia
I Alzheimer’s disease
I Vascular dementia
I Parkinson’s disease with dementia
I Frontotemporal lobar degeneration, including:
I frontotemporal dementia
I frontotemporal dementia with parkinsonism
linked to chromosome 17 (FTDP-17)
I Pick’s disease
I supranuclear palsy
I corticobasal degeneration

Scientists also see advantages to early diagnosis.
Developing tests that can reveal what is happening in the brain in the early stages of AD will help
them understand more about the cause and development of the disease. It also will help scientists
learn when and how to prescribe the use of drugs
and other treatments so they can be most effective.
EXCITING NEW DEVELOPMENTS
IN AD DIAGNOSIS

Scientists are now exploring ways to help physicians
diagnose AD earlier and more accurately. For
example, some studies are focusing on changes
in mental functioning. These changes can be

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Other Causes of Dementia
I Medication side effects
I Depression
I Vitamin B12 deficiency
I Chronic alcoholism
I Certain tumors or infections of
the brain
I Blood clots pressing on the brain
I Metabolic imbalances, including
thyroid, kidney, or liver disorders

measured through memory and recall tests. Tests
that measure a person’s abilities in areas such as
abstract thinking, planning, and language can
help pinpoint changes in these areas of cognitive
function. Researchers are working to improve
standardized tests that might be used to point
to early AD or predict which individuals are at
higher risk of developing AD in the future.
Other studies are examining the relationship between early damage to brain tissue and
outward clinical signs. Still others are looking
for changes in biomarkers in the blood or cerebro-spinal fluid that may indicate the progression
of AD (see Very Early Signs and Symptoms on
page 28 for more on this work).
One of the most exciting areas of ongoing
research in this area is neuroimaging. Over the
past decade, scientists have developed several

highly sophisticated imaging systems that have
been used in many areas of medicine, including
AD. PET scans, single photon emission
computed tomography (SPECT), and MRI are
all examples. These “windows” on the living brain
may help scientists measure the earliest changes
in brain function or structure in order to identify
people who are at the very first stages of the
disease—well before they develop clinically
apparent signs and symptoms.
To help advance this area of research, NIA
launched the multi-year AD Neuroimaging
Initiative (ADNI) in 2004. This project is following about 200 cognitively healthy individuals
and 400 people with MCI for 3 years and 200
people with early AD for 2 years. Over the course
of this study, participants undergo multiple MRI
and PET scans so that study staff can assess how
the brain changes in the course of normal aging
and MCI, and with the progression of AD. By
using MRI and PET scans at regularly scheduled
intervals, study investigators hope to learn when
and where in the brain degeneration occurs as
memory problems develop.
Another innovative aspect of ADNI is that
scientists are correlating the participants’ imaging
information with information from clinical,
memory, and other cognitive function tests, and
with information from blood, cerebrospinal fluid,
and urine samples. Results from these samples
may provide valuable biomarkers of disease
progress, such as changing levels of beta-amyloid
and tau, indicators of inflammation, measures of
oxidative stress, and changing cognitive abilities.
An important ADNI achievement is the
creation of a publicly accessible database of
images, biomarker data, and clinical information
available to qualified researchers worldwide.

Biological samples also are available for approved
biomarker projects. NIA hopes that this initiative
will help create rigorous imaging and biomarker
standards that will provide measures for the
success of potential treatments. This would
substantially increase the pace and decrease the
cost of developing new treatments. The ADNI
study is being replicated in similar studies by
researchers in Europe, Japan, and Australia.
These types of neuroimaging scans are still
primarily research tools, but one day they may be
used more commonly to help physicians diagnose
AD at very early stages. It is conceivable that
these tools also may someday be used to monitor
the progress of the disease and to assess responses
to drug treatment.

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AD Research: Better Questions, New Answers

New Technologies Help People Participate in AD Research at Home

T

raditionally, AD scientists have collected data by
asking people to come to a clinic once or twice a
year over a period of years. They give the participants
a physical exam and ask them to take a series of
memory, language, and other cognitive function tests.
These studies collect much useful information, but
they have their limitations. For one thing, participants
are seen only once or twice during the year, so the
data collected represent only a “snapshot” in time.
The studies cannot effectively capture day-to-day
fluctuations in behaviors and cognitive abilities.
Another limitation is that participants are seen in
a research setting, not in their natural community
environment. For many, coming to the clinic can be
inconvenient, difficult, or both.
Advances in technology, as shown in the two
research projects described here, offer some hope
for dealing with these challenges by bringing
research to people right in their own homes.

MOTION DETECTORS TELL
AN INTERESTING STORY

Scientists who are trying to develop methods for
diagnosing AD as early as possible continually
grapple with two challenges in conducting their
research. First, they need to find easy and accurate
ways to collect data from older people, who often
have physical, emotional, or cognitive problems.
Second, they need to find ways to assess accurately
the very early changes in physical or cognitive
abilities that could indicate that AD is progressing.
Under an NIA grant, the Oregon Center for Aging
and Technology (ORCATECH) at Oregon Health &

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Science University is exploring the use of unobtrusive,
simple technology and intelligent systems to detect
and monitor subtle changes in movement that may
indicate age-related cognitive changes. This project is
building on research that has suggested that motorfunction changes may arise before memory changes
become apparent (see Very Early Signs and
Symptoms on page 28 for more on this research).
All of the 300 study participants are 80 years or
older or have a spouse of a similar age, and live
independently in Portland-area retirement communities. Wireless, infrared motion sensors, like those
used to automatically open grocery store doors, have
been placed strategically throughout the participants’
homes to gather data about changes in their walking
or dressing speed over time. Special software also
has been installed on each participant’s home
computer to measure motor skills and speed in typing
or using a mouse. The sensors and computer software
collect data about motion, not what the volunteer
is actually doing. Privacy is largely not a concern
therefore, because the volunteers are not directly
observed and no video or photographs are taken.
The 3-year study began in early 2007, so results
are not yet available. However, a small pilot study
using the same type of sensors showed a clear
difference in the walking speeds of people age 65
and older who had MCI, compared with cognitively
healthy people of the same age, over time periods
of nearly a year. These data suggest that a remote
sensing system like this is a feasible technology and is
potentially sensitive enough to distinguish accurately
between affected and unaffected people.

This photo shows ORCATECH
study participants at home. The
small device between the photographs on the wall is an infrared
motion sensor.
USING TECHNOLOGY
TO COLLECT DATA AT HOME

Researchers at nearly 30 sites nationwide are
comparing various ways of collecting data, including
the use of an in-home “kiosk” that combines a
touch-screen computer monitor with a telephone
handset, an interactive voice-response system, and
traditional mail and telephone. All three methods
gather the same data about several areas known to
be important in early detection of cognitive decline:
memory; language skills; attention and concentration;
activities of daily living; quality of life; health care
and resource use; and changes in “global” well-being
as measured by self-rating of health, cognition, and

mood. This study is looking at questions such as
how likely people are to complete the questions
using each method, which method is the most
efficient, and how sensitive each method is.
Having a data collection system that is easy to
use and that collects data accurately and completely
may encourage wider participation in AD clinical
trials. It also may reduce the expense and burden of
conducting AD research. Early results from this study
show that the older participants were skeptical at first
about using the kiosk, but once they learned how to
use it, they became enthusiastic and excited about
participating.

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AD Research: Better Questions, New Answers

The

Search

for New Treatments

M

ore and more, scientists are able
to think about ways to treat, slow,
or perhaps even prevent AD at a
number of possible points during
the years-long continuum of disease progression.
This continuum begins with the very earliest
disease stage, even before symptoms are evident,
moves to the first signs of memory and cognitive
problems, then continues through the mild and
moderate stages, and ends with the very late stages
and the person’s death.
As a result, researchers who focus on developing
AD treatments think a lot about the importance
of timing: When would it be best to intervene
and what interventions are most appropriate at
which time? These questions are similar to those
asked with other conditions, such as heart disease.
For example, a physician would prescribe different
treatments for a patient who is seemingly healthy
but who is at risk of having future heart disease
than for a patient who is actually having a heart
attack or whose heart disease is well established. The
same decision process now can be applied to AD.
It has become clear that there probably is no
single “magic bullet” that will, by itself, prevent or
cure AD. Therefore, investigators are working to
develop an array of options from which physicians
can choose. For people who already have AD, the

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most immediate need is for treatments to control
cognitive loss as well as problem behaviors, such as
aggression, agitation, wandering, depression, sleep
disturbances, hallucinations, and delusions. Safe
medications that remain effective over time are
needed to ease a broad range of symptoms and to
improve a person’s cognitive function and ability
to carry out activities of daily living. Scientists also
are investigating treatments that combine medications with lifestyle strategies to lessen the risk of
developing cognitive decline or AD. Eventually,
scientists hope to develop treatments that attack
the earliest manifestations and underlying causes
of AD, thereby slowing, delaying, or preventing
the disease from progressing and damaging cognitive function and quality of life. Scientists use
clinical trials to pursue all these goals.
Today, NIA, other NIH institutes, and private
industry are conducting many clinical trials of
AD interventions (see page 59 for more about
clinical trials). These studies focus on several
key areas:
I

I
I

Helping people with AD maintain their mental
functioning
Managing symptoms
Slowing, delaying, or preventing AD

HELPING PEOPLE WITH
AD MAINTAIN THEIR MENTAL
FUNCTIONING

In the mid-1970s, scientists discovered that
levels of a neurotransmitter (a chemical that carries
messages between neurons) called acetylcholine
fell sharply in people with AD. This discovery was
one of the first that linked AD with biochemical
changes in the brain. Scientists found that
acetylcholine is a critical player in the process of
forming memories. It is used by neurons in the
hippocampus and cerebral cortex, which are areas
of the brain important to memory function. This
discovery was an important initial breakthrough in
the search for drugs to treat AD.
Four medications, tested in clinical trials, have
been approved by the FDA for use in treating AD
symptoms. Donepezil (Aricept®), rivastigmine
(Exelon®), and galantamine (Razadyne®) are prescribed to treat mild to moderate AD symptoms.
Donepezil was recently approved to treat severe
AD as well. These drugs, known as cholinesterase
inhibitors, act by stopping or slowing the action of
acetylcholinesterase, an enzyme that breaks down
acetylcholine. They help to maintain higher levels
of acetylcholine in the brain. In some people, the
drugs maintain abilities to carry out activities of
daily living. They also may maintain some thinking, memory, or speaking skills, and can help with
certain behavioral symptoms. However, they will
not stop or reverse the underlying progression of
AD and appear to help people only for months to
a few years. The newest approved AD medication
is memantine (Namenda®), which is prescribed to
treat moderate to severe AD symptoms. This drug
appears to work by regulating levels of glutamate,
another neurotransmitter involved in memory
function. Like the cholinesterase inhibitors,
memantine will not stop or reverse AD.

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MANAGING SYMPTOMS

“My father is often agitated. He paces up and down,
wringing his hands and crying. I know he’s sad or
anxious about something but he can’t tell me what’s
bothering him. Asking him about it just makes him
more upset.”
“Last week, I visited Mom in the nursing home. We
had a great time. Then yesterday, I went to see her
again. When I walked into her room, she didn’t know
me. She thought I was her sister.”
“My husband used to be such an easy going, calm
person. Now, he suddenly lashes out at me and uses
awful language. Last week, he got angry when our
daughter and her family came over and we sat down
to eat. I never know when it’s going to happen. He’s
changed so much—it scares me sometimes.”
“Gran hums all the time. She used to be a singer. Is
she trying to relive her past?”
As AD begins to affect memory and mental
abilities, it also begins to change a person’s emotions and behaviors. Between 70 and 90 percent
of people with AD eventually develop one or more
behavioral symptoms. These symptoms include
sleeplessness, wandering and pacing, aggression,
agitation, anger, depression, and hallucinations
and delusions. Some of these symptoms may
become worse in the evening (a phenomenon
called “sundowning”) or during daily routines,
especially bathing.

The damage of AD affects many different parts
of the brain. This presents a problem because even
small tasks require the brain to process signals that
often involve more than one region of the brain. If
this processing is disrupted because of AD, the
person may not be able to do the task or may act
in a strange or inappropriate way.
In light of our growing understanding about the
effects of AD on the brain, behaviors like the ones
highlighted above suddenly make sense or even
provide a loving opportunity for caregivers:
For a man who can no longer distinguish between past
and present, the anguish caused by the death of a parent may be as real today as it was many years before.
Sitting down to a family meal may produce
intense anxiety when a person has no idea what to do
with the knife and fork in front of him and all the
conversation and activity feel overwhelming.
Memories of favorite songs from long ago resurface and
provide a compelling link to a happy time in the past.
Behavioral symptoms, often emotional and
upsetting, are one of the hardest aspects of the
disease for families and other caregivers to deal
with. They are also a visible sign of the terrible
change that has taken place in the person with
AD. Researchers are slowly learning more about
why behavioral symptoms occur and are conducting clinical trials on new treatments—both drug
and non-drug—to deal with difficult behaviors.

Coping with Behavioral Symptoms
For more information on how to deal with
behavioral issues and symptoms, visit the
caregiving section of NIA’s Alzheimer’s
Disease Education and Referral (ADEAR)
Center website at: www.nia.nih.gov/
alzheimers/topics/caregiving.

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SLOWING, DELAYING,
OR PREVENTING AD

AD research has developed to the point where
scientists are looking beyond treating symptoms
to addressing the underlying disease process.
Slowing the progress of AD could do much to
maintain the functioning of people with AD and
reduce physical and emotional stress on caregivers.
Delaying AD’s effects also could help to postpone
or prevent placement in an assisted living facility
or nursing home, and reduce the financial costs of
the disease. Preventing AD altogether is, of course,
the ultimate long-term goal.
NIA and pharmaceutical companies support
treatment clinical trials that are aimed at slowing, delaying, or preventing AD. The advances in
our knowledge about the mechanisms and risk
factors associated with AD have expanded the
types of interventions under study. These trials
are examining a host of possible interventions,
including cardiovascular treatments, hormones,
type 2 diabetes treatments, antioxidants, omega-3
fatty acids, immunization, cognitive training, and
exercise, among others.
For example, NIA funds pilot trials to learn
whether treating one or another aspect of type 2
diabetes will affect cognitive health and AD progression. A pilot trial is a relatively small clinical
trial that collects initial data on the safety,
effectiveness, and best dosage of a potential
treatment. This information helps investigators
decide which treatments should be tested in
larger, full-scale trials. One 4-month pilot trial
has examined the effects on AD of administering
a nasal-spray form of insulin. This trial is
founded on evidence that AD is associated with
reduced levels of insulin in cerebrospinal fluid
and that treatment with insulin improves

memory performance. The trial will provide
useful data on the safety, feasibility, and
potential effectiveness of this innovative treatment
approach. Investigators may be able to use the
results to plan future full-scale clinical trials.
Beyond pilot studies, investigators also are
conducting full-scale AD clinical trials of various
interventions. One of these trials, the Alzheimer’s
Disease Cooperative Study (ADCS), is testing
whether one omega-3 fatty acid (DHA), found in
the oil of certain fish, can slow the progression of
cognitive and functional decline in people with
mild to moderate AD. During the 18-month
clinical trial, investigators will measure the
progress of the disease using standard tests for
functional and cognitive change. Researchers also
will evaluate whether taking DHA supplements
has a positive effect on possible physical and
biological markers of AD, such as brain atrophy

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and proteins in blood and spinal fluid. The ADCS
is a federally established consortium conducting
clinical trials on AD, with sites across the United
States and Canada.
Full-scale AD prevention trials are underway as well. One such trial, Prevention of
Alzheimer’s Disease with Vitamin E and
Selenium (PREADVISE), is being conducted in
conjunction with a National Cancer Institutefunded trial called the Selenium and Vitamin E

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Cancer Prevention Trial (SELECT). SELECT
is evaluating whether taking selenium and/
or vitamin E supplements can prevent prostate
cancer in healthy men older than 60 years.
PREADVISE is evaluating whether these
supplements can help prevent memory loss and
dementia by protecting brain cells from oxidative
damage (see The Aging Process on page 42 for
more on oxidative damage). About 6,000 of the
more than 30,000 men enrolled in SELECT are
participating in PREADVISE.

Participating in a Clinical Trial

R

apid advances in our
knowledge about AD have
led to the development of many
promising new drugs and treatment
strategies. However, before these
new strategies can be used in clinical practice, they must be shown
to work in people. This means
that clinical trials—and volunteer
participants—are an essential
part of AD research. Advances
in prevention and treatment are
possible thanks to volunteers who
participate in clinical trials.
Clinical trials are the primary
way that researchers find out if
a promising treatment is safe.
Clinical trials tell researchers which
treatments are the most effective
and for which people they may
work best. Trials can take place
in various settings, such as private
research facilities, teaching
hos-pitals, specialized AD research
centers, and doctors’ offices. FDA
approval is necessary before
scientists can begin a clinical trial.
Participating in a clinical trial
is a big step for anyone, including
people with AD and their caregivers. That is why physicians and
clinical trials staff spend time talking
with participants about what it is
like to be in a trial and the pros and
cons of participating. It is also why
they get a signed informed consent
form before a person enrolls in

WHAT ARE THE PHASES
OF CLINICAL TRIALS?

small number of participants and
examines its action in the body
and its safety. The main goals of
Phase I trials are to establish the
highest dose of a new drug that
people can tolerate and to define
the dose at which people may
begin to experience harmful side
effects. These trials generally last
only a few months.
If results show that the treatment appears to be safe, it will
go on to Phase II and Phase
III clinical trials. Phase II trials
involve larger numbers of people
studied over longer periods of
time than Phase I trials. In these
trials, the study team wants to
know whether the treatment is
safe and effective at changing
the course of the disease. Phase
II trials occasionally also involve
the use of a placebo (an inactive
substance that looks like the study
drug). Results from Phase II trials
give study staff an indication of
the effective dose to take into
Phase III trials. Phase III trials are
large studies that compare an
experimental treatment with a
placebo or standard treatment
to determine safety and efficacy
(whether the treatment has the
power to produce an effect).
After these phases are complete

During Phase I trials, a research
team gives the treatment to a

Continued on next page

a trial. Here are some facts that
potential participants might want to
know about clinical trials.
WHAT KIND OF
TRIALS ARE THERE?

Treatment trials with existing drugs
or behavioral strategies assess
whether an intervention already
approved for other purposes may
be useful in treating age-related
cognitive decline or AD. For
example, trials have tested whether
drugs used to lower cholesterol
help slow progression of AD.
Treatment trials with experimental
drugs or strategies show whether
a new drug or treatment approach
can help improve cognitive function
or lessen symptoms in people with
AD, slow the progression to AD,
or prevent it. Interventions tested
in these trials are developed from
knowledge about the mechanisms
involved in the AD process. Experimental drugs, for example, are
first tested in tissue culture and in
animals to determine their actions in
the body. Safety and effectiveness
studies are also conducted in
animals before the compounds
are tested in humans.

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AD Research: Better Questions, New Answers

Participating in a Clinical Trial
and investigators are satisfied that
the treatment is safe and effective,
the study team may submit its
data to the FDA for approval. FDA
experts review the data and
decide whether to approve the
drug or treatment for use in patients
with the disease under study.
WHAT HAPPENS WHEN
A PERSON SIGNS UP FOR A
CLINICAL TRIAL?

First, it is important to learn
about the trial. Staff at the clinical
research center explain the trial
in detail to potential participants
and describe possible risks
and benefits. Staff also talk
about the participants’ rights as
research volunteers, including
their right to leave the trial at
any time. Participants and their
family members are entitled to
have this information repeated
and explained until they feel they
understand the nature of the trial
and any potential risks.
After all questions have been
answered, participants who are
still interested in joining the trial
are asked to sign an informed
consent form. In some cases, a
participant may no longer be
able to provide informed consent
because of problems with memory
and thinking. In such cases, it is
still possible for an authorized

60 A L ZHE IME R’S DI S EAS E

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representative (usually a family
member) to give permission for the
person to participate. Laws and
regulations regarding informed
consent differ across States and
research institutions, but all are
intended to ensure that participants
are protected and well cared for.
Next, people go through a
screening process to see if they
qualify to participate in the trial.
If they qualify and can safely
participate, then they are enrolled
in the trial.
WHAT HAPPENS
DURING A TRIAL?

If participants agree to join the
trial and an evaluation process
shows they meet all the criteria for
participation, then a “baseline”
visit is scheduled with the trial
staff. This visit generally involves
cognitive and physical tests. This
gives the team information against
which to measure future mental
and physical changes.
In most clinical trials, participants are randomly assigned to
different study groups so that
each study group has people
in it of about the same average
characteristics (such as age, sex,
educational level, or cognitive
ability). One group, the test
group, receives the experimental
drug or intervention. Other

Unraveling the Mystery

groups may receive a different
drug, a placebo, or a different
intervention. Comparing results for
different groups gives researchers
confidence that changes in the
test group are the result of the
experimental treatment and not
some other factor, such as the
placebo effect (this is when people
feel an effect because they think
they are getting the test medication
even though they are really
getting a placebo). In many trials,
no one—not even the research
team—knows who is getting the
treatment and who is getting the
placebo or other intervention. This
means that the participant, family
member, and the staff are “blind”
to the treatment being received.
This kind of trial is called a doubleblind, placebo-controlled trial.
As the trial progresses,
partici-pants and family members
usually must follow strict medication
or treatment instructions and keep
detailed records of symptoms. Every
so often, participants visit the clinic
or research center to have physical
and cognitive exams, give blood
and urine samples, and talk with
trial staff. These visits allow the investigators to collect information on the
effects of the test drug or treatment,
see how the disease is progressing,
and see how the participant and
the caregiver are doing.

WHAT SHOULD
PEOPLE CONSIDER
BEFORE PARTICIPATING IN
A CLINICAL TRIAL?

People who have participated in
AD clinical trials say that it’s a good
idea to consider the following issues
before deciding to join a trial.
Expectations and motivations. The test drug or treatment
may relieve a symptom, change
a clinical measurement, or reduce
the risk of death, but clinical trials
generally do not have miraculous
results and participants may not
receive any direct benefit. With
a complex disease like AD, it is
unlikely that one treatment will
cure or prevent the disease. Some
people choose not to participate
or decide to drop out of a study
because this reality does not meet
their expectations. Others choose
to stay in a trial because they
realize that even if they get no
or only a slight benefit, they are
making a valuable contribution to
knowledge that will help people
in the future.
I Uncertainty. Some families
have a hard time with the uncertainties of participation—for
example, not knowing whether
the person is taking the test
treatment, a placebo, or a control
treatment, not being able to
I

choose which study group to be
in, or not knowing for a long time
whether the study was successful.
Ongoing and open communication with study staff can help to
reduce this frustration.
I Finding the right clinical
trial. Some clinical trials involve
participants who are cognitively
healthy or have only mild symptoms because they are testing a
drug that might delay a decline
in cognitive function. Other trials
involve participants who have
more advanced AD because they
are testing a treatment that might
lessen behavioral symptoms. Or, a
trial may be testing new strategies
to help caregivers. Even if a participant is not eligible for one trial,
another trial may be just right.
I The biggest benefit of all.
Many families find that the biggest
benefit of participating in a clinical
trial is the regular contact with the
study team. These visits provide an
opportunity to get state-of-the-art
AD care and to talk regularly with
AD experts who have lots of practical experience and a broad perspective on the disease. The study
team understands and can provide
advice about the emotional and
physical aspects of the person with
AD and the caregivers’ experience. Team members can suggest
ways to cope with the present and

give insights into what to expect
in the future. They also can share
information about support groups
and other helpful resources.
FOR MORE INFORMATION

To learn more about AD clinical
trials, visit the Alzheimer’s Disease
Education and Referral (ADEAR)
Center’s Clinical Trials Database
website (www.nia.nih.gov/
alzheimers/clinical-trials). This
NIA website includes a list of
AD and dementia clinical trials
currently in progress at research
centers throughout the United
States. It also provides information
about the phases of clinical trials
and how to participate, explains
the drug development process,
and provides links to other useful
websites.
Also, visit the clinical trials websites of the National Institutes
of Health (www.clinicaltrials.gov)
or the Alzheimer’s Association
(www.alz.org).

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PART

4

Improving Support
for

Families
and Other

Caregivers

O

ne of the greatest costs of AD can
be the physical and emotional toll
on family members, caregivers, and
friends of people with the disease.
The changes in a loved one’s personality and
mental abilities; the need to provide constant,
loving attention for years on end; and the demands
of bathing, dressing, and other caregiving duties in
the later stages of the disease can be hard to bear.
Many caregivers must assume new and unfamiliar
roles in the family, and these changes can be both
difficult and sad. Not surprisingly, caregivers of
people with dementia spend significantly more
time on caregiving tasks than do caregivers of
people with other types of illnesses.

One of the hardest decisions that many
families face is whether and when to place
a loved one with AD in a nursing home or
other type of care facility. Once this decision
is made, families must decide what type of
care is best for the person and the family.
Many investigators are working to identify
strategies that can lead to improved quality of
care in various facilities, including adult day
care centers, assisted living facilities, continuing
care retirement communities, nursing homes,
and special care units (separate areas within
nursing homes or assisted living facilities
designed especially for people with
dementia).

Who Are AD Family Caregivers?
Many primary caregivers are family
members, and NIA-funded research
has shown that the value of informal
family caregiving of people with
cognitive impairment adds up to
billions of dollars every year. Who
are these family caregivers?
Spouses: This is the largest group
of caregivers. Most are older, too,
and many have their own health
problems.
Daughters: The second largest
group of primary caregivers is
daughters. Many are married and

raising children of their own.
Juggling two sets of responsibilities
is often tough for these members
of the “sandwich generation.”
Daughters-in-law: Many women
in this group help take care of an
older person with AD. They are
the third largest group of family
caregivers.
Sons: Although many are involved
in the daily care of a parent with
AD, sons often focus on the financial, legal, and business aspects of
caregiving.

Brothers and sisters: Siblings
may assume primary responsibility
for care if they live close by. Many
of these caregivers also are older
and may be coping with their own
frailties or health problems.
Grandchildren: Older children
may become major helpers in
caring for a grandparent with AD.
Grandchildren may need extra
support if their parents’ attention is
heavily focused on the ill grandparent or if the grandparent with
AD lives in the family’s home.

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Improving Support for Families and Other Caregivers

Research Findings Benefit

Caregivers

A

lthough research on family caregiver
support is still in its early days, we have
already learned much about the unique
aspects of caregivers’ personalities and
situations. For example, it is well established that
AD caregivers often experience stress, anxiety,
depression, and other mental health problems as a
result of the continuing and demanding nature of
AD care. This chronic stress can have detrimental
effects on the physical health of caregivers. The
physical and emotional effects of AD caregiving
can last a long time, even after the death of the
person with AD.
On the other hand, research also has shown
that caregiving can have important positive effects,
including:
I
I
I

I
I

A new sense of purpose or meaning in life
Fulfillment of a lifelong commitment to a spouse
An opportunity to give back to a parent some
of what the parent has given to them
Renewal of religious faith
Closer ties with people through new relationships or stronger existing relationships

AD caregivers do not all have the same
psychological and physical response to caregiving.
For example, caregivers who have strong support
systems and well-developed coping skills may be
able to weather the stresses of caring for a loved
one with AD. Others who have few breaks from
caregiving responsibilities and/or have preexisting
illnesses may be more vulnerable to the physical
and emotional stresses associated with dementia
care. Caregiver research is beginning to discover
effective ways to ease the burden of caregiving.
Researchers have learned that:
The information and problem-solving needs
of caregivers evolve over time as AD progresses.
Therefore, support programs should be tailored
to the needs of the caregiver at various stages of
caregiving. Programs can respond by offering

I

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services and information geared to different
stages of the disease.
I Traditions and attitudes about caregiving
vary across cultural groups. For example, some
researchers have found that African-American
caregivers use fewer formal in-home services than
do white caretakers. Some populations may find
it difficult to publicly admit that a family member
has AD and may be reluctant to seek help with
caregiving issues. Therefore, programs and services
for caregivers must be culturally appropriate and
sensitive to factors that positively and negatively
influence caregivers’ attitudes and ability to carry
out their responsibilities.
I Use of multiple types of support over an
extended period of time helps caregivers. For
example, the Resources for Enhancing Alzheimer’s
Caregiver Health (REACH) clinical trial showed
that caregivers who received 6 months of intensive help with caregiving strategies had significant
improvements in overall quality of life. They also
had lower rates of clinical depression compared to
caregivers who did not participate in the program.
The caregiving strategies included information
sharing, instruction, role plays, problem-solving,
skills training, stress-management techniques, and
telephone support groups. Caregivers reported
that taking part in REACH helped them feel
more confident in working with their loved

Where Are People with
Alzheimer’s Disease Cared For?
I
I
I
I
I

Home
Assisted living facilities (those in the early stages)
Adult day care centers
Nursing homes
Special care units

ones, made life easier for them, improved their
caregiving ability, improved the care recipient’s
life, and helped them keep their loved one at
home.
I Developing ways to help caregivers become
educated about AD, improve flexibility in
responding to caregiving demands, and learn a
variety of practical strategies can help. Studies
are teaching caregivers how to read the emotional
and physical cues of the person with AD and to
understand the sequence of events that often
leads to inappropriate behaviors. They are also
helping caregivers respond to the needs of the
person with AD in a variety of creative ways,
such as maintaining flexibility in the face of
many demands, becoming educated about the
disease, learning practical strategies, using available

For Information About AD Support Groups
To find out whether an AD support group is operating in your area, contact:
I NIA’s Alzheimer’s Disease Education and Referral (ADEAR) Center at 1-800-438-4380 or
visit www.nia.nih.gov/alzheimers/alzheimers-disease-research-centers
I Alzheimer’s Association at 1-800-272-3900 or visit www.alz.org

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Improving Support for Families and Other Caregivers

resources, involving other family members and
friends, and balancing the needs of the person
with their own needs.
I Helping caregivers deal with the complicated
issue of whether and when to place a loved one
in a nursing home is an important aspect of
caregiver support. People with dementia are
at much greater risk of nursing home placement
than are other older people of the same age.
Placing a loved one in a nursing home may relieve
some of the burden of caregiving, but it does not
necessarily reduce caregiver stress or emotional
distress. Moreover, nursing home costs now
average more than $70,000 per year.
One clinical trial tested the effects of an
enhanced counseling and support program on
nursing home placement and caregiver health.
This program for caregivers consisted of six sessions
of individual and family counseling, support
group participation, and on-demand telephone
counseling. Participants in the program were able
to delay placement of their loved ones in nursing
homes by about 18 months. Researchers attributed
the effects of the program to greater tolerance for
memory and behavior problems in the person with
AD, improved satisfaction with the support
provided by family and friends, and fewer
symptoms of depression. Moreover, it appears
that the extra time at home did not come at the
expense of the caregivers’ sense of well-being.

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Helping caregivers stay physically active has
big benefits. Researchers have found that regular
moderate exercise is an important stress reliever for
caregivers. Exercise helps to reduce blood pressure
increases due to stress, improves sleep quality, and
reduces psychological distress and depression.

I

EARLY-STAGE AD SUPPORT GROUPS:
A VITAL SOURCE OF HELP

For families and friends who care for a person with
AD, talking with others who are going through the
same experience can be a vital lifeline. AD support
groups provide a place where caregivers can seek
respite, express concerns, share experiences, get
tips, and receive emotional comfort. NIA-funded
Alzheimer’s Disease Centers, the Alzheimer’s
Association, and many other organizations sponsor
in-person and online AD support groups all
around the country.
Improved diagnostic tests and increasing awareness of AD mean that more and more people are
now being diagnosed at early stages of AD. People

in the early stages often still have good coping
skills and are intensely aware of themselves and
their symptoms. They also may feel considerable
distress, embarrassment, and isolation because of a
perceived stigma associated with the disease. As a
result, a growing number of people with early-stage
AD and their family members are looking for coping strategies, meaningful activities, and mental
stimulation. They are eager to educate themselves
about AD, share common experiences, and break
the potential barriers and isolation caused by their
diagnosis. This has led to the formation of earlystage support groups specifically designed to meet
their needs.
Some early-stage support groups follow a
structured model, with 1- to 2-hour sessions
scheduled over 6 to 8 weeks. The sessions are
led by a facilitator and discussion topics are
determined in advance. Guest speakers provide
information and help on specific topics such as
legal and financial planning. In some programs,
the person with AD and the caregiver meet in sep-

arate groups; in others, people with AD and their
caregivers are together for part of the session and
apart for the remainder.
Other types of early-stage support groups are
less structured. Members discuss topics of their
own choosing, and the groups meet regularly over
an extended time. Members with AD may stay in
the group as long as they are able to meaningfully
take part in the discussion and activities.
Early-stage support groups are not for everyone.
Some people with early AD and their families may
not benefit because of family conflict, denial, cognitive impairment, or discomfort with the intimacy
of a group experience. However, most participants
report positive outcomes, such as a greater sense
of control over their lives and feelings that they
are not alone. Many participants find early-stage
support groups helpful because they instill a spirit of camaraderie, build coping skills, and forge
relationships and emotional support that continue
to help the person with AD and the caregiver even
after the sessions end.

What Happens Next?
It is a question many people and their families ask when AD is first diagnosed.
Members of an early-stage support group at the Northwestern University Alzheimer’s
Disease Center in Chicago wrote What Happens Next? to help people with early-stage
dementia cope with their feelings and the practical aspects of everyday life.
To view the booklet online, visit www.nia.nih.gov/alzheimers/publication/
what-happens-next.

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Taking Care of Mom or Dad at a Distance

T

aking care of a parent with AD who lives
hundreds of miles away is a real worry facing
many adults. “How can we make sure Mom gets the
best care possible if we’re not there all the time?”
“What can I do to help Dad live at home for as long
as possible?”
That was the dilemma facing Ken Nixon and his
two brothers in 2001. Their mother lived in an Arkansas farming community and wanted to stay there. Ken
and his brothers lived 3 to 5 hours away—close, but
not close enough.
With funding from NIA, Ken and his brothers
created a multi-purpose, Internet-based system called
AttentiveCare that is currently available to others faced
with the same long-distance caregiving challenges.
Back in 2001, broadband Internet service had just
become available in their mother’s community, so the

Ken Nixon and his grandson use AttentiveCare to
check in with Ken’s mother.

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brothers decided to see whether videoconferencing
could be a way to keep in touch with her. They installed a computer with a video camera in her home so
they could check on her daily, helping fulfill her wish to
continue living independently on the family farm while
assuring themselves that she was faring well.
“We had a need, and we patched the system
together at first,” says Ken. “It exceeded our
expectations in being able to keep our mother
independent and connected to the family. We could
call and have coffee with her every morning, and it
got her day started off right. She had something to
look forward to every day—one or two of her boys
was going to visit.”
After 6 months of using the home-grown system,
Nixon decided to develop it to help other caregivers.
In 2003, he applied for and received a grant from
NIA to refine the AttentiveCare prototype and test its
feasibility in providing informal, long-distance care to
people with AD.
He later received another grant to evaluate the
software, services, and caregiver usage and benefits
of the system in a variety of caregiving situations. The
participants in this study are distance caregivers of
persons with early- to moderate-stage AD who had
the AttentiveCare system installed in their own homes
and the homes of their family members with AD.
AttentiveCare now features videoconferencing,
multimedia reminders to help care recipients function
independently, and slide shows to keep care recipients connected with family. The system’s journal and
data logging capability also allows family caregivers
to maintain and share information about the care
recipient’s health and well-being, whether they are
across the street or thousands of miles away.

Conclusion

T

he future builds upon the events and
experiences of the past. That’s certainly true
of AD research. Our knowledge of AD is
advancing rapidly, and we have much to
celebrate in our scientific successes.
At the same time, we cannot forget that AD remains
an urgent problem for our Nation. The challenge is
to continue building on these discoveries so that we
can create a brighter future in which the potential of
successfully managing AD or even preventing this
terrible disease can become a reality.

Glossary
Acetylcholine—a neurotransmitter that plays
an important role in many neurological functions,
including learning and memory.
Amygdala—an almond-shaped structure
involved in processing and remembering strong
emotions such as fear. It is part of the limbic
system and located deep inside the brain.
Amyloid plaque—a largely insoluble
deposit found in the space between nerve cells
in the brain. Plaques are made of beta-amyloid,
other molecules, and different kinds of nerve
and non-nerve cells.
Amyloid precursor protein (APP)—the
larger protein from which beta-amyloid is formed.
Apolipoprotein E—a protein that carries
cholesterol in blood and that appears to play some
role in brain function. The gene that produces this
protein comes in several forms, or alleles: ε2, ε3,
and ε4. The APOE ε2 allele is relatively rare and
may provide some protection against AD (but it
may increase risk of early heart disease). APOE
ε3 is the most common allele and appears to play
a neutral role in AD. APOE ε4 occurs in about
40 percent of all people with AD who develop
the disease in later life; it increases the risk of
developing AD.

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Axon—the long extension from a neuron that
transmits outgoing signals to other cells.
Beta-amyloid—a part of the amyloid precursor
protein found in plaques, the insoluble deposits
outside neurons.
Brain-derived neurotrophic factor
(BDNF)—a growth factor that stimulates survival,
growth, and adaptability of some neurons.
Brain stem—the portion of the brain that
connects to the spinal cord and controls automatic
body functions, such as breathing, heart rate, and
blood pressure.
Capillary—a tiny blood vessel. The brain has
billions of capillaries that carry oxygen, glucose
(the brain’s principal source of energy), nutrients,
and hormones to brain cells so they can do their
work. Capillaries also carry away carbon dioxide
and cell waste products.
Cerebellum—the part of the brain
responsible for maintaining the body’s balance
and coordination.
Cerebral cortex—the outer layer of nerve cells
surrounding the cerebral hemispheres.
Cerebral hemispheres—the largest
portion of the brain, composed of billions of
nerve cells in two structures connected by the
corpus callosum. The cerebral hemispheres control
conscious thought, language, decision making,
emotions, movement, and sensory functions.

Cerebrospinal fluid—the fluid found in
and around the brain and spinal cord. It protects
these organs by acting like a liquid cushion and
by providing nutrients.
Chromosome—a threadlike structure in
the nucleus of a cell that contains DNA. DNA
sequences make up genes. Most human cells
have 23 pairs of chromosomes containing
approximately 30,000 genes.
Clinical trial—a research study involving
humans that rigorously tests safety, side effects,
and how well a medication or behavioral
treatment works.
Cognitive functions—all aspects of conscious
thought and mental activity, including learning,
perceiving, making decisions, and remembering.
Computed tomography (CT) scan—
a diagnostic procedure that uses special x-ray
equipment and computers to create cross-sectional
pictures of the body.
Corpus callosum—thick bundles of nerve cell
fibers that connect the two cerebral hemispheres.
Dementia—a broad term referring to a decline
in cognitive function to the extent that it interferes
with daily life and activities.

DNA (deoxyribonucleic acid)—a long,
double-stranded molecule within the nucleus of
the cell that forms chromosomes and genes.
Early-onset Alzheimer’s disease—a rare
form of AD that usually affects people between
ages 30 and 60. It is called familial AD (FAD) if it
runs in the family.
Entorhinal cortex—an area deep within the
brain where damage from AD often begins.
Enzyme—a protein that causes or speeds up a
biochemical reaction.
Free radical—a highly reactive molecule
(typically oxygen or nitrogen) that combines
easily with other molecules because it contains an
unpaired electron. The combination with other
molecules sometimes damages cells.
Gene—the biologic unit of heredity passed from
parent to child. Genes are segments of DNA and
contain instructions that tell a cell how to make
specific proteins.
Genetic risk factor—a variant in a cell’s
DNA that does not cause a disease by itself but
may increase the chance that a person will
develop a disease.

Dendrite—a branch-like extension of a neuron
that receives messages from other neurons.

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Glossary

Glial cell—a specialized cell that supports,
protects, or nourishes nerve cells.
Hippocampus—a structure in the brain that
plays a major role in learning and memory and is
involved in converting short-term to long-term
memory.
Hypothalamus—a structure in the brain
under the thalamus that monitors activities such
as body temperature and food intake.
Late-onset Alzheimer’s disease—the
most common form of AD. It occurs in people
aged 60 and older.
Limbic system—a brain region that links
the brain stem with the higher reasoning elements
of the cerebral cortex. It controls emotions,
instinctive behavior, and the sense of smell.
Magnetic resonance imaging (MRI)—
a diagnostic and research technique that uses
magnetic fields to generate a computer image of
internal structures in the body. MRIs are very clear
and are particularly good for imaging the brain
and soft tissues.
Metabolism—all of the chemical processes
that take place inside the body. In some metabolic
reactions, complex molecules are broken down to

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release energy. In others, the cells use energy to
make complex compounds out of simpler ones
(like making proteins from amino acids).
Microtubule—an internal support structure for
a neuron that guides nutrients and molecules from
the body of the cell to the end of the axon.
Mild cognitive impairment (MCI)—
a condition in which a person has memory
problems greater than those expected for his or
her age, but not the personality or cognitive
problems that characterize AD.
Mutation—a permanent change in a cell’s DNA
that can cause a disease.
Myelin—a whitish, fatty layer surrounding
an axon that helps the axon rapidly transmit
electrical messages from the cell body to the
synapse.
Nerve growth factor (NGF)—a substance
that maintains the health of nerve cells. NGF also
promotes the growth of axons and dendrites, the
parts of the nerve cell that are essential to its ability
to communicate with other nerve cells.
Neurodegenerative disease—a disease
characterized by a progressive decline in the
structure, activity, and function of brain tissue.
These diseases include AD, Parkinson’s disease,
frontotemporal lobar degeneration, and dementia
with Lewy bodies. They are usually more
common in older people.

Neurofibrillary tangle—a filamentous
collection of twisted and hyperphosphorylated tau
found in the cell body of a neuron in AD.
Neuron—a nerve cell.
Neurotransmitter—a chemical messenger
between neurons. These substances are released by
the axon on one neuron and excite or inhibit
activity in a neighboring neuron.
Nucleus—the structure within a cell that
contains the chromosomes and controls many
of its activities.
Oxidative damage—damage that can occur
to cells when they are exposed to too many free
radicals.
Positron emission tomography (PET)—
an imaging technique using radioisotopes that
allows researchers to observe and measure activity
in different parts of the brain by monitoring blood
flow and concentrations of substances such as
oxygen and glucose, as well as other specific
constituents of brain tissues.

Synapse—the tiny gap between nerve cells
across which neurotransmitters pass.
Tau—a protein that helps to maintain the
structure of microtubules in normal nerve cells.
Abnormal tau is a principal component of the
paired helical filaments in neurofibrillary tangles.
Thalamus—a small structure in the front of the
cerebral hemispheres that serves as a way station
that receives sensory information of all kinds and
relays it to the cortex; it also receives information
from the cortex.
Transgenic—an animal that has had a gene
(like human APP) inserted into its chromosomes.
Mice carrying the mutated human APP gene often
develop plaques in their brains as they age.
Ventricle—a cavity within the brain that is
filled with cerebrospinal fluid.
Vesicle—a small container for transporting
neurotransmitters and other molecules from one
part of the neuron to another.

Single photon emission computed
tomography (SPECT)—an imaging technique
that allows researchers to monitor blood flow to
different parts of the brain.

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For

Information
INFORMATION AND
SUPPORT RESOURCES

Alzheimer’s Disease Education
and Referral (ADEAR) Center
P.O. Box 8250
Silver Spring, MD 20907-8250
1-800-438-4380 (toll-free)
www.nia.nih.gov/alzheimers

This service of the National Institute on Aging
(NIA) offers information and publications on
diagnosis, treatment, patient care, caregiver
needs, long-term care, education and training,
and research related to Alzheimer’s disease. Staff
members answer telephone, email, and written
requests and make referrals to local and national
resources. The ADEAR website offers free, online
publications in English and Spanish; email alerts
and online Connections newsletter registration; an
AD clinical trials database; and more.
Alzheimer’s Association
225 North Michigan Avenue, Floor 17
Chicago, IL 60601-7633
1-800-272-3900 (toll-free)
www.alz.org

The Alzheimer’s Association is a national,
non-profit organization with a network of
local chapters that provide education and
support for people diagnosed with AD, their
families, and caregivers. Chapters offer

74 A L ZHE IME R’S DI S EAS E

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referrals to local resources and services and sponsor support groups and educational programs.
Online and print publications are also available.
The Association also funds AD research.
Alzheimer’s Foundation of America
322 Eighth Avenue, 7th Floor
New York, NY 10001
1-866-232-8484 (toll-free)
www.alzfdn.org

The Alzheimer’s Foundation of America provides
care and services to individuals confronting
dementia and to their caregivers and families,
through member organizations dedicated to
improving quality of life. Services include a
toll-free hotline, consumer publications and
other educational materials, and conferences and
workshops.
Dana Alliance for Brain Initiatives
505 Fifth Avenue, 6th floor
New York, NY 10017
1-212-223-4040
www.dana.org/danaalliances

The Dana Alliance for Brain Initiatives, a
non-profit organization of more than 265 leading
neuroscientists, helps advance public awareness
about the progress and promise of brain research
and disseminates information about the brain.

CAREGIVING SUPPORT AND SERVICES

Caregiver Action Network
2000 M Street NW, Suite 400
Washington, DC 20036
1-202-772-5050
www.caregiveraction.org

The Caregiver Action Network helps educate
and support people who care for loved ones with
chronic illness, disability, or the frailties of old age.
The Network offers an online library of information and educational materials, workshops, and
other resources.
Eldercare Locator
1-800-677-1116 (toll-free)
www.eldercare.gov

Eldercare Locator is a nationwide, directoryassistance service helping older people and their
caregivers locate local support and resources. It is
funded by the U.S. Administration on Aging, whose
website at www.aoa.gov also features AD information
for families, caregivers, and health professionals.

National Hospice and
Palliative Care Organization
1731 King Street, Suite 100
Alexandria, VA 22314
1-800-658-8898 (toll-free)
www.nhpco.org

This nonprofit organization works to enhance the
quality of life for people who are terminally ill. It
provides information, resources, and referrals to
local hospice services, and offers publications and
online resources.
Well Spouse Association
63 West Main Street, Suite H
Freehold, NJ 07728
1-800-838-0879 (toll-free)
www.wellspouse.org

The nonprofit Well Spouse Association gives
support to spouses and partners of people who are
chronically ill and/or disabled. It offers support
groups and a newsletter.

Family Caregiver Alliance
785 Market Street, Suite 750
San Francisco, CA 94103
1-800-445-8106 (toll-free)
www.caregiver.org

The Family Caregiver Alliance is a nonprofit
organization that offers support services and
information for people caring for adults with
AD, stroke, traumatic brain injuries, and
other cognitive disorders.

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For

Information
RESEARCH AND CLINICAL TRIALS

RECOMMENDED READING

Alzheimer’s Disease Cooperative Study
University of California, San Diego
9500 Gilman Drive M/C 0949
La Jolla, CA 92093-0949
1-858-622-5880
www.adcs.org

The ADEAR Center offers fact sheets; easy-toread materials; booklets about topics such as being
diagnosed with early-stage AD, caregiving, home
safety, and comfort and care at the end of life;
and more. See the ADEAR Center listing under
“Information and Support Resources” above for
contact information.

The Alzheimer’s Disease Cooperative Study
(ADCS) is a cooperative agreement between NIA
and the University of California, San Diego, to
advance research in the development of drugs to
treat AD. The ADCS is a consortium of medical
research centers and clinics working to develop
clinical trials of medicines to treat behavioral
symptoms of AD, improve cognition, slow the rate
of decline caused by AD, delay the onset of AD,
or prevent the disease altogether. The ADCS also
develops new and more reliable ways to evaluate
patients enrolled in clinical trials.

Consumers and professionals interested in AD also
may wish to refer to the following materials:

Ballard, E.L., & Poer, C.M. Lessons Learned:
Shared Experiences in Coping. Durham, NC:
The Duke Family Support Program, 1999.
Available for $8 from the Duke Family Support
Program, 3600 DUMC, Durham, NC 27710;
1-800-672-4213; www.dukefamilysupport.org.
This book documents the experiences of people
caring for loved ones with AD. Filled with short
stories and advice, it is intended for caregivers
Alzheimer Research Forum
who wish to take comfort and learn from the
www.alzforum.org
experiences of others. Caregivers discuss the
The Alzheimer Research Forum, an online comcaregiving process, such as getting a diagnosis,
munity and resource center, offers professionals and finding support services, making decisions about
the general public access to an annotated index of
treatment and living arrangements, and coping
scientific papers, research news, moderated discuswith stress and caregiver burden.
sions on scientific topics, libraries of animal models
and antibodies, and directories of clinical trials,
Dash, P., & Villemarette-Pittman, N. Alzheimer’s
conferences, jobs, and research-funding sources.
Disease. New York: American Academy of
Neurology, 2005.
ClinicalTrials.gov
www.ClinicalTrials.gov
ClinicalTrials.gov is a registry of federally and
privately supported clinical trials conducted in the
United States and around the world. Users can
search for clinical trials and find information
about each trial’s purpose, who may participate,
locations, and phone numbers for more details.

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This concise volume provides an overview of
recent findings regarding the causes, diagnosis, and
treatment of AD. It is designed to help caregivers
and family members gain a better understanding

of AD and the available options for coping
with and managing this illness. Sixteen chapters
answer questions about topics such as the
definition of AD and dementia, AD versus other
causes of dementia, treatments for behavioral
symptoms and other complications of AD,
and practical issues for the patient and family.
Illustrations, a glossary, and a list of resources
are also included.
Doraiswamy, P.M., & Gwyther, L., with Adler,
T. The Alzheimer’s Action Plan. New York:
St. Martin’s Press, 2008.
This book, by a physician and social worker at
Duke University, offers information about how to
get an early and accurate AD diagnosis and why
it matters, life after the diagnosis, state-of-the-art
treatments, coping with behavioral and emotional
changes through the early and middle stages of
AD, accessing the latest clinical trials, and
understanding the future of AD.
Kuhn, D., & Bennett, D.A. Alzheimer’s Early
Stages: First Steps for Family, Friends and
Caregivers, 3rd ed.; 2013 Alameda, CA: Hunter
House Publishers, 2013.
With increased awareness of the symptoms of AD
and improved diagnostic techniques, more people
are learning that they or a family member have a
memory disorder. This book, written by experts
at Rush University Alzheimer’s Disease Center in
Chicago, helps readers understand and find ways
to cope with the early stages of the disease. It also
includes an extensive resource list of websites,
organizations, and references to consumer and
professional literature.

Mace, N.L., & Rabins, P.V. The 36-Hour Day:
A Family Guide to Caring for People With
Alzheimer’s Disease, Related Dementias, and
Memory Loss in Later Life, 5th ed.; 2011
Baltimore: Johns Hopkins University Press, 2011.
This book offers guidance and comfort for families
caring for loved ones with AD, other dementias,
and memory loss in later life. The fourth edition
includes chapters on topics such as getting
medical help for the person with dementia,
behavioral symptoms of dementia, nursing homes
and other living arrangements, and research in
dementia. New information discusses diagnostic
evaluation, caregiver resources, legal and
financial information, nursing homes and other
communal living arrangements, and the latest
updates on research, medications, and the
biological causes and effects of dementia.
Available in a large-print version.
Messer, M. Pressure Points: Alzheimer’s and
Anger. Durham, NC: Duke Family Support
Program, 2000. Available for $10 from the
Duke Family Support Program, 3600 DUMC,
Durham, NC 27710; 1-800-672-4213;
www.dukefamilysupport.org.
In simple, easy-to-read language, this book
addresses issues such as setting boundaries,
managing anger positively, and risk factors for
anger in AD care. It offers tangible action steps for
responding appropriately, rather than abusively,

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For

Information
when feeling angry. Participants in Alzheimer’s
support groups share helpful techniques and
coping mechanisms, as well as enlightening
anecdotes about caring for a loved one with AD.
Caregivers, family members of AD patients,
clergy, and health professionals all may benefit
from this publication. Two companion
booklets are also available from the ADEAR
Center: “Hit Pause”: Helping Dementia Families
Deal with Anger (for health professionals; $3.00)
and Wait a Minute! When Anger Gets Too Much
(for families and caregivers; $2.00).
Perry, G., ed., Alzheimer’s Disease: A Century
of Scientific and Clinical Research. Journal of
Alzheimer’s Disease, book edition, Fairfax, VA: IOS
Press, Inc., 2006.
This volume brings together the important
discoveries in the AD field since the disease’s
original description by Dr. Alois Alzheimer a
century ago. It traces how the importance of AD
as the major cause of late-life dementia came to
light and narrates the evolution of the concepts
related to AD throughout the years. Fifty papers
are organized into sections on historical
perspective, neuropathology, synaptic changes,
amyloid, tau, disease mechanisms, genetics, and
diagnosis and treatment.

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Petersen, R., ed. Mayo Clinic Guide to
Alzheimer’s Disease: The Essential Resource for
Treatment, Coping and Caregiving. Rochester,
MN: Mayo Clinic Health Solutions, 2009.
This guide is designed to help nonprofessionals
understand dementia and its effects on the mind,
the differences between dementia and changes
associated with normal aging, and how to improve
memory and maintain good mental function. It
includes information about changes that occur in
normal aging; the process of diagnosing dementia;
non-AD forms of dementia; how AD develops,
and AD stages, diagnosis, and treatment. New
information about mild cognitive impairment,
ways to stay mentally sharp, and research trends,
along with an action guide for caregivers, are
also included.

Restak, R. The Secret Life of the Brain.
Washington, DC: Joseph Henry Press, 2001.
This companion to the PBS documentary takes
the reader on a fascinating journey through the
developing brain, from infancy and childhood
through adulthood and old age. The author examines brain disorders and mechanisms of brain
repair and healing.
Shenk, D. The Forgetting. Alzheimer’s: Portrait
of an Epidemic. New York: Random House, Inc.,
2003.
An eloquent and moving description of AD, The
Forgetting is an exploration of, and meditation on,
the nature of memory and perceptions of self. It
is a readable, accessible description of the history
of AD, research, and the human impact of the
disease. Calling AD a “death by a thousand
subtractions,” the author describes the science
of AD in clear and easy-to-understand terms.
Snowdon, D. Aging With Grace: What the
Nun Study Teaches Us About Leading Longer,
Healthier, and More Meaningful Lives. New
York: Random House, Inc., 2002.
This book describes the participants and findings
from the Nun Study, a long-term project examining aging and AD in a unique population of 678
Catholic sisters. The nuns gave Dr. Snowdon
access to their medical and personal records and
agreed to donate their brains upon death. The
book discusses the relationship of early linguistic
ability to risk of AD, the association of stroke and
depression with AD, and the role of heredity and
lifestyle in healthy aging.

Tanzi, R.E., & Sisodia, S.S. Alzheimer’s Disease:
Advances in Genetics, Molecular and Cellular
Biology. New York: Springer Publishing
Company, 2007.
This book examines every major aspect of AD—
clinical, epidemiologic, structural, chemical,
genetic, molecular, and therapeutic. This edition
includes expanded coverage of related dementing
disorders, including prion diseases, Pick’s disease,
frontotemporal disorders, an in-depth discussion
of transgenic models, and the biochemistry
of presenilins. It also discusses treatment of
symptoms with therapeutic drugs and AD clinical trials. The broad coverage of AD in this book
will be of special interest to clinicians, educators,
investigators, and health administrators.
Uetz, D., & Lindsay, A. Into the Mist:
When Someone You Love Has Alzheimer’s.
Philadelphia: Xlibris Corporation, 2005.
This book combines information from
researchers, experts, and families in a
comprehensive guide for AD caregivers. It
offers personal accounts of three families caring
for a loved one from the earliest stages to the
last stages, illustrating the commonalities and
differences among AD patients and the ways their
families handle the most difficult challenges. It
also provides information to help families cope
with the psychological aspects of AD, behavior
problems, and communication difficulties. The
book covers such topics as the stages of AD,
Medicare, Medicaid, long-term care insurance,
geriatric care management, the diagnosis of AD,
causes and prevention, and drug treatments.

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Credits
Writer

Photography

Anne Brown Rodgers

Front Cover – Doug Sanford, Photogroup
Inside front cover, page 8, 55 – Blend Images

Medical Illustrator

Page 1 – Blend Stock

Stacy Jannis
Jannis Productions

Pages 9, 19, 39, 61 – Photodisc
Page 13 – Dynamic Graphics; scans on computer
screen courtesy of William Jagust, M.D., University of
California, Berkeley

3D Modeling

Bill Dempsey
Rebekah Fredenburg

Page 16 – Fancy Photography
Page 20 – Comstock

Graphic Design

Fatima Ameen and Jeffrey Dever
Dever Designs

Project Coordinator

Page 28 – University of Pittsburgh
Page 33 – Cognitive Neurology and Alzheimer’s Disease
Center, Northwestern University
Page 34, back cover – Thinkstock

Susan R. Farrer
JBS International, Inc.

Pages 36, 62 – Corbis
Page 43 – Berislav Zlokovic, M.D., Ph.D., University of
Rochester, and Stacy Jannis, Jannis Productions

Special Thanks

NIA appreciates the extraordinary contributions
of the following people to the vision and creation
of this book:
Marcelle Morrison-Bogorad, Ph.D., and the staff
of the NIA Division of Neuroscience
Patricia D. Lynch, former senior public affairs
specialist, NIA Office of Communications and
Public Liaison
David M. Burton, JBS International, Inc.

Page 45 – Pixland Stock
Page 46, inside back cover – Brand X Pictures
Page 51 – Jeff Miller, University of Wisconsin-Madison
Page 53 – Oregon Center for Aging and Technology,
Oregon Health & Science University
Page 57 – Plainpicture Photography
Page 58 – Digital Vision
Page 64 – Alloy Photography
Page 66 – Marty Katz
Page 68 – Caregiver Technologies, Inc.
Page 69 – Flirt Photography
Page 78 – Stockbyte

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For additional copies of this
report or further information about
Alzheimer’s disease, please contact:
Alzheimer’s Disease Education
and Referral (ADEAR) Center
P.O. Box 8250
Silver Spring, MD 20907-8250
Phone:
800-438-4380
Email:
adear@nia.nih.gov
Website:
www.nia.nih.gov/alzheimers

U.S. Department of
Health and Human Services
NIH Publication Number: 08-3782
September 2008