UnravelingtheMystery

ALZHEIMER’S DISEASE

National Institute on Aging

National Institutes of Health
National Institute on Aging

National Institutes of Health
UnravelingtheMystery

ALZHEIMER’S DISEASE
2 Alzheimer’s Disease: Unraveling the Mystery

Over the past few decades, Alzheimer’s disease

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.

Research on Alzheimer’s disease has grown

accordingly. The small group of pioneers who

conducted research on the disease in the 1970s

has expanded to thousands of scientists in laboratories and institutions all over the world.

The lead agency for Alzheimer’s research at

the National Institutes of Health (NIH) is the

National Institute on Aging (NIA), which

launched its Alzheimer’s disease program in

1978. 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 Alzheimer’s disease, including the

National Institute of Neurological Disorders

and Stroke, the National Institute of Mental

Health, and the National Institute of Nursing

Research.

In the private sector, the Alzheimer’s

Association, other voluntary organizations,

and private industry are also working to combat this disease. They fund research, contribute to public policy decisions, inform and

educate the public, and provide critical services to people with Alzheimer’s disease and their

families. Their support for research is critical

in the effort to understand and defeat this disorder.

Thanks to these many groups, the study of

Alzheimer’s disease is moving ahead rapidly.

This booklet explains what Alzheimer’s disease

is, describes what we have learned to date, and

provides a glimpse into future directions for

research.

Preface
Alzheimer’s Disease: Unraveling the Mystery 3

Table of Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

The Impact of Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

Unraveling the Mystery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8

Part 1: A Walking Tour Through the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10

Inside the Human Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

Neurons and Their Jobs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

Plaques and Tangles: The Hallmarks of AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20

The Changing Brain in Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24

Part 2: AD Research — Finding New Answers and Asking Better Questions . . . . . . . . . . . . . .30

The Search for Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31

Genetic Factors at Work in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31

Genes and Early-onset Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33

A Different Genetic Story in Late-onset Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . .33

Other Factors at Work in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34

Beta-amyloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34

Tau . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35

Cardiovascular Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35

Oxidative Damage from Free Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36

Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36

Brain Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36

New Techniques Help in Diagnosing AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37

The Search for New Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42

Helping People with AD Maintain Their Mental Functioning . . . . . . . . . . . . . . . . . . . . . . . . .42

Slowing, Delaying, or Preventing Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43

Managing Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45

Improving Support for Families and Other Caregivers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54

For More Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57
4 Alzheimer’s Disease: Unraveling the Mystery

Often, Mary was afraid, a nameless, shapeless fear. Her impaired mind

could not put a name or an explanation to her fear. People came,

memories came, and then they slipped away. She could not tell what

was reality and what was memory of people past. The bathroom was not

where it was yesterday. Dressing became an insurmountable ordeal....Mary

gradually lost the ability to make sense out of what her eyes and ears told

her....She worried about her things: a chair, and the china that had belonged

to her mother. They said they had told her over and over, but she could not

remember where her things had gone. Perhaps someone had stolen them. She

had lost so much....

Mary was glad when her family came to visit. Sometimes she remembered

their names; more often she did not. She never remembered that they had

come last week, so she regularly scolded them for abandoning her....She was

glad when they didn’t try to remind her of what she had just said or that they

had come last week, or ask her if she remembered this person or that one. She

liked it best when they just held her and loved her. 

Introduction

This excerpt from The 36-Hour Day, a book

for families and caregivers of people with

Alzheimer’s disease (AD) and other similar

diseases, gives a glimpse into what an

Alzheimer’s patient might be thinking and

feeling. The gradual slipping away of mind

and memory is frightening and frustrating,

both for the person with the disease and for

family and friends. Not so long ago, we 

couldn’t do much for Mary or others like 

her. Happily, that situation is changing.

Thousands of scientists, voluntary organizations, health care professionals, and families

are working hard to learn more about

Alzheimer’s. They are also finding ways to

manage, treat, and eventually perhaps, prevent

this terrible disease.

Alzheimer’s is an irreversible, progressive

brain disease that slowly destroys memory and

thinking skills, eventually even the ability to

carry out the simplest tasks. Although the risk

of developing AD increases with age – in most

people with AD, symptoms first appear after

age 60 – AD is not a part of normal aging. It

is caused by a disease that affects the brain. In

the absence of disease, the human brain often

can function well into the tenth decade of life. 

O
Alzheimer’s Disease: Unraveling the Mystery 5
6 Alzheimer’s Disease: Unraveling the Mystery

Introduction

The Impact of

Alzheimer’s Disease

AD is the most common cause of dementia

among people age 65 and older. Dementia is

the loss of memory, reason, judgment, and 

language 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. 

AD is a major public

health problem for the

United States because it has

such a huge impact on individuals, families, the health care system, and

society. Scientists estimate that up to 4 million people now have AD. For every 5-year

age group beyond 65, the percentage of people

with AD doubles. 

More than 34 million people are now age

65 or older. This number is 13 percent of the

total population of the U.S. The percentage

of people over age 65 will increase rapidly over

the next few years as the “baby boom” generation reaches 65. In addition, the group of people over 85 – the group with the highest risk of

Alzheimer’s disease – is the fastest growing segment of the population. By 2050, 14 million

older Americans are expected to have

Alzheimer’s disease if the current numbers

hold and no preventive treatments become

available.

Slightly more than half of those with AD are

cared for at home, while the rest are in different kinds of care facilities. A recent study estimated that the annual cost of caring for one

person with AD in 1996 was between $18,400

and $36,100, depending on how advanced the

disease was and whether or not the person was

at home. The cost of care has been steadily

rising since then. The national cost of caring

for people with AD is now thought to be about

$100 billion every year.

The cost of care is not only financial.

Families, friends, and caregivers struggle with

great emotional and physical stress as they

cope with the physical and mental changes in

their loved ones. Caregivers must juggle many

responsibilities and adjust to new and changing roles. As the disease gets worse and caring

at home becomes increasingly difficult, family

members face difficult decisions about longterm care. The number of caregivers – and

their needs – will steadily grow as our population ages and the number of people with AD

increases.
How Many New Cases of AD Were There in 1995?

How Many New Cases May Occur in the Future?

Researchers recently projected the number of new cases of AD that could

occur every year over the next 50 years if current population trends continue

and no preventive treatments emerge. They estimate that the number of new

cases every year will double between 1995 and 2050 – from 377,000 to

959,000. Two factors will combine to cause this large increase:

● The fact that the risk of AD increases as people get older.

● The growing numbers of older people, especially those over 85.

The annual number of new cases will begin to climb sharply around the year

2040, when all the baby boomers will be over 65.

Source: Hebert et al. (2001). Alzheimer Dis Assoc Disord, 15(4), 169-173.

Estimated Number of New AD Cases, in Thousands

Alzheimer’s Disease: Unraveling the Mystery 7
8 Alzheimer’s Disease: Unraveling the Mystery

Introduction

Unraveling the Mystery

Thinking about Alzheimer’s disease leads to

questions such as: Will I get it? What causes

it? What can be done to cure it or prevent it?

Scientists ask the same types of questions, and

this booklet describes their search for answers.

It is written for people with AD, their family

members, friends, and caregivers, and anyone

else interested in AD.

Unraveling the Mystery has two sections. Part

1 gives readers the basics – it’s a “walking tour”

through the brain. Illustrations with text show

what a healthy brain looks like and how it

works, and what happens in a brain affected by

AD. Part 2 talks about current research and

the advances that are bringing us closer to

ways of managing, and eventually defeating,

AD. Throughout, terms in bold are defined in

a glossary at the end of the booklet.

The end of the booklet also includes a list of

publications and resources that family members and caregivers may find useful as they live

day-to-day with the disease. 

A booklet like this would not have been

possible 25 years ago. Other than some basics,

we knew very little about AD. We did not

even know it was a distinct disease, different

from normal aging. Today, we know much

more about Alzheimer’s disease – what it is,

who gets it, how it develops, and what course

it follows. We are better able to diagnose it

early and accurately. We even have some

promising leads on possible treatments.

Recent studies are also beginning to focus on

factors that might be used to reduce a person’s

risk of developing AD in the future. Research

conducted over the last two decades has deepened our understanding of this devastating disease. It also has expanded our knowledge of

brain function in healthy older people and

identified ways we might lessen normal agerelated declines in mental function.

Where Are People with Alzheimer’s

Disease Cared For?

● Home

● Assisted living facilities (those in the early stages) 

● Nursing homes

● Special care units
Alzheimer’s Disease: Unraveling the Mystery 9
The brain is a remarkable organ. Seemingly

without any effort, it allows us to carry out

every element of our daily lives. It manages

many of the body functions that happen without our knowledge or direction, such as breathing, blood circulation, and digestion. It also

directs all the functions we carry out consciously. We can speak, move, see, remember, feel

emotions, and make decisions because of the

complicated mix of chemical and electrical

processes that take place in our brains. 

Our brains are made of nerve cells and lots of

other cell types. Nerve cells are also called

neurons. The neurons of all animals function

in basically the same way, even though animals

can be very different from each other. What

sets people apart from other animals is the huge

number of nerve cells we have in the cerebral

cortex, regions of which are proportionally

much larger in humans than in any other animals. These regions are the parts of the brain

where cognitive functions, like thinking, learning, speaking, remembering, and making decisions, take place. The many interconnections

among the nerve cells in these regions also

make us different from other animals. 

To understand Alzheimer’s disease, it’s important to know a bit about the brain. Part 1 of

Unraveling the Mystery first gives an inside view

of the normal brain, how it works, and what

happens during aging. Then, it shows what

happens to the brain in Alzheimer’s and how

the disease slowly destroys a person’s mental

and physical capacities.

Part1 A Walking Tour 

Through the Brain

the Brain’s Vital Statistics

● Adult weight: about 3 pounds

● Adult size: a medium cauliflower

● Number of neurons: 100,000,000,000 (100 billion)

● Number of synapses (the gap between neurons):

100,000,000,000,000 (100 trillion)

Alzheimer’s Disease: Unraveling the Mystery 10
11 Alzheimer’s Disease: Unraveling the Mystery

InsidetheHumanBrain

The Three Main Players

● The cerebral hemispheres accounts for 85

percent of the brain’s weight. The billions of

neurons in the two hemispheres are connected

by a thick bundle of nerves called the corpus

callosum. Scientists now think that the two

hemispheres differ not so much in what they

focus on (the “logical versus artistic” notion),

but how they process information. The left

hemisphere appears to focus on the details

(such as recognizing a particular face in a

crowd). The right hemisphere focuses on the

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 conscious thought

and mental activity. 

● The cerebellum takes up a little more than

10 percent of the brain. It’s in charge of balance and coordination. The cerebellum also

has two hemispheres. They are always receiving information from the eyes, ears, and muscles and joints about the body’s movements

and position. Once the cerebellum processes

the information, it works through the rest of

the brain and spinal cord to send out instructions to the body. The cerebellum’s work

allows us to walk smoothly, maintain our balance, and turn around without even thinking

about it.
Hypothalamus

Hippocampus

Brain Stem

Side View of the Brain

Cerebellum

Corpus Callosum Cerebral Cortex

Thalamus
Alzheimer’s Disease: Unraveling the Mystery 13

Other Crucial Parts

Several other essential parts of the brain lie

deep inside the cerebral hemispheres:

● The limbic system links the brain stem

with the higher reasoning elements of the

cerebral cortex. It controls emotions and

instinctive behavior. This is also where the

sense of smell is located. 

● The hippocampus is important for learning

and short-term memory. This part of the brain

is considered to be the site where short-term

memories are converted into long-term memories for storage in other brain areas.

● The thalamus receives sensory and limbic

information, processes it, and then sends it to

the cerebral cortex.

● The hypothalamus is a structure under the

thalamus that monitors activities like body

temperature and food intake. It issues instructions to correct any imbalances. The hypothalamus also controls the body’s internal

clock.

● The brain stem sits at the base of the 

brain. It connects the spinal cord with the

rest of the brain. Even though it’s 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.
14 Alzheimer’s Disease: Unraveling the Mystery

The Brain in Action

New imaging techniques allow scientists to

monitor brain function in living people. This

is opening up worlds of knowledge about normal brain function and how it changes with

age or disease. 

One of these techniques is called positron

emission tomography, or PET scanning. PET

scans measure blood flow and glucose metabolism throughout the brain. (For more on

metabolism see Neurons and Their Jobs on 

p. 16.) When nerve cells in a region of the

brain become active, blood flow and metabolism in that region increase. These increases

are usually shown as red and yellow colors on a

PET scan. 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 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

sleeping or dreaming. Scientists can also

inject chemicals tagged with a tracer that will

“light up” on PET scans. These tracers can

track the activity of brain chemicals, for example neurotransmitters such as dopamine and

serotonin. Some of these neurotransmitters

are altered with age, disease, and drug 

treatment.

Hearing Words

Speaking Words

Thinking about Words

Seeing Words

InsidetheHumanBrain
PET Scan of 20-year-old Brain PET Scan of 80-year-old Brain

The Aging Brain

As a person gets older, changes occur in all

parts of the body, including the brain:

● Some neurons shrink, especially large ones

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

● Tangles and plaques develop in neurons 

and surrounding areas, though in much smaller

amounts than in AD (see p. 20 for more on

plaques and tangles). 

● Damage by free radicals increases (free 

radicals are a kind of molecule that reacts easily with other molecules; see p. 36 for more on

these molecules).

What is the impact of these changes?

Healthy older 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.

However, if given enough time to perform the

task, the scores of healthy people in their 70s

and 80s are often the same as those of young

adults. As they age, adults also often improve

their vocabulary and other forms of verbal

knowledge.

Alzheimer’s Disease: Unraveling the Mystery 15
16 Alzheimer’s Disease: Unraveling the Mystery

NeuronsandTheirJobs

The 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 all of the cell’s activities, and several other structures that perform

specific functions. The axon, which is much,

much narrower than the width of a human

hair, extends out from the cell body and transmits messages to other neurons. Sometimes,

the messages have to travel over very long distances (even up to 5 feet!). Dendrites also

branch out from the cell body. They receive

messages from the axons of other nerve cells.

Each nerve cell is connected to thousands of

other nerve cells through its axon and dendrites. Neurons are surrounded by glial cells,

which support, protect, and nourish them.

Groups of neurons in the brain have special

jobs. For example, some are involved with

thinking, learning, and memory. Others are

responsible for receiving sensory information.

Still others communicate with muscles, stimulating them into action.

Several processes all have to work smoothly

together for neurons to survive and stay

healthy. These processes are communication,

metabolism, and repair.

Communication: 

Sending Millions of

Messages a Second

Imagine the telecommunication cables that

run under our streets. All day and night, millions of telephone calls are flashing down fiber

optic cables at incredible speeds, letting people

strike deals, give instructions, share a laugh, or

learn some news. Multiply that many-fold and

that’s the brain. Neurons are the great communicators, always in touch with their neighbors. 

As a neuron receives messages from surrounding cells, an electrical charge, or nerve

impulse, builds up. This charge travels down

the axon until it reaches the end. Here, it

triggers the release of chemical messengers

called neurotransmitters, which move from 

the axon across a tiny gap to the dendrites or

cell bodies of other neurons. The typical 

neuron has up to 15,000 of these tiny gaps, or

synapses. After they move across the synapse,

neurotransmitters bind to specific receptor

sites on the receiving end of dendrites of the

nearby neurons. They can also bind directly

to cell bodies.

Once the 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; they prime

the receiving cell to become active or send an

electrical signal down the axon to more neurons in the pathway. 

During any one moment, millions of these

signals are speeding through pathways in the

brain, allowing it to receive and

process information, make

adjustments, and send out

instructions to various

parts of the body. If

neurons are disconnected, they become

sick and may die.

Neuron

Dendrites

Axon

Electrical Impulses

Neurotransmitter

Molecules

Receptor

Synapse }
NeuronsandTheirJobs

18 Alzheimer’s Disease: Unraveling the Mystery Young Rats Aged Rats

REST

0

0.1

0.2

0.35

0.6

1.35

40

Calcium

Levels

SHORT

STIMULATION

LONG

STIMULATION

This figure shows young and aged rat neurons at rest and with increasing

duration of stimulation. When neurons are stimulated, metabolism increases.

The stimulated neurons of young rats maintain calcium within normal levels.

Older rats are unable to do this. High levels of calcium in old neurons may

make them susceptible to dysfunction and death. The color scale is an index

of cellular calcium with red indicating the highest levels.

Metabolism: Turning

Chemicals and Nutrients

Into Energy to Keep

Neurons Working

Metabolism is the process by which cells and

molecules break down chemicals and nutrients

to generate energy and form building blocks

that make new cellular molecules like proteins.

Efficient metabolism needs enough blood circulating to supply the cells with oxygen and

glucose, a type of sugar. Glucose is the only

source of energy usually available to the brain.

Without oxygen or glucose, neurons will die.
Repair: Keeping Longlived Neurons in Good

Working Order

Unlike most cells, which have a fairly short

lifespan, nerve cells, which are generated in

the fetus or a short time after birth, live a long

time. Brain neurons can live for up to 100

years or longer. In an adult, when neurons die

because of disease or injury, they are not usually replaced. Recent research, however, shows

that in a few brain regions, new neurons can

be born, even in the old brain.

To prevent their own death, living neurons

must constantly maintain and remodel themselves. If cell cleanup and repair slows down

or stops for any reason, the nerve cell cannot

function well. Eventually, it dies.

Alzheimer’s Disease: Unraveling the Mystery 19

This figure shows the effects of

exercise on levels of brain-derived

neurotrophic factor (BDNF) in the

hippocampus of rats. Growth factors like BDNF help many neurons

survive. Levels of the message

that makes BDNF are much higher

in exercising rats (A) than in

sedentary animals (B). Exercise

may promote healthy neurons in

rats by causing their neurons to

make more protective BDNF. Red

and yellow denote the highest levels of BDNF, while green and blue

denote the lowest.
PlaquesandTangles: 

theHallmarksofAD

20 Alzheimer’s Disease: Unraveling the Mystery

Alzheimer’s disease disrupts each of the

three processes that keep neurons

healthy: communication, metabolism, and

repair. This disruption causes certain 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 AD patients have an abundance of two abnormal structures – betaamyloid plaques and neurofibrillary tangles.

This is especially true in certain regions of the

brain that are important in memory. Plaques

are dense, mostly insoluble (cannot be dissolved) deposits of protein and cellular material outside and around the neurons. Tangles

are insoluble twisted fibers that build up inside

the nerve cell. Though many older people

develop some plaques and tangles, the brains

of AD patients have them to a much greater

extent. Scientists have known about plaques

and tangles for many years, but recent research

has shown much about what they are made of,

how they form, and their possible roles in AD.

Amyloid Plaques

Plaques are made of beta-amyloid, a protein

fragment snipped from a larger protein called

amyloid precursor protein (APP). These

fragments clump together and are mixed with

other molecules, neurons, and non-nerve cells.

In AD, plaques develop in the hippocampus, a

structure deep in the brain that helps to

encode memories, and in other areas of the

cerebral cortex that are used in thinking and

making decisions. We still don’t know

whether beta-amyloid plaques themselves

cause AD or whether they are a by-product of

the AD process. We do know that changes in

APP structure can cause a rare, inherited form

of AD (see p. 33 for more on inherited AD).

An AD Plaque
Alzheimer’s Disease: Unraveling the Mystery 21

From APP to Beta-amyloid

APP is a protein that appears to be important

in helping neurons grow and survive. APP

may help damaged neurons repair themselves

and may help parts of neurons grow after brain

injury. In AD, something causes APP to be

snipped into fragments, one of which is called

beta-amyloid; the beta-amyloid fragments

eventually clump together into plaques.

APP is associated with the cell membrane, the thin barrier that encloses the cell. After it is made, APP sticks

through the neuron’s membrane, partly inside and partly

outside the cell.

Enzymes (substances that cause or speed up a chemical reaction) act on the APP and cut it into fragments

of protein, one of which is called beta-amyloid.

The beta-amyloid fragments begin coming together into

clumps outside the cell, then join other molecules and

non-nerve cells to form insoluble plaques.

Beta-Amyloid

Plaque

Beta-Amyloid 

Enzymes

Cell 

Membrane APP

Molecule

Cell 

Interior
PlaquesandTangles:theHallmarksofAD

Disintegrating

Microtubule

Microtubules

Stabilizing

Tau Molecules 

Healthy Neuron

Diseased Neuron

Disintegrating

Microtubules
Alzheimer’s Disease: Unraveling the Mystery 23

Neurofibrillary Tangles

Healthy neurons have an internal support

structure partly made up of structures called

microtubules. These microtubules act like

tracks, guiding nutrients and molecules from

the body of the cell down to the ends of the

axon and back. A special kind of protein, tau,

makes the microtubules stable. In AD, tau is

changed chemically. It begins to pair with

other threads of tau and they become tangled

up together. When this happens, the microtubules disintegrate, collapsing the neuron’s

transport system. This may result first in malfunctions in communication between neurons

and later in the death of the cells.

Microtubule Subunits

Fall Apart

Tangled Clumps 

of Tau Proteins 
24 Alzheimer’s Disease: Unraveling the Mystery

theChangingBrainin

Alzheimer’sDisease

PET Scan of Normal Brain PET Scan of Alzheimer’s Disease Brain

No one knows exactly what causes the

Alzheimer’s disease process to begin or

why some of the normal changes associated

with aging become so much more extreme and

destructive in patients with the disease. We

do 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 years if the patient is over 80

when diagnosed, as long as 10 or more years if

the patient is younger. Although the course of

AD is not the same in every patient, symptoms

seem to develop over the same general stages.
Alzheimer’s Disease: Unraveling the Mystery 25

Preclinical AD

AD begins in the entorhinal cortex, which is

near the hippocampus and has direct connections to it. It then proceeds to the hippocampus, the structure that is essential to the formation of short-term and long-term memories.

Affected regions begin to atrophy (shrink).

These brain changes probably start 10 to 20

years before any visible signs and symptoms

appear. Memory loss, the first visible sign, is

the main feature of mild cognitive impairment

(MCI) (see p. 41 for more on MCI). Many

scientists think MCI is often an initial, transitional phase between normal brain aging and

AD.

Cerebral

Cortex

Hippocampus Entorhinal

Cortex
theChangingBraininAlzheimer’sDisease

Mild AD

As the disease begins to affect the cerebral cortex, memory loss continues and changes in

other cognitive abilities emerge. The clinical

diagnosis of AD is usually made during this

stage. Signs of mild AD can include:

● Memory loss 

● Confusion about the location of familiar 

places (getting lost begins to occur)

● Taking longer 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

The growing number of plaques and tangles

first damage areas of brain that control memory, language, and reasoning. It is not until

later in the disease that physical abilities

decline. This leads to a situation in mild AD

in which a person seems 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 because the early signs can be

confused with changes that can happen normally with aging. Accepting these signs and

deciding to go for diagnostic tests can be a big

hurdle for patients and families to cross.

26 Alzheimer’s Disease: Unraveling the Mystery

Cortical Shrinkage

Shrinkage of

Hippocampus

Moderately

Enlarged

Ventricles
Alzheimer’s Disease: Unraveling the Mystery 27

Moderate AD

By this stage, AD damage has spread further to

the areas of the cerebral cortex that control

language, reasoning, sensory processing, and

conscious thought. Affected regions continue

to atrophy and signs and symptoms of the disease become more pronounced and widespread. Behavior problems, such as wandering

and agitation, can occur. More intensive

supervision and care become necessary, and

this can be difficult for many spouses and families. The symptoms of this stage can include:

● Increasing memory loss and confusion

● Shortened attention span

● Problems recognizing friends and 

family members

● Difficulty with language; problems with 

reading, writing, working with numbers

● Difficulty organizing thoughts and 

thinking logically

● Inability to learn new things or to cope 

with new or unexpected situations

● Restlessness, agitation, anxiety, tearfulness,

wandering – especially in the late 

afternoon or at night

● Repetitive statements or movement, 

occasional muscle twitches

● Hallucinations, delusions, suspiciousness 

or paranoia, irritability

● Loss of impulse control (shown through 

sloppy table manners, undressing at 

inappropriate times or places, or 

vulgar language)

● Perceptual-motor problems (such as 

trouble getting out of a chair or setting 

the table)

Behavior is the result of complex brain

processes, all of which take place in a fraction

of a second in the healthy brain. In AD, many

of these processes are disturbed, and this is the

basis for many distressing or inappropriate

behaviors. For example, a person may angrily

refuse to take a bath or get dressed because he

does not understand what his caregiver has

asked him to do. If he does understand, he

may not remember how to do it. The anger is

a mask for his confusion and anxiety. Or, a

person with AD may constantly follow her

husband or caregiver and fret when the person

is out of sight. To a person who cannot

remember the past or anticipate the future, the

world around her can be strange and frightening. Sticking close to a trusted and familiar

caregiver may be the only thing that makes

sense and provides security. Taking off clothes

may seem reasonable to a person with AD who

feels hot and doesn’t understand or remember

that undressing in public is not acceptable.
theChangingBraininAlzheimer’sDisease

Severe AD

In the last stage of AD, plaques and tangles are

widespread throughout the brain, and areas of

the brain have atrophied further. Patients

cannot recognize family and loved ones or

communicate in any way. They are completely

dependent on others for care. All sense of self

seems to vanish. Other symptoms can include:

● Weight loss

● Seizures, skin infections, difficulty 

swallowing

● Groaning, moaning, or grunting

● Increased sleeping

● Lack of bladder and bowel control

At the end, patients may be in bed much or

all of the time. Most people with AD die from

other illnesses, frequently aspiration pneumonia. This type of pneumonia happens when a

person is not able to swallow properly and

breathes food or liquids into the lungs.

28 Alzheimer’s Disease: Unraveling the Mystery

Extreme Shrinkage of

Cerebral Cortex Severely

Enlarged

Ventricles

Extreme

Shrinkage of

Hippocampus
Alzheimer’s Disease: Unraveling the Mystery 29

Severe AD

Mild to 

Moderate AD

Preclinical AD

Blue indicates areas affected at various stages of AD.
I

n the past 25 years, scientists have studied

Alzheimer’s disease from many angles.

They’ve looked at populations to see how

many cases of AD occur and whether there

might be links between the disease and

lifestyles or genetic backgrounds. They’ve

conducted clinical studies with healthy older

people and those at various stages of AD.

They’ve examined individual nerve cells to

see how beta-amyloid and other molecules

affect the ability of cells to function normally. 

These studies have led to better 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

ask better questions about the issues that are

still unclear. 

Part 2 of Unraveling the Mystery describes

what we’re learning from our search for: 

● The causes of AD

● New techniques to help in diagnosis

● New treatments

● Ways to improve support for families and 

other caregivers

Results from this research will bring us closer to the day when we will be able to prevent

or even cure the devastating disease that robs

our older relatives and friends of their most

precious possession – their minds.

Part2 AD Research: Finding New

Answers and Asking Better Questions

Then and Now: the Fast Pace of

Developments in AD Research

What We Didn’t Know Then

15 Years Ago

● We didn’t know any of the

genes that could cause AD.

● We had no idea of the biological pathways that were

involved in the development of

damage to the brain in AD.

10 Years Ago

● We couldn’t model the disease in animals.

5 Years Ago

● NIH did not fund any prevention clinical trials.

● We had no way to identify

people at high risk of developing AD.

1 Year Ago

● We didn’t understand anything about how plaques and

tangles relate to each other.

What We Know Now (2002)

● We know the 3 major genes

for early-onset AD and 1 of the

major risk factor genes for

late-onset AD.

● We know a lot about the

pathways that lead to the

development of beta-amyloid

plaques in the brain – one of

the main features of AD.

● Scientists have developed

special kinds of mice that produce beta-amyloid plaques.

● NIH is funding clinical trials

that are looking at possible

ways to prevent AD.

● We can identify individuals

at high risk through imaging,

neuropsychological tests, and

structured interviews.

● By developing another kind

of mice that have both plaques

and tangles, we now know

that plaques can influence the

development of tangles.

Alzheimer’s Disease: Unraveling the Mystery 30
31 Alzheimer’s Disease: Unraveling the Mystery

theSearchforCauses

One 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 it and another

remain healthy?

Some diseases, like 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 cause a disease process to

start. The importance of each one of these factors may be different for each individual. 

AD fits into this second group of diseases.

We don’t yet fully understand what causes AD,

but we know 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

In the last few years, painstaking detective

work by scientists has paid off in discoveries of

genetic links to the two main types of AD.

One type is the more 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 the most common form and

occurs in those 65 and older.
32 Alzheimer’s Disease: Unraveling the Mystery

DNA, Chromosomes, and Genes: 

the Body’s Amazing Control Center

The nucleus of almost every human cell contains a vast

chemical information database. This database carries all

the instructions the cell needs to do its job. This database

is DNA. DNA exists as two long, intertwined, thread-like

strands packaged in units called chromosomes. Each cell

has 46 chromosomes in 23 pairs. Chromosomes are

made up of four chemicals, or bases, arranged in various

sequence patterns. People inherit material in each chromosome from each parent.

Each chromosome has many thousands of segments,

called genes. The sequence of bases in a gene tells the

cell how to make specific proteins. Proteins determine

the physical characteristics of living organisms. They

also direct almost every aspect of the organism’s construction, operation, and repair. Even slight alterations in

a gene can produce an abnormal protein, which, in turn,

can lead to cell malfunction, and eventually, to disease.

Any rare change in a gene’s DNA that causes a disease

is called a mutation. Other more common (or frequent)

changes in a gene’s DNA don’t 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.

Cell Nucleus Containing

23 Pairs of Chromosomes

Genes

Chromosomes

Bases

DNA Strand
Genes and Early-onset

Alzheimer’s Disease

Over the past several decades, researchers

working on AD realized that some cases, particularly of early-onset AD, ran in families.

This led them to examine DNA samples from

such 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

(APP) to be produced. On chromosome 14,

the mutation causes an abnormal protein

called presenilin 1 to be produced. On chromosome 1, the mutation causes yet another

abnormal protein to be produced. This protein, called presenilin 2, is very similar to presenilin 1. Even if only one of these genes

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.

Even though early-onset AD is very rare and

mutations in these three genes do not play a

role in the more common late-onset AD, these

findings were crucial because they showed that

genetics was indeed a factor in AD, and they

helped to identify some key players in the AD

disease process. Importantly, they showed that

mutations in APP can cause AD, highlighting

the key role of beta-amyloid in the disease.

Many scientists believe that mutations in each

of these genes cause an increased amount of

the damaging beta-amyloid to be made in the

brain.

The findings also laid

the foundation for many

other studies that have

pushed back the boundaries of our knowledge

and created new possibilities for future treatment. For example, in the

last several years, a series of highly sophisticated experiments have shown that presenilin

may actually be one of the enzymes (substances that cause or speed up a chemical reaction) that clips APP to form beta-amyloid (the

protein fragment that is the main component

of AD plaques). This discovery has helped

clarify how presenilins might be involved in

the early stages of AD. It has also given scientists crucial new targets for drug therapy and

has spurred many new studies in the test tube,

in animals, and even in people.

A Different Genetic Story in

Late-onset Alzheimer’s Disease

While some scientists were focused on 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, these investigators had narrowed their search to a region of chromosome

19. At the same time, other colleagues were

looking for proteins that bind to beta-amyloid.

They were hoping to clarify some of the steps

in the very early stages of the disease process.

They found that one form of a protein called

apolipoprotein E (ApoE) did bind quickly and

tightly to beta-amyloid. They also found that

the gene that produces ApoE was located in

the same region of chromosome 19 pinpointed

by the geneticists. This finding led them to

suggest that one form of this gene was a risk

factor for late-onset Alzheimer’s disease.

Alzheimer’s Disease: Unraveling the Mystery 33
34 Alzheimer’s Disease: Unraveling the Mystery

Other studies since then have shown that

the gene that produces 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. APOE ε3 is the most

common allele. Researchers think it plays a

neutral role in AD. APOE ε4 occurs in about

40 percent of all AD patients who develop the

disease in later life. It is not limited to people

whose families have a history of AD, though.

AD patients with no known family history of

the disease are also more likely to have an

APOE ε4 allele than people who do not have

AD. Dozens of studies have confirmed that

the APOE ε4 allele increases the risk of developing AD. These studies have also helped to

explain some of the variation in the age at

which AD develops. However, inheriting an

APOE ε4 allele doesn’t 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. 

Although we still don’t exactly know how

APOE ε4 increases AD risk, one theory is that

when its protein product binds quickly and

tightly to beta-amyloid, the normally soluble

amyloid becomes insoluble. This may mean

that it is more likely to be deposited in

plaques. 

While scientists are working to understand

more fully the APOE gene and its role in AD,

they have also identified regions on other

chromosomes that might contain genetic risk

factors. For example, in 2000, three teams of

scientists, using three different strategies, published studies showing that chromosome 10

has a region that may contain several genes

that might increase a person’s risk of AD.

Identifying these genes is one important step

in the research process that will lead to new

understanding about the ways in which

changes in protein structures cause the disease

process to begin and the sequence of events

that occurs as the disease develops. Once they

understand these processes, scientists can

search for new ways to diagnose, treat, or even

prevent AD.

Other Factors 

at Work in AD 

Even if genetics explains some of what might

cause AD, it doesn’t explain everything. So,

researchers have looked at other possibilities

that may reveal how the Alzheimer’s disease

process starts and develops.

Beta-Amyloid

We still don’t know whether beta-amyloid

plaques cause AD or whether they are a byproduct of the disease process. We do know,

however, that forming beta-amyloid from APP

is a key process in AD. That’s why finding out

more about beta-amyloid is an important

avenue of ongoing AD research. Investigators

are studying:

● The nature of beta-amyloid

● Ways in which it is toxic to neurons

● Ways in which plaques form and 

are deposited

● Ways in which beta-amyloid and plaques 

might be reduced in the brain
Tau

In the last few years, scientists have been giving an increasing amount of attention to tau,

the other hallmark of Alzheimer’s disease.

This protein is commonly found in nerve cells

throughout the brain. In AD, tau undergoes

changes that cause it to gather together abnormally in tangled filaments in neurons (for

more on this, see p. 23 in A Walking Tour

Through the Brain). In studying tau and

what can go wrong, investigators have found

that tau abnormalities are also central to other

rare neurodegenerative diseases. These diseases, called tauopathies, include frontotemporal dementia, Pick’s disease, supranuclear palsy,

and corticobasal degeneration. They share a

number of characteristics, but also each have

distinct features that set them apart from each

other and from AD. Characteristic signs and

symptoms include changes in personality,

social behavior, and language ability; difficulties in thinking and making decisions; poor

coordination and balance; psychiatric symptoms; and dementia. Recent advances, include

the discovery of mutations in the tau gene that

cause one tauopathy called frontotemporal

dementia with parkinsonism linked to chromosome 17 (FTDP-17). The development of several mouse models that produce tau tangles

will allow researchers to address the many

questions that remain about these diseases.

The development of a “double transgenic”

mouse that has both tau tangles and betaamyloid plaques will also lead to further

insights about AD.

Cardiovascular Risk Factors

Several recent studies in populations have

found a possible link between factors related to

cardiovascular disease and AD. One of these

studies found that elevated levels of an amino

acid called homocysteine, a risk factor for

heart disease, are associated with an increased

risk of developing AD. The relationship

between AD and homocysteine is particularly

interesting because blood levels of homocysteine can be reduced by increasing intake of

folic acid and vitamins B6 and B12. In fact, in

other studies, scientists have shown that folic

acid may protect against nerve cell loss in

brain regions affected by AD. Investigators

have also found that the use of statins, the

most common type of cholesterol-lowering

drugs, is associated with a lower risk of developing AD.

Alzheimer’s Disease: Unraveling the Mystery 35

An AD Tangle
36 Alzheimer’s Disease: Unraveling the Mystery

Oxidative Damage 

From Free Radicals

Another promising area of investigation relates

to a longstanding theory of aging. This theory

suggests that over time, damage from a kind of

molecule called a free radical can build up in

neurons, causing a loss in function. Free radicals can help cells in certain ways, such as

fighting infection. However, too many can

injure cells because they are very active and

can readily change other nearby molecules,

such as those in the neuron’s cell membrane or

in DNA. The resulting molecules can set off a

chain reaction, releasing even more free radicals that can further damage neurons. This

kind of damage is called oxidative damage. It

may contribute to AD by upsetting the delicate machinery that controls the flow of substances in and out of the cell. 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. Some epidemiological and laboratory studies suggest that anti-oxidants from dietary supplements or food may

provide some protection against developing

AD. Other studies suggest that low-calorie

diets may protect against the development of

AD by slowing down metabolic rates.

Inflammation

Another set of hints about the causes of AD

points to inflammation in the brain. This

process is part of the immune system and helps

the body react to injury or disease. Fever,

swelling, pain, or redness in other parts of the

body are often signs of inflammation. Because

cells and compounds that are known to be

involved in inflammation are found in AD

plaques, some researchers think it may play a

role in AD. 

They disagree, though, on whether inflammation is a good or a bad thing. Some think it is

harmful – that it sets off a vicious cycle of

events that ultimately causes neurons to die.

Evidence from many studies supports this idea.

Other scientists believe that some aspects of

the inflammatory process may be helpful – that

they are part of a healing process in the brain.

For example, certain inflammatory processes

may play a role in combating the accumulation

of plaques. Many studies are now underway to

examine the different parts of the inflammatory

process more fully and their effects on AD.

Brain Infarction

We’ve all heard the sensible advice about ways

to live a long and healthy life: eat right, exercise, don’t smoke, wear a seat belt. All of these

habits can help prevent heart attacks, stroke,

and injuries. This advice may even have some

relevance for AD as well. Results from one

long-term study of aging and AD show that participants who had evidence of stroke in certain

brain regions had more symptoms of dementia

than could be explained by the number of

plaques and tangles in their brain tissue. These

findings suggest that damage to blood vessels in

the brain may not be enough to cause AD, but

that it could make AD clinical symptoms worse.

Free Radicals

Mitochondrion

Protein

Phospholipid

Cell Membrane
NewTechniquesHelp

inDiagnosingAD

Ahealthy man in his early 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 a couple of miles

from his house. He has no idea how he got there. 

Not so long ago, this man’s condition would

have been swept into a broad catch-all category

called “senile dementia” or “senility.” Today,

the picture is very different. We now know

that Alzheimer’s and other illnesses with

dementia are distinct diseases. Armed with

this knowledge, we have rapidly improved our

ability to accurately diagnose AD. We are still

some distance from the ultimate goal – a reliable, valid, inexpensive, and early diagnostic

marker – but experienced physicians now can

diagnose AD with up to 90 percent accuracy.

Early diagnosis has several advantages. For

example, many conditions cause symptoms

that mimic those of Alzheimer’s disease.

Finding out early that the problem isn’t AD

but is something else can spur people into 

Alzheimer’s Disease: Unraveling the Mystery 37

The Religious Orders Study and the Nun Study: Lives

of Service Continue Even After Death

One way that scientists have tried to unravel the mystery of AD

and other complex diseases, like heart disease or cancer, is to

compare the characteristics, lifestyles, and disease rates of different groups of people. This approach has often provided

clues as to why some people get a disease and others don’t.

Another way is to study one group of people over time. The

notion here is that data gathered over a period of years will

reveal important clues about the origins of the disease under

investigation. The knowledge gained also may lay the foundation for future treatment or prevention strategies. The

Framingham Heart Study is one famous example of this kind of

study. It has followed two generations of Massachusetts residents for 50 years, and its findings have revolutionized the way

we think about, treat, and prevent heart disease.

the Human Side of AD Research

(Continued on next page)
38 Alzheimer’s Disease: Unraveling the Mystery

The National Institute on Aging is funding two

Alzheimer’s disease studies that are using this approach

– but with a unique twist. These studies involve members of religious communities.

Since 1990, scientists have been working with more

than 650 nuns of the School Sisters of Notre Dame, who

are located in various parts of the U.S. The Nun Study is

an expansion of a pilot project begun in

1986 with a School Sisters of Notre

Dame convent in Mankato, Minnesota.

Since 1993, scientists have also been

investigating the mental and physical

capacities of older nuns, priests, and

brothers in the Religious Orders Study.

More than 30 religious communities in a

dozen States are participating in this

study.

All of the participants in both studies

agree to have detailed physical and mental function exams every year. Volunteers

may spend decades in the study, repeating the tests each year. These exams

help researchers better understand the

effects on the brain of aging, AD, and

other disorders. Participants also agree

to donate their brains to the study when

they die. This allows the investigators to

match many years’ worth of clinical and psychological

information with the results of examinations of afterdeath brain tissue. These volunteers consider participating in these studies a wonderful chance to continue their

lives of service to others. As one participant in the Nun

Study put it, “[They] can have my brain. What good is it

going to do me when I’m six feet under?”

The large numbers enrolled in the study ensure that

some volunteers will still have normal brain function at

the time of death. Others will have developed the clinical

signs of AD. Still others will have other neurological disorders, such as Parkinson’s disease. The yearly examinations enable researchers to detect signs of AD among

participants and to track, year by year, the progress and

treatment of the disease among those who develop it.

But why work with religious orders? What’s special

about them? One reason why members of religious

orders are good study participants is that they often live

together and have similar lifestyles, educational levels,

daily routines, and activities. This cuts down on the variations among participants that make it difficult for scientists to interpret research results. It also makes it easy

for study staff to keep track of volunteers over time and

to maintain complete information on them.

Working with these participants has allowed the

research teams to explore several exciting ideas. For

example, the Religious Orders Study team recently

worked with their participants to examine a 

“use-it-or-lose-it” brainpower hypothesis. At an initial

evaluation, the researchers asked more than 700 priests

and nuns about the amount of time they spent in seven
getting treatment for the real condition. For

the small percentage of dementias that are

treatable or even reversible, early diagnosis

increases the chances of successful treatment.

Even when the cause of the dementia turns

out to be Alzheimer’s disease, it’s good to find

out sooner rather than later. One benefit is

medical. The drugs now available to treat AD

can help some people maintain their mental

abilities for months to years, though they do

not change the underlying course of the disease (see p. 42 for more on these drugs).

Other benefits are practical. The sooner the

person with AD and family know, the more

time they have to make future living arrangements, handle financial matters, establish a

durable power of attorney, deal with other

legal issues, create a support network, or even

make plans to join a research study. Being

able to participate for as long as possible in

making decisions about the present and future

is important to many people with AD. 

Finally, scientists also see advantages to early

diagnosis. Developing tests that can reveal

what is happening in the brain in the early

stages of Alzheimer’s disease will help them

understand more about the cause and development of the disease. It will also help scientists

learn when and how to start drugs and other

treatments so that they can be most effective.

Scientists are now exploring ways to help

physicians diagnose AD earlier and more accurately. For example, some studies are focusing

on changes in personality and mental functioning. These changes can be measured

through memory and recall tests. Tests that

measure a person’s abilities in areas such as

abstract thinking, planning, and language can

also help pinpoint changes in function.

Alzheimer’s Disease: Unraveling the Mystery 39

common activities that involve significant information processing – watching television; listening to the radio; reading newspapers or

magazines; reading books; playing cards,

checkers, and puzzle games; and going to

museums. After tracking the participants for 

4 1/2 years, the researchers found that, on

average, the risk of developing AD was 47 percent lower in those who did these activities

most frequently than in those who did them

least frequently. The reasons for this finding

aren’t entirely clear yet, but it may be that

mentally stimulating activities protect the brain

in some way. Or, perhaps some other mechanism may be at work that strengthens information processing skills to compensate for

age-related declines in other cognitive areas.

The Nun Study has one particularly rich

treasure trove to work with – the autobiographies written by the nuns when they entered

the order. These personal records provide

basic information on the nuns’ early lives and

families and are an objective measure of each

woman’s ability to think, remember, and present ideas in writing. Study investigators have

found a fascinating link between their early

writing skills and later cognitive abilities. The

researchers performed an analysis of the autobiographies to determine the grammatical

complexity and the “density” of ideas in each.

They then examined brain tissue from nuns

who had died. The investigators found that

most of the nuns whose brain tissue showed

significant signs of AD had written autobiographies with low grammatical complexity and

idea density. Though the reasons for this link

aren’t fully understood, a higher linguistic ability early in life may provide some protection

against the influences that lead to AD.
40 Alzheimer’s Disease: Unraveling the Mystery

Researchers are working hard to improve these

standardized tests so that they can better track

the changes that might 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 blood chemistry that might indicate the progression of Alzheimer’s disease. 

One of the most exciting areas of ongoing

research in this area is neuroimaging. Over

the last decade, scientists have developed several highly sophisticated imaging systems that

have been used in many areas of medicine,

including Alzheimer’s disease. Positron emission tomography (PET), single photon emission computed tomography (SPECT), and

magnetic resonance imaging (MRI) are all

examples. These “windows” on the living

brain can help scientists measure the earliest

changes in brain function or structure in order

to identify those people who are at the very

first stages of the disease – even before they

develop signs and symptoms. 

These types of scans are still primarily

research tools, but one day, neuroimaging

might be used more commonly to help physicians diagnose AD early. These tools may

even be used someday to monitor the progress

of the disease and assess patient responses to

drug treatment.

Causes of Dementia

Other Causes 

of Dementia

● Alzheimer’s disease

● vascular dementia 

● frontotemporal dementia,

including:

● frontotemporal dementia 

with parkinsonism linked 

to chromosome 17 

(FTDP-17) 

● Pick’s disease

● supranuclear palsy

● corticobasal degeneration

Dementia 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 treatable or curable; others are less responsive to treatment.

Treatable Causes 

of Dementia

● medication side effects

● depression

● vitamin B12 deficiency

● chronic alcoholism

● certain tumors or 

infections of the brain

● blood clots pressing 

on the brain

● metabolic imbalances,

including thyroid, kidney,

or liver disorders

A PET Scan in Progress
Alzheimer’s Disease: Unraveling the Mystery 41

Current Tools for Diagnosing AD

A definitive diagnosis of Alzheimer’s disease is still only

possible after death, during an autopsy, when the

plaques and tangles can actually be seen. But with the

tools now available, experienced physicians can be pretty

confident about making an accurate diagnosis in a living

person. Here’s how they do it.

They take a detailed patient history, including:

● A description of how and when symptoms developed

● A description of the patient’s and his or her 

family’s overall medical condition and history

● An assessment of the patient’s emotional state 

and living environment

They get information from family members or close

friends:

● People close to the patient 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:

● Blood and other medical tests help determine 

neurological functioning and identify possible non-AD

causes of dementia.

They do a computerized tomography (CT) scan or a

magnetic resonance imaging (MRI) test:

● Brain scans like these can detect strokes or tumors or

can reveal changes in the brain’s structure and function

that indicate early AD.

They conduct neuropsychological testing:

● Q&A tests or other tasks that measure memory,

language skills, ability to do arithmetic, and other 

abilities related to brain functioning help indicate what

kind of cognitive changes are occurring.

Criteria for “Probable” Alzheimer’s Disease

Because no simple and reliable biological test for AD is

available, the National Institute of Neurological and

Communicative Disorders and Stroke and the Alzheimer’s

Association together established criteria to help physicians diagnose AD. These criteria also help physicians

distinguish between AD and other forms of dementia.

“Probable” Alzheimer’s disease is determined when a

person has:

● Dementia confirmed by clinical and 

neuropsychological examination

● Problems in at least two areas of 

mental functioning

● Progressive worsening of memory and 

other mental functioning

● No disturbances of consciousness 

(no “blacking out”)

● Symptoms beginning between ages 40 and 90

● No other disorders that might account 

for the dementia

As they get older, some people develop a memory

deficit greater than that expected for their age. However,

other aspects of cognition are

not affected, so these people

do not meet all the accepted

criteria for AD. Thus, they are

said to have “mild cognitive

impairment” (MCI). About 40

percent of these individuals

will develop AD within 3

years. Others, however, do not seem to progress to AD,

at least in the time frame studied thus far (up to approximately 6 years). Understanding more about the characteristics and development of MCI is essential in helping

clinicians diagnose early stages of AD.
42 Alzheimer’s Disease: Unraveling the Mystery

theSearchfor

NewTreatments

Research over the last two decades has

revealed many pieces of the Alzheimer’s

disease puzzle. Using recent advances in

genetics and molecular biology, scientists have

begun to put these pieces into place. In doing

so, they’ve vastly increased our understanding

of AD and opened many avenues that could

lead to effective treatments. 

It has become clear that there probably isn’t

a “magic bullet” that will, by itself, prevent or

cure AD. However, scientists may be able to

identify a number of interventions that can 

be used to reduce risk and treat the disease.

Today, it is estimated that the National

Institute on Aging, other NIH Institutes, and

private industry are conducting clinical trials

(studies involving humans that rigorously test

how well an intervention works) on around

30 compounds that may be active against AD.

These studies focus on three main areas:

● Helping people with AD maintain their 

mental functioning

● Slowing the progress of AD, delaying its 

onset, or preventing it

● Managing symptoms

Helping People with AD

Maintain their Mental

Functioning

In the mid-1970s, scientists discovered that

levels of a neurotransmitter called acetylcholine fell sharply in people with Alzheimer’s

disease (see p. 16 in A Walking Tour Through

the Brain for more on neurotransmitters). 

This discovery was one of the first that linked

AD with biochemical changes in the brain. 

Since then, scientists have conducted hundreds of studies on acetylcholine. They have

found that acetylcholine is important for several reasons. It is a critical player in the

process of forming memories. It is also commonly used by neurons in the hippocampus

and cerebral cortex – two regions devastated

by AD. These findings led naturally to the

idea that increasing levels of acetylcholine,

replacing it, or slowing its breakdown could

stop the disease.

The Food and Drug Administration (FDA)

has approved four medications for the treatment of mild to moderate AD symptoms. The

first, tacrine (Cognex), has been replaced by

three newer drugs – donepezil (Aricept),

rivastigmine (Exelon), and galantamine

(Reminyl). All act by stopping or slowing the

action of acetylcholinesterase, an enzyme that

normally breaks down acetylcholine. These

drugs improve some patients’ ability to carry

out activities of daily living, such as eating and

dressing. The drugs also help with behavioral

symptoms, such as delusions and agitation, and

can also improve thinking, memory, and

speaking skills. However, these medications

will not stop or reverse AD and appear to help

patients only for months to a few years.

Helping people with AD carry out their

daily lives and maintain their mental abilities

is one of the most important goals of AD treatment research. Many investigators are working to develop new and better drugs that can

preserve this critical function for as long as

possible.
Slowing, Delaying, 

or Preventing

Alzheimer’s Disease

Understanding all the steps involved in the

development of AD – from beginning to end –

is important in and of itself. It also can have a

big payoff down the road, for if we have this

knowledge we might be able to develop drugs

that slow, delay, or even prevent the disease

process. That’s the thinking behind this area of

AD treatment research.

For example, estrogen is a hormone produced

by a woman’s ovaries during her childbearing

years. Over the past 25 years, animal studies

have suggested that estrogen has some positive

effects on memory function. Some human

studies have supported this notion. Estrogen

also has other effects that may be important in

AD. These findings have created scientific

interest in the relationship among estrogen,

memory, and cognitive function. Several

recent studies have examined the effects of

estrogen in post-menopausal women with mild

to moderate AD. None of them found that

estrogen had a helpful effect on women who

already have AD. We still don’t know

whether normally aging women who take 

estrogen or combined estrogen/progestin after

menopause will be protected from 

Alzheimer’s Disease: Unraveling the Mystery 43

Science on the Cutting Edge

Immunizing Against AD: Just a Neat Idea 

or a Real Possibility?

Getting vaccinated against measles, tetanus, polio, and

other diseases is common practice these days. A person

is injected with a weakened form of a disease-causing

bacterium or virus. His or her immune system mobilizes

to fight against it, and this protects the person against

getting the disease. One scientist wondered whether this

approach could work for Alzheimer’s disease as well.

Researchers have developed special kinds of mice

(called transgenic mice) that gradually develop AD betaamyloid plaques in the brain. These mice are invaluable

tools to test how plaques can be stopped from forming.

Over the course of several studies, scientists tested the

effects of injections of a vaccine composed of beta-amyloid and a substance known to stimulate the immune system. They found that long-term immunization resulted in

much less beta-amyloid being deposited in the brains of

the mice. Similar transgenic mice that had been immunized also performed far better on

memory tests than did a group of

these mice that had not been

immunized.

These exciting developments led

to preliminary studies in humans to

test the safety and effectiveness of

the vaccine. Based on positive results, a further study

was designed to measure the immune response in participants with AD who received immunizations with the betaamyloid vaccine. In this study, which began in the fall of

2001, inflammation unexpectedly developed in the brains

of some of the participants. As a result of this complication, the pharmaceutical companies that were conducting

the research stopped the trial and are continuing to closely monitor the health of the participants.

Despite their disappointment with this development, the

scientists and funders involved in this research emphasize

that a tremendous amount of valuable information has

been gained from this work so far. It is not unusual for

such a revolutionary concept to have setbacks, and they

are moving forward with other possible strategies.
44 Alzheimer’s Disease: Unraveling the Mystery

developing AD or age-related cognitive decline.

The NIA is supporting a clinical trial on cognitively normal older women with a family history

of dementia to see whether taking estrogen can

prevent or delay the development of AD.

A recent clinical trial showed that combined

estrogen/progestin therapy taken over a certain

period of time has negative effects on heart disease and some cancers. However, the risk of

the women in the estrogen AD prevention trial

developing AD is much higher than their risk

of other illnesses resulting from their taking

estrogen. Therefore, it may be that the benefits of hormone replacement therapy in preventing memory loss may outweigh potential

risks in other areas. Clearly, more research is

needed on this complex issue.

Investigators are looking at other possibilities

as well. For example, inflammation of tissue in

the brain and overproduction of free radicals

are two processes that are thought to be a feature of AD. The NIA is now supporting clinical trials in both of these areas to see whether

specific anti-inflammatory agents and agents

that protect against oxidative damage can slow

or prevent the development of AD.

Scientists are also conducting clinical trials

to see whether substances already used to

reduce cardiovascular risk factors also help

reduce AD risk. The NIA has several ongoing

and planned clinical trials to test whether supplementation with folic acid and vitamins B6

and B12 can slow the rate of cognitive decline

in cognitively normal men and women, women

at increased risk of developing dementia, and

in people diagnosed with AD. The Institute

will also conduct a study of statins, the most

common type of cholesterol-lowering drug, to

see whether these drugs can slow the rate of

disease progression in AD patients.

Another area of work involves nerve growth

factor (NGF). NGF is one of several growth

factors in the body that maintain the health of

neurons. NGF also promotes the growth of

axons and dendrites, the neuron branches that

connect with other neurons and that are

essential in nerve cells’ ability to communicate

(see p. 16 in A Walking Tour Through the

Brain for more on the structure and function

of neurons). Studies have turned up a number

of clues that link NGF to the neurons that use

acetylcholine as a neurotransmitter, so

researchers have been eager to see what happens when NGF is added to aging brain tissue.

In animal studies, researchers have been able

to reverse most of the age-related neuronal

shrinkage and loss of ability to make acetylcholine. This success has led to a small-scale,

privately-funded gene therapy trial that is testing whether this procedure can be done safely

in humans and whether it might lessen symptoms of AD.

Finally, a number of clinical trials are focusing on the earliest stages of the disease process.

For example, scientists are developing drugs

that prevent enzymes from clipping beta-amyloid out from APP. Others are working on

ways to stop beta-amyloid from clumping

together into plaques. Teams of investigators

are also studying certain enzymes that seem to

be able to break beta-amyloid into pieces after

it is released from cells but before it has a

chance to form into plaques. Still other scientists are exploring the role of neurotransmitter

systems other than acetylcholine, such as glutamate. One especially active area of research

involves the possibility that a vaccine might be

able to stimulate the immune system into getting rid of plaques once they have formed, stopping beta-amyloid and plaque buildup, or even

getting rid of plaques once they have formed.
Alzheimer’s Disease: Unraveling the Mystery 45

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 Gran in the nursing home.

We had a great time. Then yesterday, I went to see

her again. When I walked in her

room, she started screaming and

calling for help. I didn’t know 

what to do.”

“Mom has been getting up in the

night and wandering around the

house. Last night, I found her all

dressed and trying to get out the

front door. None of us is getting

any sleep anymore.”

“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.”

As Alzheimer’s disease makes

inroads into memory and mental

abilities, it also begins to change

a person’s emotions and behaviors. Between 70 to 90 percent

of people with Alzheimer’s disease eventually develop one or

more behavioral symptoms.

These 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. 

Unlike a stroke, in which damage to part 

of the brain occurs all at once, the damage of

Alzheimer’s disease spreads slowly over time 

and affects many different parts of the brain. 

(Continued on page 48)
46 Alzheimer’s Disease: Unraveling the Mystery

Participating in a Clinical Trial

Rapid advances in our knowledge about AD have led to

the development of many new drugs and treatment

strategies. However, before these new strategies can be

adopted, they must be shown to work in patients. This

means that clinical trials – studies in people to rigorously

test how well a treatment works – have become an

increasingly important part of AD research. Advances in

treatment are only possible through the participation of

patients and family members in clinical trials.

Clinical trials are the primary way that researchers find

out if a promising treatment is safe and effective for

patients. Clinical trials also tell researchers which treatments are more effective than others. Trials take place at

private research facilities, teaching hospitals, specialized

AD research centers, and doctors’ offices.

Participating in a clinical trial is a big step for people

with AD and their caregivers. That’s why physicians and

clinical trials staff spend lots of time talking with participants about what it’s like to be in a trial and the pros and

cons of participating. Here are some things that potential

participants might want to know about clinical trials.

What kind of trials are there?

● Treatment trials with existing drugs assess whether

an already approved drug or compound is useful for other

purposes. For example, one current trial is testing

whether anti-inflammatory drugs already used to treat

arthritis might help to prevent AD.

● Treatment trials with experimental drugs or strategies find out whether a brand new drug or treatment

strategy can help improve cognitive function or lessen

symptoms in people with AD, slow the progression to AD,

or prevent it. Potential drugs tested in these trials are

developed from knowledge about the mechanisms

involved in the AD disease process. These compounds

are rigorously tested in tissue culture and in animals for

their action. Safety and effectiveness studies are also

conducted in animals before the compounds are tested in

humans.

What are the phases of clinical trials?

● During Phase I trials, a study team gives the treatment

to a small number of volunteers and examines its action

in the body, its safety, and its effects at various doses.

Phase I trials generally last only a few months.

● If results show that the treatment appears safe, it will

be tested in Phase II and Phase III clinical trials. These

trials involve larger numbers of people over longer periods

of time. In these trials, the study team wants to know

whether the treatment is safe and effective and what side

effects it might have.

After these phases are complete and investigators are

satisfied that the treatment is safe and effective, the study

team may submit its data to the Food and Drug

Administration (FDA) for approval. The FDA reviews the

data and decides whether to approve the drug or treatment for use in patients.

What happens when a person signs up for 

a clinical trial?

First it is important to learn about the study. Study staff

explain the trial in detail to potential research participants

and describe possible risks and benefits. Staff also talk

about participants’ rights as research volunteers, including

their right to leave the study at any time. Participants and

their family members are entitled to have this 

the Human Side of AD Research
Alzheimer’s Disease: Unraveling the Mystery 47

information repeated and explained until they feel they

understand the nature of the study and any potential risks.

Once all questions have been answered and if there is

still interest in being a part of the study, a patient participant is asked to sign an informed consent form. Laws

and regulations regarding informed consent differ across

States and research institutions, but all are intended to

ensure that patient participants are protected and well

cared for.

In some cases, a patient participant may no longer be

able to provide informed consent because of problems

with memory and confusion. In such cases, it is still possible for an authorized representative (usually a family

member) to give permission for the patient to participate.

For example, the patient participant may have previously

included research participation as part of his or her

durable power of attorney. The person (proxy) exercising

the durable power of attorney can decide to let the

patient participate in a trial if they are convinced that the

patient would have wanted to consent if able to do so.

Even so, it is still important that patients assent to be in

the study, even if they can no longer formally consent to

it. Different States have different laws about who is a

legal representative. These laws are in a state of flux 

as researchers and the public grapple with the ethical

issues of proxy consent.

Next, patients go through a screening process to see if

they qualify to participate in the study. If they qualify and

can safely participate, they can proceed with the other

parts of the study.

What happens during a trial?

If participants agree to join the study and the screening

process shows they’re a good match, they have a “baseline” visit with the study staff. This visit generally

involves a full physical exam and extensive cognitive and

physical tests. This gives the study team information

against which to measure future mental and physical

changes. Participants also receive the test drug or treatment. As the study progresses, participating patients 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 study staff.

These visits allow the investigators to assess the effects

of the test drug or treatment, see how the disease is progressing, and see how the participant and the caregiver

are doing.

In most clinical trials, participants are randomly

assigned to a study group. One group, the test group,

receives the experimental drug. Other groups may

receive a different drug or a placebo (an inactive substance that looks like the study drug). Having the different groups is important because only by comparing them

can researchers be confident that changes in the test

group are the result of the experimental treatment and

not some other factor. In many trials, no one – not even

the study team – knows who is getting the experimental

drug and who is getting the placebo or other drug. This

is called “masking” meaning that the patient/family

member and the staff are “blind” to the treatment being

received.

What should people consider before participating in 

a clinical trial?

Expectations and motivations. Clinical trials generally don’t have miraculous results. The test drug or treatment may relieve a symptom, change a clinical measurement, or reduce the risk of death. With a complex disease like AD, it is unlikely that one drug will cure or prevent the disease. Some people choose not to participate

or drop out of a study because this reality doesn’t meet

their expectations. Others participate because they realize that even if the benefit to them may be slight, they

are making a valuable contribution to knowledge that will

help future patients.

Uncertainty. Some families have a hard time with the

uncertainties of participation – not knowing whether the

person is on the test drug or the placebo, not being able

to choose which study group to be in, not knowing for a

long time whether the study was successful or not.

Ongoing and open communication with study staff can

help to counter this frustration.

Finding the right clinical trial. Some clinical trials

want participants who are cognitively healthy or have

(Continued on page 48)
48 Alzheimer’s Disease: Unraveling the Mystery

Even small tasks require the brain to engage in a

complex process that can involve more than one

region of the brain. If this process is disrupted,

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, behavior that

may seem bizarre suddenly makes sense: 

For a man who can no longer distinguish between

past and present, the anguish caused by the death of

his parent may be as real today as it was many years

before. 

An unknown young man suddenly appearing in

her room may be threatening and terrifying to a

woman who does not recognize her grandson. 

Feelings of responsibility toward a long-ago night

job resurface and compel a woman to get up in the

night to go to work.

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. 

Behavioral symptoms are one of the hardest

aspects of the disease for families and other caregivers to deal with. They are emotional and

upsetting. 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 they occur, and they are studying new

treatments – both drug and non-drug – to deal

with them. 

A number of ongoing and planned clinical trials are looking at ways to treat agitation. These

trials include participants who are living in nursing homes or at home. They involve the study

of a variety of drugs, including a beta-blocker, an

anti-seizure medication, a cholinesterase

inhibitor, and an antipsychotic.

only mild symptoms because they are testing a drug that

might delay the decline in cognitive function. Other trials

are interested in working with participants who have

more advanced AD because they are testing a drug that

might lessen behavioral symptoms, or they are testing

new strategies to help caregivers. Even though a participant may not be eligible for one trial, another trial may

be just right.

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

also talk on an ongoing basis with experts in AD who

have lots of practical experience and a broad perspective on the disease. The study team understands and

can provide advice on the emotional and physical

aspects of the person with AD and the caregivers’ experience. They 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 about AD clinical trials, visit the

NIA’s Alzheimer’s Disease Education and Referral

(ADEAR) Center’s Clinical Trials Database website

(www.alzheimers.org/trials/index.html). This website

includes a list of clinical trials on Alzheimer’s disease

and dementia currently in progress at centers 

throughout the U.S. It also provides information on the

phases of clinical trials and how to participate, and

explains the drug development process. The site also

provides links to other useful websites with related 

information. For additional information, visit the 

clinical trials websites of the Alzheimer’s Association 

www.alz.org/ResourceCenter/ByTopic/Research.htm and

the National Institutes of Health www.clinicaltrials.gov/.
ImprovingSupport

forFamiliesand

OtherCaregivers

Perhaps one of the greatest costs of

Alzheimer’s disease is the physical and

emotional toll on family, caregivers, and

friends. 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 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 

Alzheimer’s Disease: Unraveling the Mystery 49

Caregivers vary depending on the culture and ethnic group involved. Most primary caregivers are

family members.

● Spouses: This is the largest group of caregivers. Most are older, too, and many have their

own health problems to deal with.

● Daughters: The second largest group of primary caregivers are 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: Though 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, but many are

older and are coping with their own frailties or health

problems.

● Grandchildren: Older children may become major

helpers in caring for a person with AD. Adolescent or

young grandchildren may need extra help and support if

their parents’ attention is heavily focused on the ill grandparent, or if the grandparent with AD lives in the family’s

home.

● Other: Friends, neighbors, and fellow faith community

members also often help care for a person with AD.

Who are the AD Caregivers?
50 Alzheimer’s Disease: Unraveling the Mystery

significantly more time on caregiving tasks

than do caregivers of people with other types

of illnesses. 

Although research on caregiver support is

still in its early days, we’ve already learned a lot

about the unique aspects of caregivers’ personalities and situations. For example, one study

of the psychological and physical responses of

AD caregivers showed that they don’t all have

the same response to caregiving. Certain characteristics seem to make some caregivers more

vulnerable to the physical and emotional stresses associated with dementia care. These characteristics include being a male spouse, having

few breaks from caregiving responsibilities, and

having preexisting illnesses.

Caregiver research is also beginning to tease

out characteristics of support programs that

might be most useful for particular groups of

caregivers. For example, peer support programs

that link caregivers with trained volunteers

who also have been dementia caregivers appear

to help. These programs are especially good for

caregivers whose social support networks are

weak or who are in very stressful situations.

Other research has confirmed that the information and problem-solving needs of caregivers

evolve over time as the person with AD

changes. Support programs can respond by

offering services and information geared to 

different stages of the disease.

One of the most difficult decisions that many

families face is whether and when to place a

loved one with Alzheimer’s disease 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 assisted living facilities, continuing care retirement communities, nursing homes, and special care units

(a separate area within a nursing home or

assisted living facility designed especially for

patients with dementia).
Alzheimer’s Disease: Unraveling the Mystery 51

A reality check for an AD caregiver might look something

like this:

● Physical effort and time commitment: Help with

bathing, eating, dressing, and other activities of daily living

takes a lot of time. As the disease progresses, the need

for this kind of help increases. Behavior problems and

safety concerns mean that the caregiver is always “on

duty,” even when not actively helping the person.

● Financial costs: The costs of care vary, but can be

high depending on whether the person is cared for at

home or in a residential care setting and how much help

the caregiver has. Many caregivers give up their jobs or

cut back on their work hours and this also has financial

implications.

● Psychological loss: Caregivers often experience a

profound sense of loss as the disease slowly takes their

husband, wife, parent, or friend. The relationship as it

once was gradually ends and plans for the future must be

radically changed. Caregivers must come to terms with

“the long goodbye.”

Many research studies have shown that caring for a

person with AD can have some negative effects on the

caregiver...

● Employment complications

● Emotional distress

● Fatigue and poor physical health

● Social isolation

● Family conflict

● Less time for leisure, self, and other family members

...but research has shown that caregiving also has

important positive effects:

● 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

the Realities, the Positives, and the

Negatives of Caring for a Person with AD
52 Alzheimer’s Disease: Unraveling the Mystery

Studying New Ways to Help Caregivers

It was midnight, the end of a long day of taking care of

her husband. She was exhausted but she couldn’t sleep.

A year ago she would have felt totally alone, unable to

share the hardships of caregiving, and desperate for ideas

for how to cope better with his changeable moods and

withdrawal from the world. Tonight was different. She

went to the living room, switched on her computer, and

plugged into a computer-based support group for family

caregivers. She sent out a message and soon received

replies from several fellow caregivers. They knew just

what she was feeling. Their words of understanding and

support eased her mind and helped give her the strength

she needed for the days ahead.

Caring for a person with Alzheimer’s disease has special

stresses and difficulties. As a result, support groups have

always been an important feature of AD caregiver programs. Conventional support groups have been 

enormously helpful for many caregivers, but they have a

few drawbacks. Attending a group involves finding transportation and arranging for care for the person with AD.

The group’s meeting time may not coincide with the time

that a caregiver wants advice or needs to express feelings. Some caregivers do not feel comfortable discussing

their experiences publicly in a group. Members of some

ethnic or cultural groups may be particularly reluctant to

join a traditional support group.

In 1989, a researcher

had an idea for a radically

different, new kind of support system for family

caregivers. She envisioned a computer-based

system that would operate

24 hours a day, 7 days a

week. It would provide

expert medical advice and

information about the latest developments in AD

research. It would also

include a “bulletin board”

component that would

allow caregivers to share

ideas and give and get

support by posting messages on-line. The project would provide a computer if

needed and would train caregivers in how to use the

equipment. From the start, she invited the local

Alzheimer’s Association to join her in carrying out the 

idea. This partnership is still flourishing today.

Although many people doubted that adult and elderly

caregivers with little or no computer experience would

want to go online, the project, called the Alzheimer’s

Disease Support Center, was a hit from the start. In fact,

the bulletin board component, called the Caregiver Forum,

Science on the Cutting Edge
Alzheimer’s Disease: Unraveling the Mystery 53

soon became the most popular element. Users were eager

to communicate, share experiences and feelings, and learn

from each other. They soon became, as they called it, a

“computer family.”

Scientists who have been conducting research with computer-based support systems have found they have two

qualities that make them especially useful:

● They reach lots of people simultaneously. Many users

can log on to get information that is posted on the system.

In addition to providing lists of useful publications and

materials, the systems post information on traditional support groups, daycare centers, and other services. They also

provide a “Q&A” module where users can get answers to

their specific caregiving questions from a team of physicians, nurses, social workers, psychologists, and staff of the

Alzheimer’s Association. In addition, users can browse an

archive of previously asked questions and answers organized by topic. Users can also interact with each other

through the bulletin board component.

● Computer-based systems address some of the drawbacks of traditional support groups. They put control of the

support process in the hands of the user. Users can talk

with others and get help whenever they need it, day or

night. Some users log on daily; others log on only when

they have a specific question or need. Because the computer is at home, they don’t need to make special arrangements to get to a support group meeting. Users can

express themselves publicly if they want to or they can be

anonymous if that is better for them. For every user who

posts messages on the system, researchers have documented that several just read what others have posted.

These users seem to benefit from the sense of kinship with

others facing similar situations and may in time begin to

participate more actively.

One of the most fascinating findings from this project was

how quickly users overcame the potential barriers posed by

an electronic communication system. Here are just a few of

the techniques users have adopted to “humanize” the system, especially the Caregiver Forum:

● Using punctuation keys, users have incorporated an

array of icons into their messages to represent faces and

gestures. They also intentionally misspell words and

manipulate the placement of letters. All of these devices

help users convey their feelings.

:-) :)ing :-o :-| ( )s [hugs]

“I am soooooooo tired.”

“It was reeeeeeeeeally scary.”

“...this is one way I have to think not to go way

D

O

W

N”

● Users talk about all sorts of things, not just caregiving

issues. Sharing details of everyday life – weddings, children’s activities, hobbies, even the weather – seems to help

users reduce their feelings of isolation and brings a sense

of normality and balance to their relationships with others.

● Friendships begun over the computer have blossomed

into regular meetings for meals and get-togethers.

In 2000, the NIA funded a follow-up study to the original

project. Called Computer Mediated Support for Family

Caregivers, or CO-MES, the study is exploring how best to

use computers to provide information and support to family

caregivers. The study team is trying to learn more about

who uses this type of support and whether computer-based

groups help to lessen the negative effects of caregiving.

Two types of computer-based groups are being studied – a

group led by a family caregiver and a group led by a nurse.

Many of the system’s features are the same as before,

though users now access the system through the Internet.

The system also now has a chat room, which allows users

to have “real-time” conversations. At the same time, the

original computer-based support group continues to 

operate.
54 Alzheimer’s Disease: Unraveling the Mystery

Acetylcholine – a neurotransmitter that plays

an important role in learning and memory.

Amyloid precursor protein (APP) – the larger protein from which beta-amyloid is formed.

Amyloid plaques – largely insoluble deposits

found in the spaces between nerve cells in the

brain that are made of beta-amyloid, other

molecules, and different kinds of nerve and

non-nerve cells.

Apolipoprotein E – a protein that carries cholesterol in blood and that appears to play some

role in brain function. The gene that produces

ApoE comes in several forms, or alleles – ε2,

ε3, and ε4. The APOE ε2 allele is relatively

rare and may provide some protection against

AD. APOE ε3 is the most common allele and

it appears to play a neutral role in AD. APOE

ε4 occurs in about 40 percent of all AD

patients who develop the disease in later life;

it increases the risk of developing AD.

Axon – the long, tube-like part of a neuron

that transmits outgoing signals to other cells.

Beta-amyloid – a part of the APP protein

found in the insoluble deposits outside neurons

and that forms the core of plaques.

Brain stem – the part of the brain that connects the brain to the spinal cord and that

controls automatic body functions, such as

breathing, heart rate, and blood pressure.

Cerebellum – the part of the brain that is

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, decisionmaking,

emotions, movement, and sensory functions.

Chromosome – a threadlike structure in the

nucleus of a cell that contains DNA,

sequences of which make up genes; most

human cells contain 23 pairs of chromosomes.

Clinical trial – a research study involving

humans that rigorously tests how well an intervention works.

Cognitive functions – all aspects of conscious

thought and mental activity, including learning, perceiving, making decisions, and remembering.

Corpus callosum – the thick bundle of nerves

that connects the two hemispheres of the cerebral hemispheres.

Dementia – a broad term referring to the

symptoms associated with a decline in cognitive function to the extent that it interferes

with daily life and activities.

Glossary
Alzheimer’s Disease: Unraveling the Mystery 55

Dendrite – the branchlike extension of neurons that receive messages from other neurons.

DNA (deoxyribonucleic acid) – a long double

stranded molecule within the nucleus of the

cell that forms the chromosomes and contains

the genes.

Early-onset Alzheimer’s disease – a rare form

of AD that usually begins to affect 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 first begins.

Enzyme – a substance that causes or speeds up

a chemical reaction.

Free radical – a highly reactive oxygen molecule that combines easily with other molecules, sometimes causing damage to cells.

Gene – the biologic unit of heredity passed

from parent to child; genes are segments of

DNA and they contain instructions that tell a

cell how to make specific proteins.

Genetic risk factor – a change in a cell’s DNA

that does not cause a disease but may increase

the chance that a person will develop a disease.

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 longterm 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

65 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 – 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 the chemical processes that

take place inside the body. In some metabolic

reactions, complex molecules are broken down

to release energy; in others, the cells use energy to make complex compounds out of simpler

ones (like making proteins from amino acids).

Microtubules – the internal support structure

for neurons that guides nutrients and molecules from the body of the cell to the end of

the axon and back.
56 Alzheimer’s Disease: Unraveling the Mystery

Mutation – a rare change in a cell’s DNA that

can cause a disease.

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.

Neurofibrillary tangles – collections of 

twisted tau found in the cell bodies of neurons

in AD.

Neuron – a nerve cell in the brain.

Neurotransmitter – a chemical messenger

between neurons; a substance that is released

by the axon on one neuron and excites or

inhibits activity in a neighboring neuron.

Nucleus – the organ within a cell that 

contains the chromosomes and controls many

of its activities.

Positron emission tomography (PET) – an

imaging technique 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 in brain tissues.

Single photon emission computerized tomography (SPECT) – an imaging technique that

allows researchers to monitor blood flow to different parts of the brain.

Synapse – the tiny gap between nerve cells

across which neurotransmitters pass.

Tau – a protein that is a principal component

of the paired helical filaments in neurofibrillary tangles; tau helps to maintain the structure of microtubules in normal nerve cells.

Thalamus – a small organ in the front of the

cerebral hemispheres that sends sensory information to the cerebral cortex and sends other

information back to the body.

Transgenic mice – mice that have had a

human gene (like APP) inserted into their

chromosomes. Mice carrying the mutated

human APP gene often develop plaques in

their brains as they age.

Ventricle – cavity within the brain that contains cerebrospinal fluid. During AD, brain

tissue shrinks and the ventricles enlarge.
Organizations

Alzheimer’s Association. The Alzheimer’s

Association is a national, nonprofit organization

with a network of local chapters that provide

education and support for people diagnosed with

AD, their families, and caregivers. Chapters offer

referrals to local resources and services, and

sponsor support groups and educational programs. Online and print publications are also

available.

Alzheimer’s Association

919 North Michigan Avenue, Suite 1100

Chicago, IL 60611-1676

1-800-272-3900

Website: www.alz.org

Alzheimer’s Disease Cooperative Study. The

Alzheimer’s Disease Cooperative Study (ADCS)

is a cooperative agreement between the National

Institute on Aging (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

of 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.

Alzheimer’s Disease Cooperative Study

University of California, San Diego

9500 Gilman Drive - 0949

La Jolla, CA 92093-0949

858-622-5880

Website: http://antimony.ucsd.edu/

Alzheimer’s Disease Education and Referral

(ADEAR) Center. The ADEAR Center, part of

the NIA, provides publications and information

on AD, including booklets on caregiving, fact

sheets and reports on research findings, a database of clinical trials, recommended reading lists,

and the Progress Report on Alzheimer’s Disease.

Information specialists provide referrals to local

AD resources.

Alzheimer’s Disease Education and Referral

(ADEAR) Center 

PO Box 8250

Silver Spring, MD 20907

1-800-438-4380

Website: www.alzheimers.org

Children of Aging Parents. Children of Aging

Parents is a nonprofit organization that provides

information and referrals for nursing homes,

retirement communities, elderlaw attorneys,

adult day-care centers, medical insurance

providers, respite care, assisted living centers,

and State and county agencies. Also offered are

fact sheets on various topics, a bimonthly

newsletter, conferences and workshops, support

group referrals, and a speaker’s bureau.

Children of Aging Parents

1609 Woodbourne Road, Suite 302A

Levittown, PA 19057-1511

1-800-227-7294

Website: www.caps4caregivers.org

Alzheimer’s Disease: Unraveling the Mystery 57

For More Information
58 Alzheimer’s Disease: Unraveling the Mystery

Eldercare Locator. The Eldercare Locator is a

nationwide, directory assistance 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.

Eldercare Locator

1-800-677-1116

Website: www.eldercare.gov 

Family Caregiving Alliance. The Family

Caregiver Alliance (FCA) is a nonprofit organization that offers support services for those caring

for adults with AD, stroke, traumatic brain

injuries, and other cognitive disorders. FCA programs and services include an Information

Clearinghouse for FCA’s publications.

Family Caregiving Alliance

690 Market Street, Suite 600

San Francisco, CA 94104

415-434-3388

Website: www.caregiver.org

National Institute on Aging (NIA). Part of the

National Institutes of Health (NIH), the NIA is

the Federal government’s lead agency for

research on AD. NIA also offers information

about health and aging, including the Age Page

series and the NIA Exercise Kit, which contains

an 80-page exercise guide and 48-minute closedcaptioned video. Caregivers can find many Age

Pages on the website.

National Institute on Aging 

Information Center

PO Box 8057

Gaithersburg, MD 20898-8057

1-800-222-2225

1-800-222-4225 (TTY)

Website: www.nia.nih.gov

National Library of Medicine. Part of NIH, the

National Library of Medicine is the world’s

largest medical library with 6 million items,

including books, journals, technical reports,

manuscripts, microfilms, photographs and

images. A large searchable health information

database of biomedical journals, called MEDLINE/PubMed is accessible via the Internet. A

service called MEDLINEplus links the public to

general information about AD and caregiving,

plus many other sources of consumer health

information, including a searchable clinical trials

database located at http://clinicaltrials.gov.

National Library of Medicine

8600 Rockville Pike

Bethesda, MD 20894

1-888-346-3656

Website: www.nlm.nih.gov

Partnership for Caring. Partnership For Caring

(PFC) is a nonprofit organization that works to

improve how people die in our society. PFC

operates an information hotline dealing with

end-of-life issues and provides State-specific living wills, medical powers of attorney, and other

information materials. PFC also provides education and consultation services to doctors, nurses,

social workers, attorneys, and clergy concerning

end-of-life decisions. 

Partnership for Caring

1620 Eye Street NW, Suite 202

Washington, DC 20006

1-800-989-9455

Website: www.partnershipforcaring.org

Well Spouse Foundation. Well Spouse

Foundation is a nonprofit organization that gives

support to spouses and partners of the chronically ill and/or disabled. Well Spouse maintains support groups, publishes a bimonthly newsletter,

and helps organize letter writing programs to

help members deal with the effects of isolation.

Well Spouse Foundation

63 West Main Street, Suite H

Freehold, NJ 07728

1-800-838-0879

Website: www.wellspouse.org
Alzheimer’s Disease: Unraveling the Mystery 59

Recommended Reading

Check with your local library, bookseller or with

major Internet book distributors for the following:

Ballard, E.L., Poer, C.M. Lessons Learned:

Shared Experiences in Coping. Durham, NC:

The Duke Family Support Program. 1999.

Available from the Alzheimer’s Disease

Education and Referral (ADEAR) Center, PO

Box 8250, Silver Spring, MD 20907-8250. 

1-800-438-4380.

This book documents the experiences of

people caring for loved ones with AD. Filled

with short stories and advice, it is intended

for caregivers who wish to take comfort and

learn from the experiences of others.

Caregivers discuss the caregiving process,

such as getting a diagnosis, finding support

services, making decisions about treatment

and living arrangements, and coping with

stress and caregiver burden.

Davies, H.D., Jensen, M.P. Alzheimer’s: The

Answers You Need. Forest Knolls, CA: Elder

Books. 1998.

This book is designed for people in the early

stages of AD. It provides information about

the nature and causes of AD, the symptoms

and how to deal with them, the assessment

process, taking part in a drug research program, continuing to work, handling finances,

driving, and the effects of AD on a spouse

and other family members.

Mace, N.L., Rabins, P.V. The 36 Hour Day: 

A Family Guide To Caring for Persons With

Alzheimer’s Disease, Related Dementing

Illnesses, and Memory Loss in Later Life. 3rd

ed. Baltimore, MD: Johns Hopkins University

Press. 1999.

This practical and detailed reference book

provides a wealth of information to families

on caring for persons with AD or related disorders. The book presents background information on dementia, brain disorders, and the

causes of dementia, and gives practical suggestions and advice on how families and

caretakers can deal with problems.

McKhann, G., Albert, M. Keeping Your Brain

Young: The Complete Guide to Physical and

Emotional Health and Longevity. Hoboken, NJ:

John Wiley and Sons. 2002.

This book examines scientific research and

case histories to summarize the most effective ways to reduce the impact of physical

changes to the brain as we age. The authors

offer techniques to improve memory and 

recommend mental and physical exercise

programs. Their strategies to stay healthy

also include a well-balanced diet, proper

sleep, and getting treatment for depression,

vision and hearing loss, and other health

problems. The book also discusses brain 

disorders.

Petersen, R., ed. Mayo Clinic on Alzheimer’s

Disease. Rochester, MN: Mayo Clinic Health

Information. 2002.

This book discusses current knowledge of

AD and its relationship to other forms of

dementia. It also provides an overview of

treatment and caregiving, using the experience of physicians, psychiatrists, neurologists, and allied healthcare professionals at

the Mayo Clinic. Topics include how the

brain works and what can go wrong; how AD

affects a person; diagnosis treatments;

research; and caregiving.

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, to old

age. The author examines brain disorders

and mechanisms of brain repair and healing.
60 Alzheimer’s Disease: Unraveling the Mystery

Shenk, D. The Forgetting. Alzheimer’s: Portrait

of an Epidemic. New York, NY: Random House,

Inc. 2001.

An eloquent and moving description of

Alzheimer’s disease, 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. The author, calling AD a “death

by a thousand subtractions,” describes the science of AD in terms that are easy for those

who know nothing about AD to understand.

Snowdon, D. Aging With Grace: What the Nun

Study Teaches Us About Leading Longer,

Healthier, and More Meaningful Lives. New

York, NY: Random House, Inc. 2001.

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

allowed 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 to AD, and the role of heredity

and lifestyle in healthy aging.

Tanzi, R.E., Parson, A.B. Decoding Darkness:

The Search for the Genetic Causes of

Alzheimer’s Disease. Cambridge, MA: Perseus

Publishing. 2000.

This book presents a history of the medical

journey to find the genetic causes of AD. It

describes the experiences of Dr. Rudy Tanzi, a

pioneer in the search to identify AD genes.

The book is easy to read and examines the

complex research involved in molecular

genetics. The authors speculate that AD may

ultimately be effectively treated and even prevented.

Credits

Writer

Anne Brown Rodgers

Medical Illustrator

Christy Krames, MA, CMI

Editors

Patricia D. Lynch and Karen M. Pocinki 

National Institute on Aging

Design

Rodney C. Williams and Brian Taylor

RCW Communication Design Inc.

Project Coordinator

David Burton

Johnson, Bassin & Shaw Inc.

Photography

Front Cover (top), Back Cover (top), Page 45 – Corbis

Front Cover (bottom), 9 – Brand X Pictures

Back Cover (bottom), 5, 6, 49 – Getty 

Page 2, 40, 42 – Photoresearchers

Page 6, 7, 8, 41, 46, 48, 50, 51 – Rick Brady

Page 31, 33, 48, 52 – Max Hirshfeld

Page 14 – Courtesy of Dr. Susan Bookheimer,

Brain Mapping Center, UCLA School of Medicine

Page 15, 24 – Courtesy of Dr. Gary Small,

University of California at Los Angeles

Page 18 – Courtesy of Dr. Philip Landfield,

University of Kentucky and with permission of the 

Journal of Neuroscience, 2001. Dec 15, 21(24), 9744-56

Page 19 – Courtesy of Dr. Carl Cotman,

University of California at Irvine and with permission 

of Trends in Neuroscience, 2002. Jun, 25(6), 295-301

Page 20 – Courtesy of Dr. William Markesbery,

University of Kentucky

Page 35 – Courtesy of Dr. Bradley Hyman,

Harvard Medical School/Massachusetts General Hospital

Page 37 – Courtesy of Dr. David Bennett,

Rush Presbyterian-St. Luke’s Medical Center, the Benedictine

Monks, Collegeville, MN, and the Benedictine Sisters,

St. Cloud, MN 

Animation Design and Production

Stacy Jannis and Rebekah Fredenburg

Vicky Cahan, National Institute on Aging

Special thanks to:

The staff of the Neuroscience and Neuropsychology of Aging

Program, National Institute on Aging
For additional copies of this report or further

information about Alzheimer’s disease,

please contact:

Alzheimer’s Disease Education and

Referral (ADEAR) Center

PO Box 8250

Silver Spring, MD 20907-8250

Phone: 1-800-438-4380

E-mail: adear@alzheimers.org

Website address: http://www.alzheimers.org
U.S. Department of Health and Human Services

National Institutes of Health

NIH Publication Number: 02-3782

October 2002