DISEASE

Unraveling the Mystery

ALZHEIMERS

National Institute on Aging

National Institutes of Health
DISEASE

Unraveling the Mystery

ALZHEIMERS
2 ALZHE IMER’S D ISEASE Unraveling the Mystery

Over the past few 

 decades, Alzheimer’s 

 disease (AD) has 

emerged from 

obscurity. Once considered a 

rare disorder, it is now seen as 

a major public health problem 

that has a severe impact on millions of older Americans and 

their families. The National 

Institute on Aging (NIA) is the 

lead agency for AD research at 

the National Institutes of Health 

(NIH). NIA launched its AD 

program in 1978, and since 

then, the study of this disease 

has become one of NIA’s top 

priorities. Several other NIH institutes also conduct and sponsor 

studies on AD.

Thanks to the work of NIH 

institutes, other research orgaALZHE IMER’S D ISEASE Unraveling the Mystery 3

nizations around the world, and 

many private-sector research, 

education, and advocacy groups, 

the study of AD is moving 

ahead rapidly. This book explains 

what AD is, describes the main 

areas in which researchers are 

working, and highlights new 

approaches for helping families 

and friends care for people 

with AD.

TO GET THE MOST OUT OF THIS BOOK

Preface Table Contents of

4 INTRODUCTION

4 AD: A Growing National Problem

5 About This Book

8 THE BASICS OF THE HEALTHY BRAIN

 10 Inside the Human Brain

 10 The Main Players 

 12 Other Crucial Parts 

 12 The Brain in Action 

14 Neurons and Their Jobs

 14 Communication 

 16 Metabolism 

 16 Repair 

17 The Changing Brain in Healthy Aging

20 WHAT HAPPENS TO THE BRAIN IN AD

21 The Hallmarks of AD

 21 Amyloid Plaques 

 25 Neurofibrillary Tangles 

 26 Loss of Connection Between 

Cells and Cell Death 

27 The Changing Brain in AD

 27 Preclinical AD 

 28 Very Early Signs and Symptoms 

 30 Mild AD 

 31 Moderate AD 

 31 Severe AD 

34 AD RESEARCH: BETTER QUESTIONS, 

NEW ANSWERS

36 Looking for the Causes of AD

 36 Genetic Factors at Work in AD 

 40 Other Factors at Work in AD 

48 New Techniques Help in Diagnosing AD

 50 Exciting New Developments in 

AD Diagnosis 

 54 The Search for New Treatments

 55 Helping People with AD Maintain Their 

Mental Functioning 

 56 Managing Symptoms 

 57 Slowing, Delaying, or Preventing AD 

62 IMPROVING SUPPORT FOR 

FAMILIES AND OTHER CAREGIVERS

64 Research Findings Benefit Caregivers

 66 Early-Stage AD Support Groups: 

A Vital Source of Help 

69 CONCLUSION

70 GLOSSARY

74 FOR MORE INFORMATION

 74 Information and Support Resources

 75 Caregiving Support and Services

 76 Research and Clinical Trials

 76 Recommended Reading

p a r t 1

p a r t 2

p a r t 3

p a r t 4

Learn the Basics of the Healthy Brain

The parts of the brain (pages 10-13)

How neurons work (pages 14-16)

 The changing brain in healthy aging 

(pages 17-19)

■

■

■

Discover What Happens 

to the Brain in AD 

The hallmarks of AD (pages 21-26)

The changing brain in AD (pages 27-33)

■

■

Explore Cutting-Edge AD Research

Looking for causes (pages 36-47)

Diagnosing AD (pages 48-53)

Searching for treatments (pages 54-61)

■

■

■

Learn about Caregiver Support

Who are AD caregivers? (page 63)

 Reducing the personal costs of caregiving 

(pages 64-67)

 Taking care of mom or dad from a distance 

(page 68)

■

■

■

TO LEARN EVEN MORE

Visit NIA’s Alzheimer’s Disease Education and Referral Center website at www.nia.nih.gov/Alzheimers.

There, you will find resources to accompany this book, such as downloadable versions of the illustrations 

and an animation that shows what happens to the changing brain in AD. And while you are there, 

explore the ADEAR Center’s many other offerings. These include free publications about AD and AD 

caregiving, clinical trials information, a list of NIA-funded Alzheimer’s Disease Centers, and NIA’s 

searchable AD Library database of thousands of materials about AD.
4 ALZHE IMER’S D ISEASE Unraveling the Mystery

This excerpt from Lessons Learned: Shared 

Experiences in Coping, by participants 

of the Duke University Alzheimer 

Support Groups, gives a glimpse into 

what a person with Alzheimer’s disease (AD) and 

a family caregiver might experience as the disease 

progresses. The gradual slipping away of mind 

and memory is frightening and frustrating, both 

for the person with the disease and for family and 

friends, and can elicit strong feelings of love, grief, 

anger, and exhaustion. 

AD is an irreversible, progressive brain disease 

that slowly destroys memory and thinking skills, 

eventually even the ability to carry out the simplest 

tasks. In most people with AD, symptoms first 

appear after age 60. AD is caused by a disease that 

affects the brain. In the absence of disease, the 

human brain often can function well into the 

10th decade of life. 

Not so long ago, we were not able to do 

much for people with AD. Today, that situation 

is changing. Thousands of scientists, voluntary 

organizations, and health care professionals are 

studying AD so that they can find ways to manage, 

treat, and one day prevent this terrible disease.

AD: A GROWING NATIONAL PROBLEM

For many older adults and their families, AD 

stands in the way of the “Golden Years.” It also 

presents a major problem for our health care system 

and society as a whole. AD is the most common 

cause of dementia among older people. Recent 

estimates of how many people in the United States 

currently have AD differ, with numbers ranging 

from 2.4 million to 4.5 million, depending on how 

AD is measured. But scientists agree that unless 

the disease can be effectively treated or prevented, 

the numbers will increase significantly if current 

population trends continue.

Our aging society makes AD an especially critical issue. A 2005 Census Bureau report on aging 

in the United States notes that the population 

age 65 and older is expected to double in size to 

about 72 million people within the next 25 years. 

Moreover, the 85 and older age group is now the 

fastest growing segment of the population. This is 

all the more important for a neurodegenerative 

ALZHE IMER’S D ISEASE Unraveling the Mystery 5

disease like AD because the number of people 

with the disease doubles for every 5-year age 

interval beyond age 65. 

AD not only affects the people with the disease, 

of course. The number of AD caregivers—and 

their needs—can be expected to rise rapidly as 

the population ages and as the number of people 

with AD grows. During their years of AD caregiving, spouses, relatives, and friends experience 

great emotional, physical, and financial challenges. 

As the disease runs its course and the abilities of 

people with AD steadily decline, family members 

face difficult, and often costly, decisions about the 

long-term care of their loved ones. 

The growing number of people with AD and 

the costs associated with the disease also put a 

heavy economic burden on society. The national 

direct and indirect costs of caring for people with 

AD are estimated to be more than $100 billion a 

year. A 2004 study provided an equally sobering 

picture of the impact of AD. It is estimated that 

if current AD trends continue, total Federal 

Medicare spending to treat beneficiaries with the 

disease will increase from $62 billion in 2000 to 

$189 billion in 2015. 

For these reasons, AD is an urgent research 

priority. We need to find ways to manage and treat 

AD because of its broad-reaching and devastating 

impact. We now know that the disease process 

begins many years, perhaps even decades, 

before symptoms emerge. Discovering ways to 

identify AD in the earliest stages and halt or slow 

its progress will benefit individuals, families, and 

the Nation as a whole.

ABOUT THIS BOOK

Thinking about AD leads to questions such as: 

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

prevent it? Will I get it? Scientists ask the same 

types of questions, and this book describes their 

search for answers. It is written for people with 

AD, their family members and friends, caregivers, 

and others interested in AD.

This book has four sections: 

Part 1 gives readers some basics about the 

healthy brain. Illustrations and text show what a 

healthy brain looks like and how it works. 

Part 2 focuses on what happens in the brain 

during AD. 

■

■

“Never have I loved my husband of 41 years more than I do today....Though he may not know I’m his wife, 

he does know that my presence means his favorite foods and drinks are near at hand....I wonder why I can 

sit daily by his side as I play tapes, relate bits and pieces of news, hold his hand, tell him I love him. Yet I am 

content when I am with him, though I grieve for the loss of his smile, the sound of my name on his lips.”

Introduction

See the glossary on page 70 for 

definitions of boldfaced terms. 

Visit the National Institute on Aging 

(NIA) Alzheimer’s Disease Education 

and Referral (ADEAR) Center website 

at www.nia.nih.gov/Alzheimers/ADvideo 

to view an animation that helps this part 

of the book come alive.
Introduction

6 ALZHE IMER’S D ISEASE Unraveling the Mystery

Part 3 talks about current research and the 

advances that are bringing us closer to ways of 

managing and eventually defeating AD. 

Part 4 focuses on issues important to AD 

caregivers and families, including current research 

that is finding ways to improve caregiver support. 

The end of the book includes a list of publications and resources that people with AD, family 

members, and caregivers may find useful as they 

live day to day with the disease. 

■

■

A book like this is possible only because of 

the major progress that scientists throughout the 

world have made. Not long ago, we knew very 

little about AD other than some facts about its 

major characteristics. Today, we are beginning 

to understand more about what AD is and who 

gets it, how and why it develops, and what course 

it follows. We are learning about the complex 

interface between AD and normal age-related 

changes in the brain. We also are getting much 

ALZHE IMER’S D ISEASE Unraveling the Mystery 7

better at diagnosing it early and accurately. Most 

important, we now have some promising leads on 

possible treatments. Studies also are beginning 

to focus on preventive strategies by examining 

lifestyle factors that might influence a person’s 

risk of developing AD. 

Since the 1970s, research supported by 

NIA and other organizations has deepened 

our understanding of this devastating disease. 

It also has expanded our knowledge of brain 

function in healthy older people and identified 

ways we might lessen normal age-related declines 

in mental function. Most importantly, this accumulated research has increased our appreciation 

for just how complex AD is. It is now clear that 

many scientific and clinical disciplines need to 

work together to untangle the genetic, biological, 

and environmental factors that, over many 

years, set a person on a course that ultimately 

results in AD.

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

19O6

■ Dr. Alois Alzheimer, a German neurologist and 

psychiatrist, describes the case of a 51-year-old 

woman, Auguste D., who had been admitted to 

a hospital 5 years earlier with a cluster of unusual 

symptoms, including problems with comprehension 

and memory, an inability to speak, disorientation, 

behavioral problems, and hallucinations. After her 

death, Dr. Alzheimer examined her brain tissue and 

described two of the hallmarks of AD—numerous 

globs of sticky proteins in the spaces between 

neurons (beta-amyloid plaques) and a tangled 

bundle of fibrils within neurons (neurofibrillary 

tangles).

191Os – 194Os

■ Belief persists that “senile dementia” is a normal part 

of aging.

195Os

■ Scientists study the biological structure of plaques 

and tangles.

196Os

■ Scientists discover a link between dementia and 

the number of plaques present in the brain. AD is 

recognized as a distinct disease, not a normal part 

of aging.

197Os 

■ Scientists find that levels of acetylcholine, a 

neurotransmitter important in memory formation, 

falls sharply in people with AD. This discovery is 

one of the first to link AD with biochemical changes 

in the brain.

■ “Alzheimer’s disease” becomes a common term as 

recognition of AD as a major public health problem 

grows.

■ NIA is established.

198Os

■ Diagnostic criteria for AD are established.

■ Genetic links to early-onset AD begin to surface.

■ Congress mandates NIA as lead Federal agency 

for AD research.

As shown in this timeline, we have learned a lot since Dr. Alzheimer presented the case of his patient, Auguste D. 

 The pace of research continues to accelerate as new findings open more and more doors to discovery.

■ Scientists start to unravel the biological pathways 

that lead to the development of beta-amyloid 

plaques in the brain. 

■ Abnormal tau protein in tangles is identified.

199Os

■ The U.S. Food and Drug Administration (FDA) 

approves tacrine (Cognex®), the first drug used to 

treat AD. This drug has since been replaced by 

other medications.

■ Genetic mutations linked to early-onset and 

late-onset AD are discovered.

■ The first transgenic mouse model of AD is 

created.

■ Additional diagnostic criteria are developed for AD.

■ Characteristics of mild cognitive impairment are 

described and defined.

■ NIA launches the Alzheimer’s Disease Education 

and Referral Center, AD Cooperative Study, and 

other initiatives to conduct and support AD treatment 

and prevention clinical trials. 

2OOOs

■ The FDA approves other AD drugs, including 

rivastigmine (Exelon®), galantamine (Razadyne®), 

donepezil (Aricept®), and memantine (Namenda®) 

to treat symptoms of AD. 

■ Early work on an AD vaccine begins. 

■ Many new AD clinical trials, initiatives, and 

studies are launched, looking at a broad array of 

translational, treatment, and prevention issues.

■ New transgenic mouse models, including one 

that develops both plaques and tangles, are 

developed.

■ Pittsburgh Compound B (PiB) is developed, allowing 

researchers to “see” beta-amyloid plaques in the 

brains of living people.

■ The growing sophistication of neuroimaging 

techniques, genetics, memory and cognitive 

tests, structured interviews, and other technologies 

improve our ability to identify people at high 

risk of AD. 
ALZHE IMER’S D ISEASE Unraveling the Mystery 9

To understand AD, it is important to 

know a bit about the brain. This part of 

Unraveling the Mystery gives an inside 

view of the normal brain, how it works, 

and what happens during aging. 

The brain is a remarkable organ. Seemingly 

without effort, it allows us to carry out every 

element of our daily lives. It manages many body 

functions, such as breathing, blood circulation, 

and digestion, without our knowledge or 

direction. It also directs all the functions we carry 

out consciously. We can speak, hear, see, move, 

remember, feel emotions, and make decisions 

because of the complicated mix of chemical and 

electrical processes that take place in our brains. 

The brain is made of nerve cells and several 

other cell types. Nerve cells also are called 

neurons. The neurons of all animals function in 

basically the same way, even though animals can 

be very different from each other. Neurons survive 

and function with the help and support of glial 

cells, the other main type of cell in the brain. Glial 

cells hold neurons in place, provide them with 

nutrients, rid the brain of damaged cells and other 

cellular debris, and provide insulation to neurons 

in the brain and spinal cord. In fact, the brain 

has many more glial cells than neurons—some 

scientists estimate even 10 times as many. 

Another essential feature of the brain is its 

enormous network of blood vessels. Even though 

the brain is only about 2 percent of the body’s 

weight, it receives 20 percent of the body’s blood 

supply. Billions of tiny blood vessels, or capillaries, 

carry oxygen, glucose (the brain’s principal source 

of energy), nutrients, and hormones to brain cells 

so they can do their work. Capillaries also carry 

away waste products. 

The Brain’s 

Vital Statistics

ADULT WEIGHT 

about 3 pounds

 ADULT SIZE 

a medium cauliflower

 NUMBER OF NEURONS 

about 100,000,000,000 (100 billion)

NUMBER OF SYNAPSES 

(the gaps between neurons) 

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

NUMBER OF CAPILLARIES 

(tiny blood vessels) 

about 400,000,000,000 (400 billion)

PART 1

Basics The

Healthy of the

Brain
10 ALZHE IMER’S D ISEASE Unraveling the Mystery The brain has many parts, each of which 

is responsible for particular functions. 

The following section describes a few 

key structures and what they do.

THE MAIN PLAYERS

Two cerebral hemispheres account for 85 per-

cent of the brain’s weight. The billions of neurons 

in the two hemispheres are connected by thick 

bundles of nerve cell fibers called the corpus cal-

losum. Scientists now think that the two hemi-

spheres differ not so much in what they do (the 

“logical versus artistic” notion), but in how they 

process information. The left hemisphere appears 

to focus on details (such as recognizing a particular 

face in a crowd). The right hemisphere focuses on 

broad background (such as understanding the rela-

tive position of objects in a space). The cerebral 

hemispheres have an outer layer called the cerebral 

cortex. This is where the brain processes sensory 

information received from the outside world, 

controls voluntary movement, and regulates 

cognitive functions, such as thinking, learning, 

speaking, remembering, and making decisions. 

The hemispheres have four lobes, each of which 

has different roles: 

The frontal lobe, which is in the front of the 

brain, controls “executive function” activities 

like thinking, organizing, planning, and 

problem solving, as well as memory, attention, 

and movement.

The parietal lobe, which sits behind the 

frontal lobe, deals with the perception and 

integration of stimuli from the senses.

■

■■

The occipital lobe, which is at the back of the 

brain, is concerned with vision.

The temporal lobe, which runs along the 

side of the brain under the frontal and pari-

etal lobes, deals with the senses of smell, taste, 

and sound, and the formation and storage of 

memories. 

The cerebellum sits above the brain stem and 

beneath the occipital lobe. It takes up a little more 

than 10 percent of the brain. This part of the 

brain plays roles in balance and coordination. The 

cerebellum has two hemispheres, which receive 

information from the eyes, ears, and muscles and ■■ ■

Inside the Human Brain

P A R T

1 The Basics of the Healthy Brain

This illustration shows a three-dimensional side 

view of one of two cerebral hemispheres of the brain. 

To help visualize this, imagine looking at the cut side 

of an avocado sliced long ways in half, with the 

pit still in the fruit. In this illustration, the “pit” is 

several key structures that lie deep within the brain 

(the hypothalamus, amygdala, and hippocampus) 

and the brain stem.

Side View of the Brain

Front View of the Brain
12 ALZHE IMER’S D ISEASE Unraveling the Mystery ALZHE IMER’S D ISEASE Unraveling the Mystery 13

joints about the body’s movements and position. 

Once the cerebellum processes that information, it 

sends instructions to the body through the rest of 

the brain and spinal cord. The cerebellum’s work 

allows us to move smoothly, maintain our balance, 

and turn around without even thinking about it. It 

also is involved with motor learning and remembering how to do things like drive a car or write 

your name.

The brain stem sits at the base of the brain. It 

connects the spinal cord with the rest of the brain. 

Even though it is the smallest of the three main 

players, its functions are crucial to survival. The 

brain stem controls the functions that happen 

automatically to keep us alive—our heart rate, 

blood pressure, and breathing. It also relays 

information between the brain and the spinal 

cord, which then sends out messages to the 

muscles, skin, and other organs. Sleep and 

dreaming are also controlled by the brain stem.

OTHER CRUCIAL PARTS

Several other essential parts of the brain lie deep 

inside the cerebral hemispheres in a network of 

structures called the limbic system. The limbic 

system links the brain stem with the higher 

reasoning elements of the cerebral cortex. It plays 

a key role in developing and carrying out instinctive behaviors and emotions and also is important in perceiving smells and linking them with 

memory, emotion, and instinctive behaviors. The 

limbic system includes:

The amygdala, an almond-shaped structure 

involved in processing and remembering strong 

emotions such as fear. It is located in the temporal 

lobe just in front of the hippocampus.

■

■

The hippocampus, which is buried in the 

temporal lobe, is important for learning and 

short-term memory. This part of the brain is 

thought to be the site where short-term 

memories are converted into long-term 

memories for storage in other brain areas.

The thalamus, located at the top of the brain 

stem, receives sensory and limbic information, 

processes it, and then sends it to the cerebral 

cortex.

The hypothalamus, a structure under 

the thalamus, monitors activities such as body 

temperature and food intake. It issues instructions 

to correct any imbalances. The hypothalamus also 

controls the body’s internal clock.

THE BRAIN IN ACTION 

Sophisticated brain-imaging techniques allow 

scientists to monitor brain function in living 

people and to see how various parts of the brain 

are used for different kinds of tasks. This is 

opening up worlds of knowledge about brain 

function and how it changes with age or disease. 

One of these imaging techniques is called 

positron emission tomography, or PET 

scanning. Some PET scans measure blood 

flow and glucose metabolism throughout the 

brain. (For more on metabolism, see page 16.) 

During a PET scan, a small amount of a radioactive substance is attached to a compound, such 

as glucose, and injected into the bloodstream. 

This tracer substance eventually goes to the brain. 

When nerve cells in a region of the brain become 

active, blood flow and glucose metabolism in 

that region increase. When colored to reflect 

metabolic activity, increases usually look red 

and yellow. Shades of blue and black indicate 

decreased or no activity within a brain region. 

■

■

■

P A R T 1 The Basics of the Healthy Brain

In essence, a PET scan produces a “map” of 

the active brain. 

Scientists can use PET scans to see what happens in the brain when a person is engaged in 

a physical or mental activity, at rest, or even 

while sleeping or dreaming. Certain tracers can 

track the activity of brain chemicals, for example 

neurotransmitters such as dopamine and 

serotonin. (To learn about exciting developments 

using one new tracer, see PiB and PET on page 

28.) Some of these neurotransmitters are changed 

with age, disease, and drug therapies. 
14 ALZHE IMER’S D ISEASE Unraveling the Mystery

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 much of the cell’s activities. The cell 

body also contains other structures, called 

organelles, that perform specific tasks. 

The axon, which is much narrower than the 

width of a human hair, extends out from the cell 

body. Axons transmit messages from neuron to 

neuron. Sometimes, signal transmissions—like 

those from head to toe—have to travel over very 

long distances. Axons are covered with an insulating layer called myelin (also called white matter 

because of its whitish color). Myelin, which is 

made by a particular kind of glial cell, increases 

the speed of nerve signal transmissions through 

the brain. 

Dendrites also branch out from the cell body. 

They receive messages from the axons of other 

neurons. Each neuron is connected to thousands 

of other nerve cells through its axon and dendrites. 

Groups of neurons in the brain have special 

jobs. For example, some are involved with 

thinking, learning, and memory. Others are 

responsible for receiving information from the 

sensory organs (such as the eyes and ears) or the 

skin. Still others communicate with muscles, 

stimulating them into action.

Several processes all have to work smoothly 

together for neurons, and the whole organism, 

to survive and stay healthy. These processes are 

communication, metabolism, and repair.

COMMUNICATION

Imagine the many miles of fiber-optic cables that 

run under our streets. Day and night, millions of 

televised and telephonic messages flash at incredible 

speeds, letting people strike deals, give instructions, 

share a laugh, or learn some news. Miniaturize it, 

multiply it many-fold, make it much more complex, 

and you have the brain. Neurons are the great communicators, always in touch with their neighbors. 

Neurons communicate with each other through 

their axons and dendrites. When a dendrite receives an incoming signal (electrical or chemical), 

an “action potential,” or nerve impulse, can be 

generated in the cell body. The action potential 

travels to the end of the axon and once there, the 

passage of either electrical current or, more 

typically, the release of chemical messengers, 

called neurotransmitters, can be triggered. The 

neurotransmitters are released from the axon 

terminal and move across a tiny gap, or synapse, 

to specific receptor sites on the receiving, or postsynaptic, end of dendrites of nearby neurons. A 

typical neuron has thousands of synaptic connections, mostly on its many dendrites, with other 

neurons. Cell bodies also have receptor sites for 

neurotransmitters.

and Their

NeuronsJobs

P A R T 1 The Basics of the Healthy Brain

Neurons in the Brain
ALZHE IMER’S D ISEASE Unraveling the Mystery 17

I

n the past several decades, investigators have 

learned much about what happens in the 

brain when people have a neurodegenerative 

disease such as Parkinson’s disease, AD, or 

other dementias. Their findings also have revealed 

much about what happens during healthy aging. 

Researchers are investigating a number of changes 

related to healthy aging in hopes of learning more 

about this process so they can fill gaps in our 

knowledge about the early stages of AD.

As a person gets older, changes occur in all parts 

of the body, including the brain:

Certain parts of the brain shrink, especially 

the prefrontal cortex (an area at the front of the 

frontal lobe) and the hippocampus. Both areas 

are important to learning, memory, planning, and 

other complex mental activities.

Changes in neurons and neurotransmitters 

affect communication between neurons. In certain 

brain regions, communication between neurons 

can be reduced because white matter (myelincovered axons) is degraded or lost.

Changes in the brain’s blood vessels occur. 

Blood flow can be reduced because arteries narrow 

and less growth of new capillaries occurs.

■

■

■

In some people, structures called plaques and 

tangles develop outside of and inside neurons, 

respectively, although in much smaller amounts 

than in AD (see The Hallmarks of AD on page 21 

for more information on plaques and tangles). 

Damage by free radicals increases (free radicals 

are a kind of molecule that reacts easily with other 

molecules; see The Aging Process on page 42 for 

more on these molecules).

Inflammation increases (inflammation is the 

complex process that occurs when the body 

responds to an injury, disease, or abnormal 

situation). 

What effects does aging have on mental 

function in healthy older people? Some people 

may notice a modest decline in their ability to 

learn new things and retrieve information, such 

as remembering names. They may perform worse 

on complex tasks of attention, learning, and 

memory than would a younger person. However, 

if given enough time to perform the task, the 

scores of healthy people in their 70s and 80s are 

often similar to those of young adults. In fact, as 

they age, adults often improve in other cognitive 

areas, such as vocabulary and other forms of verbal 

knowledge. 

It also appears that additional brain regions can 

be activated in older adults during cognitive tasks, 

■

■

■

The Changing Brain

HealthyAging in

Once the post-synaptic receptors are activated, 

they open channels through the cell membrane 

into the receiving nerve cell’s interior or start other 

processes that determine what the receiving nerve 

cell will do. Some neurotransmitters inhibit nerve 

cell function (that is, they make it less likely that 

the nerve cell will send an electrical signal down 

its axon). Other neurotransmitters stimulate nerve 

cells, priming the receiving cell to become active 

or send an electrical signal down the axon to more 

neurons in the pathway. A neuron receives signals 

from many other neurons simultaneously, and the 

sum of a neuron’s neurotransmitter inputs at any 

one instant will determine whether it sends a signal down its axon to activate or inhibit the action 

of other neighboring neurons. 

During any one moment, millions of these signals are speeding through pathways in the brain, 

allowing the brain to receive and process information, make adjustments, and send out instructions 

to various parts of the body. 

METABOLISM

All cells break down chemicals and nutrients to 

generate energy and form building blocks that 

make new cellular molecules such as proteins. 

This process is called metabolism. To maintain 

metabolism, the brain needs plenty of blood 

constantly circulating through its billions of 

capillaries to supply neurons and other brain 

cells with oxygen and glucose. Without oxygen 

and glucose, neurons will quickly die.

REPAIR

Nerve cells are formed during fetal life and for a 

short time after birth. Unlike most cells, which 

have a fairly short lifespan, neurons in the brain 

live a long time. These cells can live for up to 100 

years or longer. To stay healthy, living neurons 

must constantly maintain and repair themselves. 

In an adult, when neurons die because of disease 

or injury, they are not usually replaced. Research, 

however, shows that in a few brain regions, new 

neurons can be generated, even in the old brain. 

P A R T 1 The Basics of the Healthy Brain
ALZHE IMER’S D ISEASE Unraveling the Mystery 19

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

18 ALZHE IMER’S D ISEASE Unraveling the Mystery

such as taking a memory test. Researchers do not 

fully understand why this happens, but one idea is 

that the brain engages mechanisms to compensate 

for difficulties that certain regions may be having. 

For example, the brain may recruit alternate brain 

networks in order to perform a task. These findings have led many scientists to believe that major 

declines in mental abilities are not inevitable as 

people age. Growing evidence of the adaptive 

(what scientists call “plastic”) capabilities of the 

older brain provide hope that people may be able 

to do things to sustain good brain function as 

they age. A variety of interacting factors, such as 

lifestyle, overall health, environment, and genetics 

also may play a role.

Another question that scientists are asking 

is why some people remain cognitively healthy 

as they get older while others develop cognitive 

impairment or dementia. The concept of 

“cognitive reserve” may provide some insights. 

Cognitive reserve refers to the brain’s ability to 

operate effectively even when some function is 

disrupted. It also refers to the amount of damage 

that the brain can sustain before changes in 

cognition are evident. People vary in the cognitive 

reserve they have, and this variability may be 

because of differences in genetics, education, 

occupation, lifestyle, leisure activities, or other life 

experiences. These factors could provide a certain 

amount of tolerance and ability to adapt to change 

and damage that occurs during aging. At some 

point, depending on a person’s cognitive reserve 

and unique mix of genetics, environment, and life 

experiences, the balance may tip in favor of a disease process that will ultimately lead to dementia. 

For another person, with a different reserve and 

a different mix of genetics, environment, and life 

experiences, the balance may result in no apparent 

decline in cognitive function with age. 

Scientists are increasingly interested in the 

influence of all these factors on brain health, and 

studies are revealing some clues about actions 

people can take that may help preserve healthy 

brain aging. Fortunately, these actions also benefit 

a person’s overall health. They include:

 Controlling risk factors for chronic disease, 

such as heart disease and diabetes (for example, 

keeping blood cholesterol and blood pressure at 

healthy levels and maintaining a healthy weight)

Enjoying regular exercise and physical activity

 Eating a healthy diet that includes plenty of 

vegetables and fruits

 Engaging in intellectually stimulating activities 

and maintaining close social ties with family, 

friends, and community

Vascular Disease on page 43 and Lifestyle 

Factors on page 45 provide more information 

about these issues and how they may influence the 

risk of developing AD. 

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P A R T 1 The Basics of the Healthy Brain

The phrase “use it or lose it” may make you think 

of your muscles, but scientists who study brain 

health in older people have found that it may apply 

to cognitive skills as well. In 2006, scientists funded 

by NIA and the National Institute of Nursing Research 

completed a study of cognitive training in older adults. 

This study, the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study, was the first 

randomized controlled trial to demonstrate long-lasting, 

positive effects of brief cognitive training in older adults. 

The ACTIVE study included 2,802 healthy adults 

age 65 and older who were living independently. 

Participants were randomly assigned to four groups. 

Three groups took part in up to 10 computer-based 

training sessions that targeted a specific cognitive 

ability—memory, reasoning, and speed of processing 

(in other words, how fast participants could respond 

to prompts on a computer screen). The fourth group 

(the control group) received no cognitive training. Sixty 

percent of those who completed the initial training also 

took part in 75-minute “booster” sessions 11 months 

later. These sessions were designed to maintain 

improvements gained from the initial training. 

The investigators tested the participants at the 

beginning of the study, after the initial training and booster 

sessions, and once a year for 5 more years. They found 

that the improvements from the training roughly counteracted the degree of decline in cognitive performance 

that would be expected over a 7- to 14-year period 

among older people without dementia:

Immediately after the initial training, 87 percent 

of the processing-speed group, 74 percent of 

the reasoning group, and 26 percent of 

the memory group showed improvement 

in the skills taught. 

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After 5 years, people in each group performed 

better on tests in their respective areas of training 

than did people in the control group. The reasoning 

and processing-speed groups who received booster 

training had the greatest benefit. 

The researchers also looked at the training’s effects 

on participants’ everyday lives. After 5 years, all three 

groups who recieved training reported less difficulty 

than the control group in tasks such as preparing 

meals, managing money, and doing housework. 

However, these results were statistically significant for 

only the group that had the reasoning training.

As they get older, many people worry about their 

mental skills getting “rusty.” The ACTIVE study offers 

hope that cognitive training may be useful because it 

showed that relatively brief and targeted cognitive 

exercises can produce lasting improvements in the 

skills taught. Next steps for researchers are to determine ways to generalize the training benefits beyond 

the specific skills taught in ACTIVE and to find out 

whether cognitive training programs could prevent, 

delay, or diminish the effects of AD. 

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ALZHE IMER’S D ISEASE Unraveling the Mystery 21

A

lzheimer’s disease disrupts critical metabolic 

 processes that keep neurons healthy. These 

 disruptions cause nerve cells in the brain 

 to stop working, lose connections with 

other nerve cells, and finally die. The destruction 

and death of nerve cells causes the memory failure, 

personality changes, problems in carrying out 

daily activities, and other features of the disease. 

The brains of people with AD have an abundance 

of two abnormal structures—amyloid plaques 

and neurofibrillary tangles—that are made of 

misfolded proteins (see Protein Misfolding on 

page 41 for more information). This is especially 

true in certain regions of the brain that are 

important in memory. 

The third main feature of AD is the loss of 

connections between cells. This leads to diminished cell function and cell death.

AMYLOID PLAQUES

Amyloid plaques are found in the spaces between 

the brain’s nerve cells. They were first described 

by Dr. Alois Alzheimer in 1906. Plaques consist 

of largely insoluble deposits of an apparently toxic 

protein peptide, or fragment, called beta-amyloid.

We now know that some people develop 

some plaques in their brain tissue as they age. 

However, the AD brain has many more plaques 

in particular brain regions. We still do not know 

whether amyloid plaques themselves cause AD or 

whether they are a by-product of the AD process. 

We do know that genetic mutations can increase 

production of beta-amyloid and can cause rare, 

inherited forms of AD (see Genes and EarlyOnset Alzheimer’s Disease on page 38 for 

more on inherited AD).

The HallmarksofAD

PART 2

Brain

in

to the

AD

What Happens

To view a video showing what happens to 

the brain in AD, go to www.nia.nih.gov/

Alzheimers/ADvideo.
22 ALZHE IMER’S D ISEASE Unraveling the Mystery ALZHE IMER’S D ISEASE Unraveling the Mystery 23

P A R T 2

From APP to Beta-Amyloid Plaques

What Happens to the Brain in AD

the APP molecule at one 

end of the beta-amyloid 

peptide, releasing sAPPβ

from the cell (Figure 3). 

Gamma-secretase then 

cuts the resulting APP 

fragment, still tethered in 

the neuron’s membrane, 

at the other end of the 

beta-amyloid peptide. 

Following the cleavages 

at each end, the betaamyloid peptide is 

released into the space 

outside the neuron and 

begins to stick to other 

beta-amyloid peptides (Figure 4). These small, 

soluble aggregates of two, three, four, or even 

up to a dozen beta-amyloid peptides are called 

oligomers. Specific sizes of oligomers may 

be responsible for reacting with receptors on 

neighboring cells and synapses, affecting their 

ability to function. 

It is likely that some oligomers are cleared from 

the brain. Those that cannot be cleared clump 

together with more beta-amyloid peptides. As the 

process continues, oligomers grow larger, becoming 

entities called protofibrils and fibrils. Eventually, other 

proteins and cellular material are added, and these 

increasingly insoluble entities combine to become the 

well-known plaques that are characteristic of AD.

For many years, scientists thought that plaques 

might cause all of the damage to neurons that is seen 

in AD. However, that concept has evolved greatly 

in the past few years. Many scientists now think that 

oligomers may be a major culprit. Many scientists 

also think that plaques actually may be a late-stage 

attempt by the brain to get this harmful beta-amyloid 

away from neurons. 

Amyloid precursor protein (APP), the starting 

 point for amyloid plaques, is one of many proteins 

associated with the cell membrane, the barrier that 

encloses the cell. As it is being made inside the cell, 

APP becomes embedded in the membrane, like a toothpick stuck through the skin of an orange (Figure 1).

In a number of cell compartments, including the 

outermost cell membrane, 

specific enzymes snip, or 

cleave, APP into discrete 

fragments. In 1999 and 

2000, scientists identified 

the enzymes responsible 

for cleaving APP. These enzymes are called alphasecretase, beta-secretase, and gamma-secretase. 

In a major breakthrough, scientists then discovered 

that, depending on which enzyme is involved and 

the segment of APP where the cleaving occurs, APP 

processing can follow one of two pathways that 

have very different consequences for the cell.

In the benign pathway, alpha-secretase cleaves the 

APP molecule within the portion that has the potential to 

become beta-amyloid. This eliminates the production of 

the beta-amyloid peptide and the potential for plaque 

buildup. The cleavage releases from the neuron a fragment called sAPPα, which has beneficial properties, 

such as promoting neuronal growth and survival. The 

remaining APP fragment, still tethered in the neuron’s 

membrane, is then cleaved by gamma-secretase at 

the end of the beta-amyloid segment. The smaller of 

the resulting fragments also is released into the space 

outside the neuron, while 

the larger fragment remains 

within the neuron and 

interacts with factors in the 

nucleus (Figure 2).

In the harmful pathway, 

beta-secretase first cleaves 

Figure 1

Figure 2

Figure 3

Figure 4

From APP to Beta-Amyloid Plaque
24 ALZHE IMER’S D ISEASE Unraveling the Mystery ALZHE IMER’S D ISEASE Unraveling the Mystery 25

P A R T 2 What Happens to the Brain in AD

NEUROFIBRILLARY TANGLES

The second hallmark of AD, also described by 

Dr. Alzheimer, is neurofibrillary tangles. Tangles 

are abnormal collections of twisted protein 

threads found inside nerve cells. The chief 

component of tangles is a protein called tau.

Healthy neurons are internally supported 

in part by structures called microtubules, 

which help transport nutrients and other 

cellular components, such as neurotransmittercontaining vesicles, from the cell body 

down the axon. 

Tau, which usually has a certain number of 

phosphate molecules attached to it, binds to 

microtubules and appears to stabilize them. In 

AD, an abnormally large number of additional 

phosphate molecules attach to tau. As a result 

of this “hyperphosphorylation,” tau disengages 

from the microtubules and begins to come 

together with other tau threads. These tau

threads form structures called paired helical 

filaments, which can become enmeshed 

with one another, forming tangles 

within the cell. The microtubules can 

disintegrate in the process, collapsing the neuron’s internal transport 

network. This collapse damages 

the ability of neurons to communicate with each other.

Healthy and Diseased Neurons

24 25

Inside a 

Healthy Neuron

Inside a Diseased Neuron

Formation of Tau Tangles
P A R T 2 What Happens to the Brain in AD

LOSS OF CONNECTION BETWEEN 

CELLS AND CELL DEATH 

The third major feature of AD is the gradual 

loss of connections between neurons. Neurons 

live to communicate with each other, and this 

vital function takes place at the synapse. Since 

the 1980s, new knowledge about plaques and 

tangles has provided important insights into 

their possible damage to synapses and on the 

development of AD. 

26 ALZHE IMER’S D ISEASE Unraveling the Mystery ALZHE IMER’S D ISEASE Unraveling the Mystery 27

No one knows exactly what starts 

the AD process or why some of the 

normal changes associated with 

aging become so much more extreme 

and destructive in people with the disease. We 

know a lot, however, about what happens in the 

brain once AD takes hold and about the physical 

and mental changes that occur over time. The 

time from diagnosis to death varies—as little as 

3 or 4 years if the person is older than 80 when 

diagnosed to as long as 10 or more years if the 

person is younger. Several other factors besides 

age also affect how long a person will live with 

AD. These factors include the person’s sex, 

the presence of other health problems, and the 

severity of cognitive problems at diagnosis. 

Although the course of the disease is not the same 

in every person with AD, symptoms seem to 

develop over the same general stages. 

PRECLINICAL AD

AD begins deep in the brain, in the entorhinal 

cortex, a brain region that is near the hippocampus 

and has direct connections to it. Healthy neurons 

in this region begin to work less efficiently, lose 

their ability to communicate, and ultimately die. 

This process gradually spreads to the hippocampus, the brain region that plays a major role in 

learning and is involved in converting short-term 

memories to long-term memories. Affected 

regions begin to atrophy. Ventricles, the fluidfilled spaces inside the brain, begin to enlarge 

as the process continues.

Scientists believe that these brain changes 

begin 10 to 20 years before any clinically 

detectable signs or symptoms of forgetfulness appear. That’s why they are increasingly 

interested in the very early stages of the disease 

process. They hope to learn more about what 

happens in the brain that sets a person on the 

path to developing AD. By knowing more about 

the early stages, they also hope to be able to 

in

Changing Brain

AD

The

Loss of Connection 

Between Cells

The AD process not only inhibits communication between neurons but can also damage 

neurons to the point that they cannot function 

properly and eventually die. As neurons die 

throughout the brain, affected regions begin to 

shrink in a process called brain atrophy. By the 

final stage of AD, damage is widespread, and 

brain tissue has shrunk significantly. 

Preclinical AD

This illustration shows 

the damage caused by AD: 

plaques, tangles, and the 

loss of connection between 

neurons.
This chart shows current thinking about the 

evolution from healthy aging 

to AD. Researchers view it as 

a series of events that occur 

in the brain over many years. 

This gradual process, which 

results from the combination of 

biological, genetic, environmental, and lifestyle factors, 

eventually sets some people 

on a course to MCI and 

possibly AD. Other people, 

whose genetic makeup may 

be the same or different and 

who experience a different 

combination of factors over a 

lifetime, continue on a course 

of healthy cognitive aging. 

Birth 40 60 80 Death

 Life Course

AD brain 

changes start 

decades before 

symptoms 

show

Amnestic MCI: 

memory problems; 

other cognitive 

functions OK; 

brain compensates 

for changes

Total loss of 

independent 

function

Healthy Aging Amnestic MCI Clinically Diagnosed AD 

Cognitive 

decline 

accelerates 

after AD 

diagnosis

Normal age-related 

memory loss

Charting the Course from Healthy Aging to AD 

a much higher percentage of them go on to develop AD than do people without these memory 

problems. About 8 of every 10 people who fit 

the definition of amnestic MCI go on to develop 

AD within 7 years. In contrast, 1 to 3 percent of 

people older than 65 who have normal cognition 

will develop AD in any one year. 

However, researchers are not yet able to say 

definitively why some people with amnestic MCI 

do not progress to AD, nor can they say who 

will or will not go on to develop AD. This raises 

pressing questions, such as: In cases when MCI 

progresses to AD, what was happening in the brain 

that made that transition possible? Can MCI be 

prevented or its progress to AD delayed? 

Scientists also have found that genetic 

factors may play a role in MCI, as they do in 

AD (see Genetic Factors at Work in AD on 

page 36 for more information). And, they have 

found that different brain regions appear to 

be activated during certain mental activities in 

cognitively healthy people and those with MCI. 

These changes appear to be related to the early 

stages of cognitive impairment. 

Other Signs of Early AD Development 

As scientists have sharpened their focus on the 

early stages of AD, they have begun to see hints of 

other changes that may signal a developing disease 

process. For example, in the Religious Orders Study, 

a large AD research effort that involves older nuns, 

priests, and religious brothers, investigators have 

PiB and PET 

29

I

magine being able to see deep inside the brain tissue of 

a living person. If you could do that, you could find out 

whether the AD process was happening many years before 

symptoms were evident. This knowledge could have a 

profound impact on improving early diagnosis, monitoring 

disease progression, and tracking response to treatment. 

Scientists have stepped closer to this possibility with the 

development of a radiolabeled compound called Pittsburgh 

Compound B (PiB). PiB binds to beta-amyloid plaques in the 

brain and it can be imaged using PET scans. Initial studies 

showed that people with AD take up more PiB in their brains 

than do cognitively healthy older people. Since then, scientists have found high levels of PiB in some cognitively healthy 

people, suggesting that the damage from beta-amyloid may 

already be underway. The next step will be to follow these 

cognitively healthy people who have high PiB levels to see 

whether they do, in fact, develop AD over time. 

28 ALZHE IMER’S D ISEASE Unraveling the Mystery

develop drugs or other treatments that will 

slow or stop the disease process before significant 

impairment occurs (see The Search for New 

Treatments on page 54 for more information). 

VERY EARLY SIGNS AND SYMPTOMS 

At some point, the damage occurring in the brain 

begins to show itself in very early clinical signs and 

symptoms. Much research is being done to identify 

these early changes, which may be useful in 

predicting dementia or AD. An important part of 

this research effort is the development of increasingly sophisticated neuroimaging techniques (see 

Exciting New Developments in AD Diagnosis 

on page 50 for more on neuroimaging) and the use 

of biomarkers. Biomarkers are indicators, such as 

changes in sensory abilities, or substances that appear in body fluids, such as blood, cerebrospinal 

fluid, or urine. Biomarkers can indicate exposure 

to a substance, the presence of a disease, or the 

progression over time of a disease. For example, 

high blood cholesterol is a biomarker for risk of 

heart disease. Such tools are critical to helping 

scientists detect and understand the very early 

signs and symptoms of AD.

Mild Cognitive Impairment 

As some people grow older, they develop memory 

problems greater than those expected for their age. 

But they do not experience the personality changes 

or other problems that are characteristic of AD. 

These people may have a condition called mild 

cognitive impairment (MCI). MCI has several 

subtypes. The type most associated with memory 

loss is called amnestic MCI. People with MCI are 

a critically important group for research because 

P A R T 2 What Happens to the Brain in AD

ALZHE IMER’S D ISEASE Unraveling the Mystery

In this PET scan, the red and yellow colors 

indicate that PiB uptake is higher in the brain 

of the person with AD than in the cognitively 

healthy person.
ALZHE IMER’S D ISEASE Unraveling the Mystery 31

Accepting these signs as something other than 

normal and deciding to go for diagnostic tests can 

be a big hurdle for people and families. Once this 

hurdle is overcome, many families are relieved to 

know what is causing the problems. They also can 

take comfort in the fact that despite a diagnosis 

of MCI or early AD, a person can still make 

meaningful contributions to his or her family 

and to society for a time.

MODERATE AD 

By this stage, AD damage has spread to the areas 

of the cerebral cortex that control language, 

reasoning, sensory processing, and conscious 

thought. Affected regions continue to shrink, 

ventricles enlarge, and signs and symptoms of the 

disease become more pronounced and widespread. 

Behavioral problems, such as wandering and 

agitation, can occur. More intensive supervision 

and care become necessary, which can be 

difficult for many spouses and families. The 

symptoms of this stage can include:

Increasing memory loss and confusion

Shortened attention span

Inappropriate outbursts of anger

Problems recognizing friends and family members

 Difficulty with language and problems with 

reading, writing, and 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

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 Hallucinations, delusions, suspiciousness or 

paranoia, irritability

 Loss of impulse control (shown through 

undressing at inappropriate times or places 

or vulgar language)

 An inability to carry out activities that involve 

multiple steps in sequence, such as dressing, 

making a pot of coffee, or setting the table

Behavior is the result of complex brain 

processes, all of which take place in a fraction of 

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

those processes are disturbed, and these disrupted 

communications between neurons are 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 can be 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 can be strange and frightening. 

Sticking close to a trusted and familiar caregiver 

may be the only thing that makes sense and 

provides security. 

SEVERE AD

In the last stage of AD, plaques and tangles are 

widespread throughout the brain, most areas of 

the brain have shrunk further, and ventricles have 

enlarged even more. People with AD cannot 

recognize family and loved ones or communicate 

in any way. They are completely dependent on 

others for care. Other symptoms can include:

Weight loss 

Seizures

Skin infections

Difficulty swallowing 

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30 ALZHE IMER’S D ISEASE Unraveling the Mystery

explored whether changes in older adults’ ability to 

move about and use their bodies might be a sign of 

early AD. The researchers found that participants 

with MCI had more movement difficulties than the 

cognitively healthy participants but less than those 

with AD. Moreover, those with MCI who had lots 

of trouble moving their legs and feet were more 

than twice as likely to develop AD as those with 

good lower body function.

It is not yet clear why people with MCI might 

have these motor function problems, but the 

scientists who conducted the study speculate that 

they may be a sign that damage to blood vessels in 

the brain or damage from AD is accumulating in 

areas of the brain responsible for motor function. 

If further research shows that some people with 

MCI do have motor function problems in addition to memory problems, the degree of difficulty, 

especially with walking, may help identify those at 

risk of progressing to AD. 

Other scientists have focused on changes in 

sensory abilities as possible indicators of early 

cognitive problems. For example, in one study they 

found associations between a decline in the ability 

to detect odors and cognitive problems or dementia.

These findings are tentative, but they are 

promising because they suggest that, some day, it 

may be possible to develop ways to improve early 

detection of MCI or AD. These tools also will help 

scientists answer questions about causes and very 

early development of AD, track changes in brain 

and cognitive function over time, and ultimately 

track a person’s response to treatment for AD. 

MILD AD

As AD spreads through the brain, the number of 

plaques and tangles grows, shrinkage progresses, 

and more and more of the cerebral cortex is 

affected. Memory loss continues and changes 

in other cognitive abilities begin to emerge. The 

clinical diagnosis of AD is usually made during 

this stage. Signs of mild AD can include:

Memory loss 

 Confusion about the location of familiar places 

(getting lost begins to occur)

 Taking longer than before to accomplish 

normal daily tasks

Trouble handling money and paying bills

Poor judgment leading to bad decisions

Loss of spontaneity and sense of initiative

 Mood and personality changes, increased 

anxiety and/or aggression

In mild AD, a person may seem to be healthy 

but is actually having more and more trouble 

making sense of the world around him or her. The 

realization that something is wrong often comes 

gradually to the person and his or her family. 

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P A R T 2 What Happens to the Brain in AD

Mild to Moderate AD
32 ALZHE IMER’S D ISEASE Unraveling the Mystery ALZHE IMER’S D ISEASE Unraveling the Mystery 33

Groaning, moaning, or grunting

Increased sleeping

Lack of bladder and bowel control

Near the end, the person may be in bed much or 

all of the time. The most frequent cause of death for 

people with AD is aspiration pneumonia. This type 

of pneumonia develops when a person is not able to 

swallow properly and takes food or liquids into the 

lungs instead of air.

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P A R T 2 What Happens to the Brain in AD

The Buddy Program at Northwestern University

The Buddy Program at Northwestern University

The medical school curriculum 

demands that students spend 

enormous amounts of time in the 

classroom and clinic learning the 

information and skills necessary 

for a career in medicine. However, little or no time is set aside 

for students to be with patients 

outside the hospital or clinic 

setting. As a result, it is hard for 

medical students to get to know 

the human side of the diseases 

they are learning about.

A program at Northwestern 

University’s Cognitive Neurology 

and Alzheimer’s Disease Center 

is adding just that element to its 

medical education. The Buddy 

Program, begun in 1998, 

matches first-year medical 

students with people diagnosed 

with AD or another form of 

dementia. About 10 to 15 

medical students participate 

every year. They first take a 

3-hour orientation course on AD, 

family issues, and communication 

skills. Then, for the next year, they 

spend at least 4 hours a month 

with a person with dementia in 

addition to monthly meetings 

with the program coordinators. 

Together with the person’s 

caregiver and the program’s 

professional staff, students and 

their “buddies” choose activities 

for their visits together. Activities 

can include shopping, visiting 

museums, exercising together, or 

even just sharing a coffee or a 

meal. The students also are able 

to observe their buddies’ clinical 

evaluations at the Center. Other 

medical schools have started 

similar programs.

The people with AD and 

their families are selected from 

Northwestern’s Alzheimer’s 

Disease Center and other 

related programs at the university. 

Families are contacted about 

participating, and the people 

with AD are selected based on 

their ability to understand the 

nature of the program and their 

willingness to spend time every 

month with the student buddy.

The program has clear benefits for both the medical student 

and the person with AD. For the 

medical student, it provides a 

hands-on way to learn about AD 

and related dementias, and it 

helps him or her understand the 

daily realities and issues involved 

in caring for and supporting 

people with AD and their 

families. It also introduces them 

to the career path of research 

and clinical practice in AD and 

related dementias. For the person 

with AD, participation in the 

program provides an opportunity 

for friendship and socializing 

and an outlet for sharing their 

experiences with a sympathetic 

listener. 

For many of the students, the 

program is a transformative 

experience. They become very 

close to their buddies and family 

caregivers during their year 

together, and continue the friendship even after the year is over. 

The Buddy Program pairs medical students and people with AD 

to spend time with—and learn from—each other.

Severe AD

AD Spreads Through the Brain
ALZHE IMER’S D ISEASE Unraveling the Mystery 35

S

cientists have studied AD from many 

angles. They have looked at populations 

to see how many cases of AD occur 

every year and whether there might 

be links between the disease and lifestyles or 

genetic backgrounds. They also have conducted 

clinical studies with healthy older people and 

those at various stages of AD. They have done 

many studies with laboratory animals. They 

have begun to look at neuronal circuits and 

networks of cells to learn how AD pathology 

develops and spreads. They even have examined 

individual nerve cells to see how beta-amyloid, 

tau, and other molecules affect the ability of 

cells to function normally. 

These studies have led to a fuller understanding of many aspects of the disease, improved 

diagnostic tests, new ways to manage behavioral 

aspects of AD, and a growing number of possible 

drug treatments. Findings from current research 

are pointing scientists in promising directions for 

the future. They are also helping researchers to 

ask better questions about the issues that are still 

unclear. 

Part 3 of Unraveling the Mystery describes what 

scientists are learning from their search for: 

The causes of AD

New techniques to help in diagnosis

New treatments

Results from this research will bring us closer 

to the day when we will be able to delay the onset 

of, prevent, or cure the devastating disease that 

robs our older relatives and friends of their most 

precious possession—their minds. 

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PART 3

AD RESEARCH:

New Answers

Better Questions,
ALZHE IMER’S D ISEASE Unraveling the Mystery 37

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

The nucleus of almost 

every human cell contains 

an encrypted “blueprint,” along 

with the means to decipher it. This 

blueprint, accumulated over eons 

of genetic trial and error, carries all 

the instructions a cell needs to do 

its job. The blueprint is made up of 

DNA, which exists as two long, 

intertwined, thread-like strands 

called chromosomes. Each cell 

has 46 chromosomes in 23 pairs. 

The DNA in chromosomes is made 

up of four chemicals, or bases, 

strung together in various sequence 

patterns. The DNA in nearly all 

cells of an individual is identical.

Each chromosome contains 

many thousands of segments, 

called genes. People inherit two 

copies of each gene from their 

parents, except for genes on the 

X and Y chromosomes, which are 

chromosomes that, among other 

functions, determine a person’s sex. 

Each person normally has one pair 

of sex chromosomes (females are 

XX and males are XY). The 

sequence of bases in a gene tells 

the cell how to make specific 

proteins. Proteins in large part determine the different kinds of cells that 

make up an organism and direct 

almost every aspect of the cell’s 

construction, operation, and repair. 

Even though all genes are present 

in most cells, the pattern in which 

they are activated varies from cell 

to cell, and gives each cell type 

its distinctive character. Even slight 

alterations in a gene can produce 

an abnormal protein, which, in turn, 

may lead to cell malfunction and, 

eventually, to disease. 

Any permanent change in the 

sequence of bases in a gene’s 

DNA that causes a disease is 

called a mutation. Mutations 

also can change the activation 

of a particular gene. Other more 

common (or frequent) changes in 

a gene’s sequence of bases do not 

automatically cause disease, but 

they can increase the chances that 

a person will develop a particular 

disease. When this happens, 

the changed gene is called a 

genetic risk factor. 

person’s risk, such as the age at which the disease 

begins. Slow and careful detective work by scientists 

has paid off in discoveries of genetic links to the two 

main types of AD. 

One type is the rare, early-onset Alzheimer’s 

disease. It usually affects people aged 30 to 60. 

Some cases of early-onset disease are inherited and 

are called familial AD (FAD). The other is 

late-onset Alzheimer’s disease. It is by far the 

more common form and occurs in those 60 and 

older. Gaining insight into the genetic factors 

associated with both forms of AD is important 

because identifying genes that either cause the 

disease or influence a person’s risk of developing it 

improves our ability to understand how and why 

the disease starts and progresses. 

for the Looking

Causes ofAD

P A R T 3 AD Research: Better Questions, New Answers

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 

AD while another remains healthy? 

Some diseases, such as measles or pneumonia, 

have clear-cut causes. They can be prevented with 

vaccines or cured with antibiotics. Others, such as 

diabetes or arthritis, develop when genetic, lifestyle, 

and environmental factors work together to start 

a disease process. The role that any or all of these 

factors play may be different for each individual. 

AD fits into the second group of diseases. 

We do not yet fully understand what causes AD, 

but we believe it develops because of a complex 

series of events that take place in the brain over a 

long period of time. Many studies are exploring 

the factors involved in the cause and development of AD.

GENETIC FACTORS AT WORK IN AD 

Genetic studies of complex neurodegenerative diseases such as AD focus on two main 

issues—whether a gene might influence 

a person’s overall risk of developing 

a disease and whether a gene might 

influence some particular aspect of a 
ALZHE IMER’S D ISEASE Unraveling the Mystery 39

The Hunt for New AD Genes 

For some time, scientists have 

suspected that, in addition 

to APOE ε4, as many as half a 

dozen other risk-factor genes exist 

for late-onset AD, but they have 

been unable to find them. In 2007, 

scientists unveiled their discovery of 

one new AD risk-factor gene.

This AD risk-factor gene is 

called SORL1. It is involved in 

recycling APP from the surface of 

cells, and its association with AD 

was identified and confirmed in 

three separate studies. Researchers found that when SORL1 is 

expressed at low levels or in a 

variant form, harmful beta-amyloid 

levels increase, perhaps by 

deflecting APP away from its 

normal pathways and forcing it 

into cellular compartments that 

generate beta-amyloid. 

As AD genetics research has 

intensified, it has become increasingly clear that scientists need 

many different samples of genetic 

material if they are to continue 

making progress in identifying new 

risk-factor genes. Genetic material 

is also essential for identifying 

associated environmental factors 

and understanding the interactions 

of genes and the environment. 

These advances ultimately will 

allow investigators to identify people 

at high risk of developing AD and 

help them focus on new pathways 

for prevention or treatment. 

In 2003, NIA launched the 

Alzheimer’s Disease Genetics 

Study to identify at least 1,000 

families with members who have 

late-onset AD as well as members 

who do not have the disease. All 

of these family members provide 

blood samples and other clinical 

data for the initiative. The material 

collected allows investigators to 

create and maintain “immortalized” 

cell lines—cells that are continuously regenerated in the laboratory. 

These cell lines are crucial for the 

exhaustive DNA analysis studies 

needed to identify risk-factor genes, 

each of which may have relatively 

small effects on AD development. 

More than 4,000 new cell lines 

are now available for researchers 

to study risk-factor genes for lateonset AD.

A new initiative, the Alzheimer’s 

Disease Genetics Consortium, 

was launched in 2007 to accelerate the application of genetics 

technologies to late-onset AD 

through collaborations among most 

of the leading researchers in AD 

genetics. The ultimate goal of this 

effort is to obtain genetic material 

from 10,000 people with AD and 

10,000 cognitively healthy people 

to comprehensively scan the whole 

genome for the remaining AD 

risk-factor genes, as well as those 

for age-related cognitive decline. 

Some of the genetic material will 

be drawn from existing samples 

of blood and tissue; other genetic 

material will be collected from new 

participants. 

New AD genetics discoveries 

are possible largely because 

of close collaboration among 

scientists, participation of volunteer 

families, new genetics technologies, statistical and analytic 

advances, and rapid data sharing. 

For example, the SORL1 studies 

involved 14 scientific institutions in 

North America, Europe, and Asia 

and the participation of more than 

6,000 people who donated blood 

and tissue for genetic typing. An 

important part of NIA’s efforts to 

promote and accelerate AD 

genetics research is to make 

biological samples and data 

publicly available to approved 

researchers. 

38 ALZHE IMER’S D ISEASE Unraveling the Mystery

P A R T 3 AD Research: Better Questions, New Answers

Genes and Early-Onset 

Alzheimer’s Disease 

In the early days of AD genetics research, scientists 

realized that some cases, particularly of the rare 

early-onset AD, ran in families. This led them to 

examine DNA samples from these families to see 

whether they had some genetic trait in common. 

Chromosomes 21, 14, and 1 became the focus of 

attention. The scientists found that some families 

have a mutation in selected genes on these chromosomes. On chromosome 21, the mutation causes an 

abnormal amyloid precursor protein to be produced 

(see page 22 for more on APP). On chromosome 

14, the mutation causes an abnormal protein called 

presenilin 1 to be produced. On chromosome 1, 

the mutation causes another abnormal protein to be 

produced. This protein, called presenilin 2, is very 

similar to presenilin 1. Even if only one of these 

genes that are inherited from a parent contains a 

mutation, the person will almost inevitably develop 

early-onset AD. This means that in these families, 

children have about a 50-50 chance of developing 

the disease if one of their parents has it.

Early-onset AD is very rare, and mutations in 

these three genes do not play a role in the more 

common late-onset AD. However, these findings 

were crucial because they showed that genetics was 

indeed a factor in AD, and they helped to identify 

some key cell pathways involved in the AD disease 

process. They showed that mutations in APP can 

cause AD, highlighting the presumed key role of 

beta-amyloid in the disease. Mutations in presenilin 1 and 2 also cause an increased amount of 

the damaging beta-amyloid to be made in the brain.

A Different Genetic Story in 

Late-Onset Alzheimer’s Disease 

While some scientists were studying the role of 

chromosomes 21, 14, and 1 in early-onset AD, 

others were looking elsewhere to see if they could 

find genetic clues for the late-onset form. By 1992, 

investigators had narrowed their search to a region 

of chromosome 19. They found a gene on 

chromosome 19 that they were able to link to 

late-onset AD. 

This gene, called APOE, produces a protein 

called apolipoprotein E. APOE comes in several 

forms, or alleles—ε2, ε3, and ε4:

The APOE ε2 allele is relatively rare and may 

provide some protection against the disease. If AD 

does occur in a person with this allele, it develops 

later in life than in those with an APOE ε4 allele. 

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 

people who develop late-onset AD and is present 

in about 25 to 30 percent of the population. People with AD are more likely to have an APOE ε4 

allele than people who do not have AD. However, 

at least one-third of people with AD do not have 

an APOE ε4 allele. Dozens of studies have confirmed that the APOE ε4 allele increases the risk 

of developing AD, but how that happens is not 

yet understood. These studies also have helped to 

explain some of the variation in the age at which 

AD develops, as people who inherit one or two 

APOE ε4 alleles tend to develop AD at an earlier 

age than those who do not. However, inheriting 

an APOE ε4 allele does not mean that a person 

will definitely develop AD. Some people with one 

or two APOE ε4 alleles never get the disease, and 

others who do develop AD do not have any APOE 

ε4 alleles. 

■

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ALZHE IMER’S D ISEASE Unraveling the Mystery 41

scientists now speculate that one reason tau may 

damage and kill neurons is because it upsets 

the normal activity of the cell, in addition to 

forming neurofibrillary tangles. 

Other studies of mutant tau in mice suggest that 

the accumulation of tau in tangles may not even be the 

culprit in memory loss. Rather, as with beta-amyloid, 

it may be that an earlier and more soluble abnormal 

form of the protein causes the damage to neurons. 

Protein Misfolding 

Researchers have found that a number of devastating neurodegenerative diseases (for example, AD, 

Parkinson’s disease, dementia with Lewy bodies, 

frontotemporal lobar degeneration, Huntington’s 

disease, and prion diseases) share a key 

characteristic—protein misfolding. 

When a protein is formed, it “folds” into a 

unique three-dimensional shape that helps it 

Neurodegenerative diseases like AD, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), 

and dementia with Lewy bodies share more than the 

basic characteristic of misfolded proteins. They also 

share clinical characteristics. For example, people 

with AD have trouble moving, a characteristic of 

Parkinson’s disease. Sleep-wake disorders, delusions, 

psychiatric disturbances, and memory loss occur in 

all of these diseases. These diseases also result from 

Researchers Explore Neurodegenerative “Cousins”

Neurodegenerative 

Diseases*

* AD = Alzheimer’s disease, AD/PD = AD with parkinsonism, ALS = amyotrophic lateral sclerosis, DLB = dementia with Lewy bodies, 

FTLD = frontotemporal lobar degeneration, VaD = vascular dementia (includes multi-infarct dementia), PD = Parkinson’s disease, 

PDD = Parkinson’s disease with dementia 

Adapted from an Emory University illustration 

AD/PD

DLB

PDD

AD

VaD

ALS

FTLD

PD

Early Symptoms

Tremor

Memory loss

 Executive function 

problems

Movement problems

Gait and balance problems

Sleep-wake disorders

Hallucinations

 Delusions

 Rigidity

Lifetime 

Influences

Genes

Environment

Systemic 

factors

Damaging Processes 

Occurring Before 

Symptoms Appear

Amyloid plaques

Tau tangles

Other abnormal 

protein deposits

Reduced oxygen 

flow to tissues

Toxic processes

a combination of genetic, lifestyle, and environmental 

causes and they develop over many years. 

This graphic shows one way of thinking about 

how these diseases may be linked as well as what 

makes them unique. By investigating the unique 

characteristics of these diseases as well as the 

characteristics they share, scientists hope to learn 

even more than they would if they focused on each 

disease by itself. 

40 ALZHE IMER’S D ISEASE Unraveling the Mystery

P A R T 3 AD Research: Better Questions, New Answers

OTHER FACTORS AT WORK IN AD

Genetics explains some of what might cause AD, 

but it does not explain everything. So, researchers 

continue to investigate other possibilities that may 

explain how the AD process starts and develops.

Beta-Amyloid 

We now know a great deal about how betaamyloid is formed and the steps by which 

beta-amyloid fragments stick together in small 

aggregates (oligomers), and then gradually form 

into plaques (see page 22 in The Hallmarks of 

AD for more on this process). Armed with this 

knowledge, investigators are intensely interested 

in the toxic effects that beta-amyloid, oligomers, 

and plaques have on neurons. This research is 

possible in part because scientists have been able 

to develop transgenic animal models of AD. 

Transgenics are animals that have been specially 

bred to develop AD-like features, such as 

beta-amyloid plaques. 

Beta-amyloid studies have moved forward to 

the point that scientists are now carrying out 

preliminary tests in humans of potential therapies 

aimed at removing beta-amyloid, halting its 

formation, or breaking down early forms before 

they can become harmful. 

For example, one line of research by a pharmaceutical company started with the observation that 

injecting beta-amyloid into AD transgenic mice 

caused them to form antibodies to the betaamyloid and reduced the number of amyloid 

plaques in the brain. This exciting finding led to 

other studies and ultimately to clinical trials in 

which human participants were immunized with 

beta-amyloid. These studies had to be stopped 

because some of the participants developed 

harmful side effects, but the investigators did 

not give up hope. Rather, they went back to the 

drawing board to rethink their strategy. More 

refined antibody approaches are now being tested 

in clinical trials, and additional research on new 

ways of harnessing the antibody response continues in the lab. 

Another important area of research is how 

beta-amyloid may disrupt cellular communication 

well before plaques form. One recent study 

described how beta-amyloid oligomers target 

specific synaptic connections between neurons, 

causing them to deteriorate. Other scientists are 

studying other potentially toxic effects that plaques 

have on neurons and in cellular communication. 

Understanding more about these processes may 

allow scientists to develop specific therapies to 

block the toxic effects.

Tau

Tau, the chief component of neurofibrillary tangles 

(see page 25 in The Hallmarks of AD for more 

on tau), is generating new excitement as an area 

of study. The recent focus on tau has been spurred 

by the finding that a mutant form of the protein 

is responsible for one form of frontotemporal 

dementia, the third most common cause of late-life 

dementia, after AD and vascular dementia. This 

form is known as frontotemporal dementia with 

parkinsonism linked to chromosome 17 (FTDP17). Finding this mutant protein was important 

because it suggested that abnormalities in the tau

protein itself can cause dementia. 

New transgenic mouse models of AD have 

helped tau research make rapid progress. For 

example, a recent model, the “triple transgenic” 

mouse, forms plaques and tangles over time in 

brain regions similar to those in human AD. 

Another recent transgenic mouse model, which 

contains only human tau, forms clumps of 

damaging tau filaments also in a region-specific 

fashion similar to AD in humans. 

These studies of tau also have suggested a 

mechanism for tau damage that is different from 

that previously suspected. With these new insights, 
ALZHE IMER’S D ISEASE Unraveling the Mystery 43

out its functions. Energy for the cell is produced 

in an efficient metabolic process. In this process, 

free radicals are produced. Free radicals can help 

cells in certain ways, such as fighting infection. 

However, because they are very active and combine 

easily with other molecules, free radicals also can 

damage the neuron’s cell membrane or its DNA. 

The production of free radicals can set off a chain 

reaction, releasing even more free radicals that 

can further damage neurons (see illustration on 

page 42). This kind of damage is called oxidative 

damage. The brain’s unique characteristics, including its high rate of metabolism and its long-lived 

cells, may make it especially vulnerable to oxidative damage over the lifespan. The discovery that 

beta-amyloid generates free radicals in some AD 

plaques is a potentially significant finding in the 

quest for better understanding of AD as well as for 

other neurodegenerative disorders and unhealthy 

brain aging. 

Researchers also are studying age-related 

changes in the working ability of synapses in 

certain areas of the brain. These changes may 

reduce the ability of neurons to communicate 

with each other, leading to increased neuronal 

vulnerability in regions of the brain important 

in AD. Age-related reductions in levels of 

particular growth factors, such as nerve growth 

factor and brain-derived neurotrophic factor, 

also may cause important cell populations to be 

compromised. Many studies are underway to tease 

out the possible effects of the aging process on the 

development of AD. 

Vascular Disease 

For some time now, hints have been emerging 

that the body’s vast network of small and large 

blood vessels—the vascular system—may make 

an important contribution in the development of 

dementia and the clinical symptoms of AD. Some 

scientists are focusing on what happens with the 

brain’s blood vessels in aging and AD. Others are 

looking at the relationship between AD and vascular problems in other parts of the body.

AD and Vascular Problems in the Brain

The brain requires a constant and dependable flow 

of oxygen and glucose to survive and flourish. The 

brain’s blood vessels provide the highways to deliver 

these vital elements to neurons and glial cells. 

Aging brings changes in the brain’s blood 

vessels—arteries can narrow and growth of new 

capillaries slows down. In AD, whole areas of 

nervous tissue, including the capillaries that supply 

42 ALZHE IMER’S D ISEASE Unraveling the Mystery

perform its specific function. This crucial process 

can go wrong for various reasons, and more 

commonly does go wrong in aging cells. As a 

result, the protein folds into an abnormal shape—

it is misfolded. In AD, the misfolded proteins are 

beta-amyloid (the cleaved product of APP; see 

From APP to Beta-Amyloid Plaques on page 22 

for more on the formation of beta-amyloid) 

and a cleaved product of tau.

Normally, cells repair or degrade misfolded 

proteins, but if many of them are formed as part 

of age-related changes, the body’s repair and 

clearance process can be overwhelmed. Misfolded 

proteins can begin to stick together with other 

misfolded proteins to form insoluble aggregates. 

As a result, these aggregates can build up, leading 

to disruption of cellular communication, and 

metabolism, and even to cell death. These 

effects may predispose a person to AD or other 

neurodegenerative diseases.

Scientists do not know exactly why or how 

these processes occur, but research into the unique 

characteristics and actions of various misfolded 

proteins is helping investigators learn more about 

the similarities and differences across age-related 

neurodegenerative diseases. This knowledge may 

someday lead to therapies. 

The Aging Process 

Another set of insights about the cause of AD 

comes from the most basic of all risk factors—

aging itself. Age-related changes, such as inflammation, may make AD damage in the brain worse. 

Because cells and compounds that are known to be 

involved in inflammation are found in AD plaques, 

some researchers think that components of the 

inflammatory process may play a role in AD. 

Other players in the aging process that may 

be important in AD are free radicals, which are 

oxygen or nitrogen molecules that combine easily 

with other molecules (scientists 

call them “highly reactive”). Free 

radicals are generated 

in mitochondria, which are 

structures found in all cells, 

including neurons. 

Mitochondria are the cell’s 

power plant, providing the 

energy a cell needs to maintain 

its structure, divide, and carry 

P A R T 3 AD Research: Better Questions, New Answers

Any given cell has hundreds of 

mitochondria. This illustration 

shows two—a healthy mitochondrion and an oxidatively stressed 

and damaged one. The arrows 

indicate the movement of free 

radicals, which can spread easily 

from damaged mitochondria to 

other parts of the cell.

This image shows the complexity of the human brain’s 

vascular system, particularly large and small arteries 

that carry oxygen from the lungs to the brain. Although 

many blood vessels are visible here, this image shows 

fewer than half of the total number in the brain. 

Mitochondria and 

Free Radicals

The Brain’s Vascular System
ALZHE IMER’S D ISEASE Unraveling the Mystery 45

Lifestyle Factors 

We know that physical activity and a nutritious diet 

can help people stay healthy as they grow older. A 

healthy diet and exercise can reduce obesity, lower 

blood cholesterol and high blood pressure, and 

improve insulin action. In addition, association 

studies suggest that pursuing intellectually 

stimulating activities and maintaining active 

contacts with friends and family may contribute 

to healthy aging. A growing body of evidence now 

suggests that these lifestyle factors may be related 

to cognitive decline and AD. Researchers who 

are interested in discovering the causes of AD are 

intensively studying these issues, too.

Physical Activity and Exercise

Exercise has many benefits. It strengthens muscles, 

improves heart and lung function, helps prevent 

osteoporosis, and improves mood and overall wellbeing. So it is not surprising that AD investigators 

began to think that if exercise helps every part of 

the body from the neck down, then it might help 

the brain as well.

Epidemiologic studies, animal studies, and 

human clinical trials are assessing the influence 

of exercise on cognitive function. Here are a few 

things these studies have found:

Animal studies have shown that exercise increases the number of capillaries that supply blood 

to the brain and improves learning and memory in 

older animals.

■

Epidemiologic studies show that higher levels 

of physical activity or exercise in older people are 

associated with reduced risk of cognitive decline 

and reduced risk of dementia. Even moderate 

exercise, such as brisk walking, is associated with 

reduced risk.

Clinical trials show some evidence of short-term 

positive effects of exercise on cognitive function, 

especially executive function (cognitive abilities 

involved in planning, organizing, and decision 

making). One trial showed that older adults who 

participated in a 6-month program of brisk 

walking showed increased activity of neurons in 

key parts of the brain. 

More clinical trials are underway to expand 

our knowledge about the relationship of exercise 

to healthy brain aging, reduced risk of cognitive 

decline, and development of AD. (See Participating in a Clinical Trial on page 59 for more 

information).

Diet 

Researchers have explored whether diet may help 

preserve cognitive function or reduce AD risk, 

with some intriguing findings. For example, 

studies have examined specific foods that are rich 

in antioxidants and anti-inflammatory properties 

to find out whether those foods affect age-related 

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44 ALZHE IMER’S D ISEASE Unraveling the Mystery

and drain it, also are lost. Blood flow to and from 

various parts of the brain can be affected, and the 

brain may be less able to compensate for damage 

that accumulates as the disease progresses. 

For some time now, study of the brain’s blood 

vessel system in AD has been a productive line of 

inquiry. One important finding has been that the 

brain’s ability to rid itself of toxic beta-amyloid by 

sending it out into the body’s blood circulation 

is lessened. Some scientists now think that poor 

clearance of beta-amyloid from the brain, combined with a diminished ability to develop new 

capillaries and abnormal aging of the brain’s blood 

vessel system, can lead to chemical imbalances in 

the brain and damage neurons’ ability to function 

and communicate with each other. These findings 

are exciting because they may help to explain part 

of what happens in the brain during the development of AD. These findings also suggest several 

new targets for potential AD therapies. 

AD and Vascular Problems in 

Other Parts of the Body

Research also has begun to tease out some 

relationships between AD and other vascular 

diseases, such as heart disease, stroke, and type 2 

diabetes. It is important to sort out the various 

effects on the brain of these diseases because they 

are major causes of illness and death in the United 

States today.

Much of this evidence comes from epidemiologic studies, which compare the lifestyles, behaviors, and characteristics of groups of people 

(see Describing Scientific Findings: The Type of 

Study Makes an Important Difference on page 

47 for more information about epidemiologic 

studies). These studies have found, for example, 

that heart disease and stroke may contribute to the 

development of AD, the severity of AD, or the development of other types of dementia. Studies also 

show that high blood pressure that develops during middle age is correlated with cognitive decline 

and dementia in later life. 

Another focus of AD vascular research is the 

metabolic syndrome, a constellation of factors that 

increases the risk of heart disease, stroke, and type 

2 diabetes. Metabolic syndrome includes obesity 

(especially around the waist), high triglyceride 

levels, low HDL (“good cholesterol”) levels, high 

blood pressure, and insulin resistance (a condition 

in which insulin does not regulate blood sugar 

levels very well). Evidence from epidemiologic 

studies now suggests that people with the metabolic syndrome have increased risk of cognitive 

impairment and accelerated cognitive decline.

Nearly one in five Americans older than age 60 

has type 2 diabetes, and epidemiologic studies 

suggest that people with this disease may be 

at increased risk of cognitive problems, including 

MCI and AD, as they age. The higher risk 

associated with diabetes may be the result of high 

levels of blood sugar, or it may be due to other 

conditions associated with diabetes (obesity, high 

blood pressure, abnormal blood cholesterol levels, 

progressive atherosclerosis, or too much insulin 

in the blood). These findings about diabetes 

have spurred research on a number of fronts—

epidemiologic studies, test tube and animal 

studies, and clinical trials. The objective of these 

studies is to learn more about the relationship 

between diabetes and cognitive problems and to 

find out in clinical trials whether treating the disease 

rigorously can positively affect cognitive health and 

possibly slow or prevent the development of AD.

P A R T 3 AD Research: Better Questions, New Answers

If you want to know more about the 

benefits of exercise and physical activity 

and learn ways to be active every day, 

NIA has free information just for you! 

Call 1-800-222-2225 or visit 

www.nia.nih.gov/Exercise. 
ALZHE IMER’S D ISEASE Unraveling the Mystery 47

the risk of developing AD was 47 percent lower in 

the people who did them the most frequently 

compared with the people who did the activities 

least frequently. Another study supported the value 

of lifelong learning and mentally stimulating 

activity by finding that, compared with older study 

participants who may have had AD or who had 

AD, healthy older participants had engaged in more 

mentally stimulating activities and spent more time 

at them during their early and middle adulthood. 

Studies of animals, nursing home residents, and 

people living in the community also have suggested 

a link between social engagement and cognitive 

performance. Older adults who have a full social 

network and participate in many social activities tend 

to have less cognitive decline and a decreased risk of 

dementia than those who are not socially engaged.

The reasons for these findings are not entirely 

clear, but a number of explanations are possible. 

Among them:

 Intellectually stimulating activities and social 

engagement may protect the brain in some way, 

perhaps by establishing a cognitive reserve.

 These activities may help the brain become 

more adaptable and flexible in some areas of 

mental function so that it can compensate for 

declines in other areas.

 Less engagement with other people or in 

intellectually stimulating activities could be 

the result of very early effects of the disease 

rather than its cause.

 People who engage in stimulating activities may 

have other lifestyle qualities that may protect 

them against developing AD. 

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46 ALZHE IMER’S D ISEASE Unraveling the Mystery

changes in brain tissue. One laboratory study 

found that curcumin, the main ingredient of 

turmeric (a bright yellow spice used in curry), 

can bind to beta-amyloid and prevent 

oligomer formation. Another study in 

mice found that diets high in DHA 

(docosahexaenoic acid), a type of 

healthy omega-3 fatty acid found 

in fish, reduced beta-amyloid 

and plaques in brain tissue.

Other studies have shown 

that old dogs perform better on 

learning tasks when they eat diets 

rich in antioxidants, such as vitamin 

E and other healthful compounds, while 

living in an “enriched” environment (one in 

which the dogs have many opportunities to play and 

interact with people and other dogs).

Scientists also have examined the effects of 

diet on cognitive function in people. A very large 

epidemiologic study of nurses found an association 

between participants who ate the most vegetables 

(especially green leafy and cruciferous vegetables) 

and a slower rate of cognitive decline compared 

with nurses who ate the least amount of these 

foods. An epidemiologic study of older adults 

living in Chicago found the same association. The 

researchers do not know the exact reason behind 

this association, but speculate that the beneficial 

effects may result from the high antioxidant and 

folate content of the vegetables. 

Dietary studies, such as the curcumin study in 

mice or the vegetables study in nurses, generally 

examine individual dietary components so that 

scientists can pinpoint their specific effects on an 

issue of interest. This approach has obvious 

limitations because people do not eat just single 

foods or nutrients. Several recent epidemiologic 

studies have taken a different approach and looked 

at an entire dietary pattern. 

In one of these studies, researchers worked 

with older adults living in New York who ate the 

“Mediterranean diet”—a diet with lots of fruits, 

vegetables, and bread; low to moderate 

amounts of dairy foods, fish, and 

poultry; small amounts of red meat; 

low to moderate amounts of wine; 

and frequent use of olive oil. The 

researchers found that sticking 

to this type of diet was associated 

with a reduced risk of AD and 

that the association seemed to 

be driven by the whole approach, 

rather than by its individual dietary 

components. A follow-up study found 

that this pattern also was associated with 

longer survival in people with AD. 

All of these results are exciting and suggestive, 

but they are not definitive. To confirm the results, 

scientists are conducting clinical trials to examine the 

relationship of various specific dietary components 

and their effect on cognitive decline and AD. 

Intellectually Stimulating 

Activities and Social Engagement 

Many older people love to read, do puzzles, play 

games, and spend time with family and friends. All 

these activities are fun and help people feel alert 

and engaged in life. Researchers are beginning to 

find other possible benefits as well, for some studies 

have shown that keeping the brain active is associated with reduced AD risk. For example, over a 

4-year period, one group of researchers tracked how 

often a large group of older people did activities 

that involved significant information processing, 

such as listening to the radio, reading newspapers, 

playing puzzle games, and going to museums. The 

researchers then looked at how many of the participants developed AD. The researchers found that 

P A R T 3 AD Research: Better Questions, New Answers

These days, the media are 

full of stories about scientific 

studies. It can be hard to know 

what to conclude about their findings. Knowing how the study was 

conducted can help put the results 

into the right perspective.

One main type of research is 

the epidemiologic study. These 

studies are observational—they 

gather information about people 

who are going about their daily 

lives. Study participants follow 

many behaviors and practices. It 

is difficult, therefore, to determine 

the exact benefits or risks of one 

particular behavior from among all 

the healthy or harmful behaviors 

followed by the participants. That 

is why, in epidemiologic studies of 

AD, scientists only say that a finding is “associated with” AD, or not. 

The epidemiologic evidence linking 

a behavior and AD is, at best, suggestive, but we do not know that 

the behavior by itself actually helps 

to cause or prevent AD. 

Other types of research—test 

tube studies and studies in animals—add to the findings from 

epidemiologic studies. Scientists 

use them to examine the same 

issue but in ways in which the 

various factors that might influence a result are controlled to 

a greater degree. This element 

of control allows scientists to be 

more certain about why they get 

the results they do. It also allows 

them to be more definitive in the 

words they use to describe their 

results. Of course, showing a 

cause-and-effect relationship in 

tissue samples or even in animal 

studies still does not mean that the 

relationship will be the same in 

humans. Clinical trials in humans 

are the gold standard for deciding whether a behavior or a 

specific therapeutic agent 

actually prevents or delays AD 

(see Participating in a Clinical 

Trial on page 59 for more on 

this kind of research). 

Describing Scientific Findings: 

The Type of Study Makes an Important Difference
Current Tools for Diagnosing AD

ALZHE IMER’S D ISEASE Unraveling the Mystery 49

With the tools now available, experienced physicians 

can be reasonably confident about 

making an accurate diagnosis of 

AD in a living person. Here is 

how they do it. 

They take a detailed 

patient history, including:

 A description of how and when 

symptoms developed.

 A description of the person’s 

and his or her family’s overall 

medical condition and history.

 An assessment of the person’s 

emotional state and living 

environment.

They get information 

from family members or 

close friends:

 People close to the person can 

provide valuable insights into 

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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 conduct neuropsychological testing:

 Question-and-answer tests 

or other tasks that measure 

memory, language skills, ability 

to do arithmetic, and other 

abilities related to brain functioning help show what kind of 

cognitive changes are occurring.

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They may do a computed 

tomography (CT) scan or a 

magnetic resonance imaging 

(MRI) test: 

 CT and MRI scans can detect 

strokes or tumors or can reveal 

changes in the brain’s structure 

that indicate early AD.

Exams and tests may be repeated 

every so often to give physicians 

information about how the person’s 

memory and other symptoms are 

changing over time. 

Based on findings from these 

exams and tests, experienced 

physicians can diagnose or rule 

out other causes of dementia, or 

determine whether the person has 

MCI, “possible AD” (the symptoms 

may be due to another cause), or 

“probable AD” (no other cause for 

the symptoms can be found). 

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network, and even consider joining a clinical trial 

or other research study. Being able to participate 

for as long as possible in making personal decisions 

is important to many people with AD. 

Early diagnosis also gives families time to recognize that life does not stop with a diagnosis of AD. 

The person is still able to participate in many of 

the daily activities he or she has always enjoyed, 

and families can encourage the person to continue 

with them for as long as possible. Finally, early 

diagnosis gives family caregivers the opportunity to 

learn how to recognize and cope with changes over 

time in their loved one as well as to develop strategies that support their own physical, emotional, 

and financial health.

48

A man in his mid-60s begins to notice that his 

memory isn’t as good as it used to be. More and more 

often, a word will be on the tip of his tongue but 

he just can’t remember it. He forgets appointments, 

makes mistakes when paying his bills, and finds that 

he’s often confused or anxious about the normal hustle 

and bustle of life around him. One evening, he suddenly finds himself walking in a neighborhood he 

doesn’t recognize. He has no idea how he got there or 

how to get home. 

Not so long ago, this man’s condition 

would have been swept into a broad 

catch-all category called “senile 

dementia” or “senility.” Although we 

now know that AD and other causes of dementia are 

distinct diseases, in the early stages it is difficult to 

differentiate between the onset of AD and other types 

of age-related cognitive decline. We have improved 

our ability to diagnose AD correctly, and doctors 

experienced in AD can diagnose the disease with up 

to 90 percent accuracy. A definitive diagnosis of AD, 

however, is still only possible after death, during an 

autopsy, and we are still far from the ultimate goal—

a reliable, valid, inexpensive, and early diagnostic 

marker that can be used in any doctor’s office. 

Early diagnosis has several advantages. For 

example, many conditions cause symptoms that 

Diagnosing AD New Techniques Help in

mimic those of AD. Finding out early that the 

observed changes in cognitive abilities are not AD 

but something else is almost always a relief and 

may be just the prod needed to seek appropriate 

medical treatment (see Causes of Dementia on 

page 50 for more information). For the small 

percentage of dementias that are treatable or 

even reversible, early diagnosis increases the 

chances of successful treatment. Increasing early 

diagnosis and improving treatment are among 

NIA’s most important goals. 

Even when the cause of a loved one’s dementia 

turns out to be AD, it is best to find out sooner 

rather than later. One benefit of knowing is medical. The drugs now available to treat AD can help 

some people maintain their mental abilities for 

months to years, although they do not change 

the underlying course of the disease (see Helping 

People with AD Maintain their Mental Functioning on page 55 for more about these drugs).

Other benefits are practical. The sooner the person with AD and the family have a firm diagnosis, 

the more time they have to make future living 

arrangements, handle financial matters, establish 

a durable power of attorney and advance directives, deal with other legal issues, create a support 

P A R T 3 AD Research: Better Questions, New Answers

ALZHE IMER’S D ISEASE Unraveling the Mystery
ALZHE IMER’S D ISEASE Unraveling the Mystery 51

highly sophisticated imaging systems that have 

been used in many areas of medicine, including 

AD. PET scans, single photon emission 

computed tomography (SPECT), and MRI are 

all examples. These “windows” on the living brain 

may help scientists measure the earliest changes 

in brain function or structure in order to identify 

people who are at the very first stages of the 

disease—well before they develop clinically 

apparent signs and symptoms. 

To help advance this area of research, NIA 

launched the multi-year AD Neuroimaging 

Initiative (ADNI) in 2004. This project is following about 200 cognitively healthy individuals 

and 400 people with MCI for 3 years and 200 

people with early AD for 2 years. Over the course 

of this study, participants undergo multiple MRI 

and PET scans so that study staff can assess how 

the brain changes in the course of normal aging 

and MCI, and with the progression of AD. By 

using MRI and PET scans at regularly scheduled 

intervals, study investigators hope to learn when 

and where in the brain degeneration occurs as 

memory problems develop. 

Another innovative aspect of ADNI is that 

scientists are correlating the participants’ imaging 

information with information from clinical, 

memory, and other cognitive function tests, and 

with information from blood, cerebrospinal fluid, 

and urine samples. Results from these samples 

may provide valuable biomarkers of disease 

progress, such as changing levels of beta-amyloid 

and tau, indicators of inflammation, measures of 

oxidative stress, and changing cognitive abilities. 

An important ADNI achievement is the 

creation of a publicly accessible database of 

images, biomarker data, and clinical information 

available to qualified researchers worldwide. 

Biological samples also are available for approved 

biomarker projects. NIA hopes that this initiative 

will help create rigorous imaging and biomarker 

standards that will provide measures for the 

success of potential treatments. This would 

substantially increase the pace and decrease the 

cost of developing new treatments. The ADNI 

study is being replicated in similar studies by 

researchers in Europe, Japan, and Australia.

These types of neuroimaging scans are still 

primarily research tools, but one day they may be 

used more commonly to help physicians diagnose 

AD at very early stages. It is conceivable that 

these tools also may someday be used to monitor 

the progress of the disease and to assess responses 

to drug treatment. 

50 ALZHE IMER’S D ISEASE Unraveling the Mystery

Scientists also see advantages to early diagnosis. 

Developing tests that can reveal what is happening in the brain in the early stages of AD will help 

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

learn when and how to prescribe the use of drugs 

and other treatments so they can be most effective.

EXCITING NEW DEVELOPMENTS 

IN AD DIAGNOSIS

Scientists are now exploring ways to help physicians 

diagnose AD earlier and more accurately. For 

example, some studies are focusing on changes 

in mental functioning. These changes can be 

measured through memory and recall tests. Tests 

that measure a person’s abilities in areas such as 

abstract thinking, planning, and language can 

help pinpoint changes in these areas of cognitive 

function. Researchers are working to improve 

standardized tests that might be used to point 

to early AD or predict which individuals are at 

higher risk of developing AD in the future. 

Other studies are examining the relationship 

between early damage to brain tissue and outward clinical signs. Still others are looking for 

changes in biomarkers in the blood or cerebrospinal fluid that may indicate the progression of 

AD (see Very Early Signs and Symptoms on 

page 28 for more on this work). 

One of the most exciting areas of ongoing 

research in this area is neuroimaging. Over the 

past decade, scientists have developed several 

Causes of Dementia

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 caused by 

neurodegenerative diseases. Dementia also has other causes, some of which are treatable.

Alzheimer’s disease

Vascular dementia 

Parkinson’s disease with dementia

Frontotemporal lobar degeneration, including:

 frontotemporal dementia

 frontotemporal dementia with parkinsonism 

linked to chromosome 17 (FTDP-17) 

Pick’s disease

supranuclear palsy

corticobasal degeneration

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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 

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Neurodegenerative Diseases that Cause Dementia Other Causes of Dementia 

P A R T 3 AD Research: Better Questions, New Answers
ALZHE IMER’S D ISEASE Unraveling the Mystery 53

USING TECHNOLOGY 

TO COLLECT DATA AT HOME 

Researchers at nearly 30 sites nationwide are 

comparing various ways of collecting data, including 

the use of an in-home “kiosk” that combines a 

touch-screen computer monitor with a telephone 

handset, an interactive voice-response system, and 

traditional mail and telephone. All three methods 

gather the same data about several areas known to 

be important in early detection of cognitive decline: 

memory; language skills; attention and concentration; 

activities of daily living; quality of life; health care 

and resource use; and changes in “global” well-being 

as measured by self-rating of health, cognition, and 

mood. This study is looking at questions such as 

how likely people are to complete the questions 

using each method, which method is the most 

efficient, and how sensitive each method is. 

Having a data collection system that is easy to 

use and that collects data accurately and completely 

may encourage wider participation in AD clinical 

trials. It also may reduce the expense and burden of 

conducting AD research. Early results from this study 

show that the older participants were skeptical at first 

about using the kiosk, but once they learned how to 

use it, they became enthusiastic and excited about 

participating. 

New Technologies Help People Participate in AD Research at Home 

52 ALZHE IMER’S D ISEASE Unraveling the Mystery

Traditionally, AD scientists have collected data by 

asking people to come to a clinic once or twice a 

year over a period of years. They give the participants 

a physical exam and ask them to take a series of 

memory, language, and other cognitive function tests. 

These studies collect much useful information, but 

they have their limitations. For one thing, participants 

are seen only once or twice during the year, so the 

data collected represent only a “snapshot” in time. 

The studies cannot effectively capture day-to-day 

fluctuations in behaviors and cognitive abilities. 

Another limitation is that participants are seen in 

a research setting, not in their natural community 

environment. For many, coming to the clinic can be 

inconvenient, difficult, or both. 

Advances in technology, as shown in the two 

research projects described here, offer some hope 

for dealing with these challenges by bringing 

research to people right in their own homes.

MOTION DETECTORS TELL 

AN INTERESTING STORY

Scientists who are trying to develop methods for 

diagnosing AD as early as possible continually 

grapple with two challenges in conducting their 

research. First, they need to find easy and accurate 

ways to collect data from older people, who often 

have physical, emotional, or cognitive problems. 

Second, they need to find ways to assess accurately 

the very early changes in physical or cognitive 

abilities that could indicate that AD is progressing. 

Under an NIA grant, the Oregon Center for Aging 

and Technology (ORCATECH) at Oregon Health & 

Science University is exploring the use of unobtrusive, 

simple technology and intelligent systems to detect 

and monitor subtle changes in movement that may 

indicate age-related cognitive changes. This project is 

building on research that has suggested that motorfunction changes may arise before memory changes 

become apparent (see Very Early Signs and 

Symptoms on page 28 for more on this research). 

All of the 300 study participants are 80 years or 

older or have a spouse of a similar age, and live 

independently in Portland-area retirement communities. Wireless, infrared motion sensors, like those 

used to automatically open grocery store doors, have 

been placed strategically throughout the participants’ 

homes to gather data about changes in their walking 

or dressing speed over time. Special software also 

has been installed on each participant’s home 

computer to measure motor skills and speed in typing 

or using a mouse. The sensors and computer software 

collect data about motion, not what the volunteer 

is actually doing. Privacy is largely not a concern 

therefore, because the volunteers are not directly 

observed and no video or photographs are taken.

The 3-year study began in early 2007, so results 

are not yet available. However, a small pilot study 

using the same type of sensors showed a clear 

difference in the walking speeds of people age 65 

and older who had MCI, compared with cognitively 

healthy people of the same age, over time periods 

of nearly a year. These data suggest that a remote 

sensing system like this is a feasible technology and is 

potentially sensitive enough to distinguish accurately 

between affected and unaffected people.

P A R T 3 AD Research: Better Questions, New Answers

This photo shows ORCATECH 

study participants at home. The 

small device between the photographs on the wall is an infrared 

motion sensor.
54 ALZHE IMER’S D ISEASE Unraveling the Mystery ALZHE IMER’S D ISEASE Unraveling the Mystery 55

More and more, scientists are able 

to think about ways to treat, slow, 

or perhaps even prevent AD at a 

number of possible points during 

the years-long continuum of disease progression. 

This continuum begins with the very earliest 

disease stage, even before symptoms are evident, 

moves to the first signs of memory and cognitive 

problems, then continues through the mild and 

moderate stages, and ends with the very late stages 

and the person’s death. 

As a result, researchers who focus on developing 

AD treatments think a lot about the importance 

of timing: When would it be best to intervene 

and what interventions are most appropriate at 

which time? These questions are similar to those 

asked with other conditions, such as heart disease. 

For example, a physician would prescribe different 

treatments for a patient who is seemingly healthy 

but who is at risk of having future heart disease 

than for a patient who is actually having a heart 

attack or whose heart disease is well established. The 

same decision process now can be applied to AD.

It has become clear that there probably is no 

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

cure AD. Therefore, investigators are working to 

develop an array of options from which physicians 

can choose. For people who already have AD, the 

most immediate need is for treatments to control 

cognitive loss as well as problem behaviors, such as 

aggression, agitation, wandering, depression, sleep 

disturbances, hallucinations, and delusions. Safe 

medications that remain effective over time are 

needed to ease a broad range of symptoms and to 

improve a person’s cognitive function and ability 

to carry out activities of daily living. Scientists also 

are investigating treatments that combine medications with lifestyle strategies to lessen the risk of 

developing cognitive decline or AD. Eventually, 

scientists hope to develop treatments that attack 

the earliest manifestations and underlying causes 

of AD, thereby slowing, delaying, or preventing 

the disease from progressing and damaging cognitive function and quality of life. Scientists use 

clinical trials to pursue all these goals.

Today, NIA, other NIH institutes, and private 

industry are conducting many clinical trials of 

AD interventions (see page 59 for more about 

clinical trials). These studies focus on several 

key areas:

 Helping people with AD maintain their mental 

functioning

Managing symptoms

Slowing, delaying, or preventing AD 

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for

Search

New Treatments

The

P A R T 3

HELPING PEOPLE WITH 

AD MAINTAIN THEIR MENTAL 

FUNCTIONING 

In the mid-1970s, scientists discovered that 

levels of a neurotransmitter (a chemical that carries 

messages between neurons) called acetylcholine 

fell sharply in people with AD. This discovery was 

one of the first that linked AD with biochemical 

changes in the brain. Scientists found that 

acetylcholine is a critical player in the process of 

forming memories. It is used by neurons in the 

hippocampus and cerebral cortex, which are areas 

of the brain important to memory function. This 

discovery was an important initial breakthrough in 

the search for drugs to treat AD.

Four medications, tested in clinical trials, have 

been approved by the FDA for use in treating AD 

symptoms. Donepezil (Aricept®), rivastigmine 

(Exelon®), and galantamine (Razadyne®) are prescribed to treat mild to moderate AD symptoms. 

Donepezil was recently approved to treat severe 

AD as well. These drugs, known as cholinesterase 

inhibitors, act by stopping or slowing the action of 

acetylcholinesterase, an enzyme that breaks down 

acetylcholine. They help to maintain higher levels 

of acetylcholine in the brain. In some people, the 

drugs maintain abilities to carry out activities of 

daily living. They also may maintain some thinking, memory, or speaking skills, and can help with 

certain behavioral symptoms. However, they will 

not stop or reverse the underlying progression of 

AD and appear to help people only for months to 

a few years. The newest approved AD medication 

is memantine (Namenda®), which is prescribed to 

treat moderate to severe AD symptoms. This drug 

appears to work by regulating levels of glutamate, 

another neurotransmitter involved in memory 

function. Like the cholinesterase inhibitors, 

memantine will not stop or reverse AD.

AD Research: Better Questions, New Answers
ALZHE IMER’S D ISEASE Unraveling the Mystery 57

SLOWING, DELAYING, 

OR PREVENTING AD 

AD research has developed to the point where 

scientists are looking beyond treating symptoms 

to addressing the underlying disease process. 

Slowing the progress of AD could do much to 

maintain the functioning of people with AD and 

reduce physical and emotional stress on caregivers. 

Delaying AD’s effects also could help to postpone 

or prevent placement in an assisted living facility 

or nursing home, and reduce the financial costs of 

the disease. Preventing AD altogether is, of course, 

the ultimate long-term goal.

NIA and pharmaceutical companies support 

treatment clinical trials that are aimed at slowing, delaying, or preventing AD. The advances 

in our knowledge about the mechanisms and risk 

factors associated with AD have expanded the 

types of interventions under study. These trials 

are examining a host of possible interventions, 

including cardiovascular treatments, hormones, 

type 2 diabetes treatments, antioxidants, omega-3 

fatty acids, immunization, cognitive training, and 

exercise, among others. 

For example, NIA funds pilot trials to learn 

whether treating one or another aspect of type 2 

diabetes will affect cognitive health and AD progression. A pilot trial is a relatively small clinical 

trial that collects initial data on the safety, 

effectiveness, and best dosage of a potential 

treatment. This information helps investigators 

decide which treatments should be tested in 

larger, full-scale trials. One 4-month pilot trial 

has examined the effects on AD of administering 

a nasal-spray form of insulin. This trial is 

founded on evidence that AD is associated with 

reduced levels of insulin in cerebrospinal fluid 

and that treatment with insulin improves 

memory performance. The trial will provide 

useful data on the safety, feasibility, and 

potential effectiveness of this innovative treatment 

approach. Investigators may be able to use the 

results to plan future full-scale clinical trials.

Beyond pilot studies, investigators also are 

conducting full-scale AD clinical trials of various 

interventions. One of these trials, the Alzheimer’s 

Disease Cooperative Study (ADCS), is testing 

whether one omega-3 fatty acid (DHA), found in 

the oil of certain fish, can slow the progression of 

cognitive and functional decline in people with 

mild to moderate AD. During the 18-month 

clinical trial, investigators will measure the 

progress of the disease using standard tests for 

functional and cognitive change. Researchers also 

will evaluate whether taking DHA supplements 

has a positive effect on possible physical and 

biological markers of AD, such as brain atrophy 

56 ALZHE IMER’S D ISEASE Unraveling the Mystery

MANAGING SYMPTOMS 

“My father is often agitated. He paces up and down, 

wringing his hands and crying. I know he’s sad or 

anxious about something but he can’t tell me what’s 

bothering him. Asking him about it just makes him 

more upset.”

“Last week, I visited Mom in the nursing home. We 

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

again. When I walked into her room, she didn’t know 

me. She thought I was her sister.”

“My husband used to be such an easy going, calm 

person. Now, he suddenly lashes out at me and uses 

awful language. Last week, he got angry when our 

daughter and her family came over and we sat down 

to eat. I never know when it’s going to happen. He’s 

changed so much—it scares me sometimes.”

“Gran hums all the time. She used to be a singer. Is 

she trying to relive her past?”

As AD begins to affect memory and mental 

abilities, it also begins to change a person’s emotions and behaviors. Between 70 and 90 percent 

of people with AD eventually develop one or more 

behavioral symptoms. These symptoms include 

sleeplessness, wandering and pacing, aggression, 

agitation, anger, depression, and hallucinations 

and delusions. Some of these symptoms may 

become worse in the evening (a phenomenon 

called “sundowning”) or during daily routines, 

especially bathing. 

P A R T 3

The damage of AD affects many different parts 

of the brain. This presents a problem because even 

small tasks require the brain to process signals that 

often involve more than one region of the brain. If 

this processing is disrupted because of AD, the 

person may not be able to do the task or may act 

in a strange or inappropriate way. 

In light of our growing understanding about the 

effects of AD on the brain, behaviors like the ones 

highlighted above suddenly make sense or even 

provide a loving opportunity for caregivers: 

For a man who can no longer distinguish between past 

and present, the anguish caused by the death of a parent may be as real today as it was many years before. 

Sitting down to a family meal may produce 

intense anxiety when a person has no idea what to do 

with the knife and fork in front of him and all the 

conversation and activity feel overwhelming. 

Memories of favorite songs from long ago resurface and 

provide a compelling link to a happy time in the past.

Behavioral symptoms, often emotional and 

upsetting, are one of the hardest aspects of the 

disease for families and other caregivers to deal 

with. They are also a visible sign of the terrible 

change that has taken place in the person with 

AD. Researchers are slowly learning more about 

why behavioral symptoms occur and are conducting clinical trials on new treatments—both drug 

and non-drug—to deal with difficult behaviors. 

AD Research: Better Questions, New Answers

Coping with Behavioral Symptoms

For more information on how to deal with 

behavioral issues and symptoms, visit the 

caregiving section of NIA’s Alzheimer’s 

Disease Education and Referral (ADEAR) 

Center website at: www.nia.nih.gov/

Alzheimers/Caregiving/HomeAndFamily.
58 ALZHE IMER’S D ISEASE Unraveling the Mystery ALZHE IMER’S D ISEASE Unraveling the Mystery 59

and proteins in blood and spinal fluid. The ADCS 

is a federally established consortium conducting 

clinical trials on AD, with sites across the United 

States and Canada. 

Full-scale AD prevention trials are underway as well. One such trial, Prevention of 

Alzheimer’s Disease with Vitamin E and 

Selenium (PREADVISE), is being conducted in 

conjunction with a National Cancer Institutefunded trial called the Selenium and Vitamin E 

Cancer Prevention Trial (SELECT). SELECT 

is evaluating whether taking selenium and/or 

vitamin E supplements can prevent prostate 

cancer in healthy men older than 60 years. 

PREADVISE is evaluating whether these 

supplements can help prevent memory loss and 

dementia by protecting brain cells from oxidative 

damage (see The Aging Process on page 42 for 

more on oxidative damage). About 6,000 of the 

more than 30,000 men enrolled in SELECT are 

participating in PREADVISE. 

P A R T 3

Participating in a Clinical Trial

Continued on next page

Rapid advances in our knowledge about AD have 

led to the development of many 

promising new drugs and treatment 

strategies. However, before these 

new strategies can be used in clinical practice, they must be shown 

to work in people. This means 

that clinical trials—and volunteer 

participants—are an essential 

part of AD research. Advances 

in prevention and treatment are 

possible thanks to volunteers who 

participate in clinical trials.

Clinical trials are the primary 

way that researchers find out if 

a promising treatment is safe. 

Clinical trials tell researchers which 

treatments are the most effective 

and for which people they may 

work best. Trials can take place 

in various settings, such as private 

research facilities, teaching hospitals, specialized AD research 

centers, and doctors’ offices. FDA 

approval is necessary before 

scientists can begin a clinical trial.

Participating in a clinical trial 

is a big step for anyone, including 

people with AD and their caregivers. That is why physicians and 

clinical trials staff spend time talking 

with participants about what it is 

like to be in a trial and the pros and 

cons of participating. It is also why 

they get a signed informed consent 

form before a person enrolls in 

a trial. Here are some facts that 

potential participants might want to 

know about clinical trials.

WHAT KIND OF 

TRIALS ARE THERE?

Treatment trials with existing drugs 

or behavioral strategies assess 

whether an intervention already 

approved for other purposes may 

be useful in treating age-related 

cognitive decline or AD. For 

example, trials have tested whether 

drugs used to lower cholesterol 

help slow progression of AD.

Treatment trials with experimental 

drugs or strategies show whether 

a new drug or treatment approach 

can help improve cognitive function 

or lessen symptoms in people with 

AD, slow the progression to AD, 

or prevent it. Interventions tested 

in these trials are developed from 

knowledge about the mechanisms 

involved in the AD process. Experimental drugs, for example, are 

first tested in tissue culture and in 

animals to determine their actions in 

the body. Safety and effectiveness 

studies are also conducted in 

animals before the compounds 

are tested in humans. 

WHAT ARE THE PHASES 

OF CLINICAL TRIALS?

During Phase I trials, a research 

team gives the treatment to a 

small number of participants and 

examines its action in the body 

and its safety. The main goals of 

Phase I trials are to establish the 

highest dose of a new drug that 

people can tolerate and to define 

the dose at which people may 

begin to experience harmful side 

effects. These trials generally last 

only a few months. 

If results show that the treatment appears to be safe, it will 

go on to Phase II and Phase 

III clinical trials. Phase II trials 

involve larger numbers of people 

studied over longer periods of 

time than Phase I trials. In these 

trials, the study team wants to 

know whether the treatment is 

safe and effective at changing 

the course of the disease. Phase 

II trials occasionally also involve 

the use of a placebo (an inactive 

substance that looks like the study 

drug). Results from Phase II trials 

give study staff an indication of 

the effective dose to take into 

Phase III trials. Phase III trials are 

large studies that compare an 

experimental treatment with a 

placebo or standard treatment 

to determine safety and efficacy 

(whether the treatment has the 

power to produce an effect). 

After these phases are complete 

AD Research: Better Questions, New Answers
ALZHE IMER’S D ISEASE Unraveling the Mystery 61

WHAT SHOULD 

PEOPLE CONSIDER 

BEFORE PARTICIPATING IN 

A CLINICAL TRIAL? 

People who have participated in 

AD clinical trials say that it’s a good 

idea to consider the following issues 

before deciding to join a trial.

Expectations and motivations. The test drug or treatment 

may relieve a symptom, change 

a clinical measurement, or reduce 

the risk of death, but clinical trials 

generally do not have miraculous 

results and participants may not 

receive any direct benefit. With 

a complex disease like AD, it is 

unlikely that one treatment will 

cure or prevent the disease. Some 

people choose not to participate 

or decide to drop out of a study 

because this reality does not meet 

their expectations. Others choose 

to stay in a trial because they 

realize that even if they get no 

or only a slight benefit, they are 

making a valuable contribution to 

knowledge that will help people 

in the future. 

Uncertainty. Some families 

have a hard time with the uncertainties of participation—for 

example, not knowing whether 

the person is taking the test 

treatment, a placebo, or a control 

treatment, not being able to 

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choose which study group to be 

in, or not knowing for a long time 

whether the study was successful. 

Ongoing and open communication with study staff can help to 

reduce this frustration.

Finding the right clinical 

trial. Some clinical trials involve 

participants who are cognitively 

healthy or have only mild symptoms because they are testing a 

drug that might delay a decline 

in cognitive function. Other trials 

involve participants who have 

more advanced AD because they 

are testing a treatment that might 

lessen behavioral symptoms. Or, a 

trial may be testing new strategies 

to help caregivers. Even if a participant is not eligible for one trial, 

another trial may be just right. 

The biggest benefit of all.

Many families find that the biggest 

benefit of participating in a clinical 

trial is the regular contact with the 

study team. These visits provide an 

opportunity to get state-of-the-art 

AD care and to talk regularly with 

AD experts who have lots of practical experience and a broad perspective on the disease. The study 

team understands and can provide 

advice about the emotional and 

physical aspects of the person with 

AD and the caregivers’ experience. Team members can suggest 

ways to cope with the present and 

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give insights into what to expect 

in the future. They also can share 

information about support groups 

and other helpful resources.

FOR MORE INFORMATION 

To learn more about AD clinical 

trials, visit the Alzheimer’s Disease 

Education and Referral (ADEAR) 

Center’s Clinical Trials Database 

website (www.nia.nih.gov/

Alzheimers/ResearchInformation/

ClinicalTrials). This NIA website 

includes a list of AD and dementia 

clinical trials currently in progress 

at research centers throughout

the United States. It also provides

information about the phases 

of clinical trials and how to 

participate, explains the drug 

development process, and provides 

links to other useful websites. 

Also, visit the clinical trials websites of the National Institutes 

of Health (www.clinicaltrials.gov)

or the Alzheimer’s Association 

(www.alz.org). 

60

and investigators are satisfied that 

the treatment is safe and effective, 

the study team may submit its 

data to the FDA for approval. FDA 

experts review the data and 

decide whether to approve the 

drug or treatment for use in patients 

with the disease under study. 

WHAT HAPPENS WHEN 

A PERSON SIGNS UP FOR A 

CLINICAL TRIAL?

First, it is important to learn 

about the trial. Staff at the clinical 

research center explain the trial 

in detail to potential participants 

and describe possible risks 

and benefits. Staff also talk 

about the participants’ rights as 

research volunteers, including 

their right to leave the trial at 

any time. Participants and their 

family members are entitled to 

have this information repeated 

and explained until they feel they 

understand the nature of the trial 

and any potential risks. 

After all questions have been 

answered, participants who are 

still interested in joining the trial 

are asked to sign an informed 

consent form. In some cases, a 

participant may no longer be 

able to provide informed consent 

because of problems with memory 

and thinking. In such cases, it is 

still possible for an authorized 

representative (usually a family 

member) to give permission for the 

person to participate. Laws and 

regulations regarding informed 

consent differ across States and 

research institutions, but all are 

intended to ensure that participants 

are protected and well cared for. 

Next, people go through a 

screening process to see if they 

qualify to participate in the trial. 

If they qualify and can safely 

participate, then they are enrolled 

in the trial.

WHAT HAPPENS 

DURING A TRIAL?

If participants agree to join the 

trial and an evaluation process 

shows they meet all the criteria for 

participation, then a “baseline” 

visit is scheduled with the trial 

staff. This visit generally involves 

cognitive and physical tests. This 

gives the team information against 

which to measure future mental 

and physical changes.

In most clinical trials, participants are randomly assigned to 

different study groups so that 

each study group has people 

in it of about the same average 

characteristics (such as age, sex, 

educational level, or cognitive 

ability). One group, the test 

group, receives the experimental 

drug or intervention. Other 

groups may receive a different 

drug, a placebo, or a different 

intervention. Comparing results for 

different groups gives researchers 

confidence that changes in the 

test group are the result of the 

experimental treatment and not 

some other factor, such as the 

placebo effect (this is when people 

feel an effect because they think 

they are getting the test medication even though they are really 

getting a placebo). In many trials, 

no one—not even the research 

team—knows who is getting the 

treatment and who is getting the 

placebo or other intervention. This 

means that the participant, family 

member, and the staff are “blind” 

to the treatment being received. 

This kind of trial is called a doubleblind, placebo-controlled trial. 

As the trial progresses, participants and family members usually 

must follow strict medication or 

treatment instructions and keep 

detailed records of symptoms. Every 

so often, participants visit the clinic 

or research center to have physical 

and cognitive exams, give blood 

and urine samples, and talk with 

trial staff. These visits allow the investigators to collect information on the 

effects of the test drug or treatment, 

see how the disease is progressing, 

and see how the participant and 

the caregiver are doing.

Participating in a Clinical Trial ( C o n t i n u e d )

P A R T 3 AD Research: Better Questions, New Answers

ALZHE IMER’S D ISEASE Unraveling the Mystery
ALZHE IMER’S D ISEASE Unraveling the Mystery 63

One of the greatest costs of AD can 

be the physical and emotional toll 

on family members, caregivers, and 

friends of people with the disease. 

The changes in a loved one’s personality and 

mental abilities; the need to provide constant, 

loving attention for years on end; and the demands 

of bathing, dressing, and other caregiving duties in 

the later stages of the disease can be hard to bear. 

Many caregivers must assume new and unfamiliar 

roles in the family, and these changes can be both 

difficult and sad. Not surprisingly, caregivers of 

people with dementia spend significantly more 

time on caregiving tasks than do caregivers of 

people with other types of illnesses. 

One of the hardest decisions that many 

families face is whether and when to place 

a loved one with AD in a nursing home or 

other type of care facility. Once this decision 

is made, families must decide what type of 

care is best for the person and the family. 

Many investigators are working to identify 

strategies that can lead to improved quality of 

care in various facilities, including adult day 

care centers, assisted living facilities, continuing 

care retirement communities, nursing homes, 

and special care units (separate areas within 

nursing homes or assisted living facilities 

designed especially for people with 

dementia). 

Who Are AD Family Caregivers? 

Many primary caregivers are family 

members, and NIA-funded research 

has shown that the value of informal 

family caregiving of people with 

cognitive impairment adds up to 

billions of dollars every year. Who 

are these family caregivers?

Spouses: This is the largest group 

of caregivers. Most are older, too, 

and many have their own health 

problems.

Daughters: The second largest 

group of primary caregivers is 

daughters. Many are married and 

raising children of their own. 

Juggling two sets of responsibilities 

is often tough for these members 

of the “sandwich generation.”

Daughters-in-law: Many women 

in this group help take care of an 

older person with AD. They are 

the third largest group of family 

caregivers.

Sons: Although many are involved 

in the daily care of a parent with 

AD, sons often focus on the financial, legal, and business aspects of 

caregiving.

Brothers and sisters: Siblings 

may assume primary responsibility 

for care if they live close by. Many 

of these caregivers also are older 

and may be coping with their own 

frailties or health problems.

Grandchildren: Older children 

may become major helpers in 

caring for a grandparent with AD. 

Grandchildren may need extra 

support if their parents’ attention is 

heavily focused on the ill grandparent or if the grandparent with 

AD lives in the family’s home. 

PART 4

for

and Other

Improving Support

Families

Caregivers
64 ALZHE IMER’S D ISEASE Unraveling the Mystery ALZHE IMER’S D ISEASE Unraveling the Mystery 65

services and information geared to different 

stages of the disease.

Traditions and attitudes about caregiving 

vary across cultural groups. For example, some 

researchers have found that African-American 

caregivers use fewer formal in-home services than 

do white caretakers. Some populations may find 

it difficult to publicly admit that a family member 

has AD and may be reluctant to seek help with 

caregiving issues. Therefore, programs and services 

for caregivers must be culturally appropriate and 

sensitive to factors that positively and negatively 

influence caregivers’ attitudes and ability to carry 

out their responsibilities.

Use of multiple types of support over an 

extended period of time helps caregivers. For 

example, the Resources for Enhancing Alzheimer’s 

Caregiver Health (REACH) clinical trial showed 

that caregivers who received 6 months of intensive help with caregiving strategies had significant 

improvements in overall quality of life. They also 

had lower rates of clinical depression compared to 

caregivers who did not participate in the program. 

The caregiving strategies included information 

sharing, instruction, role plays, problem-solving, 

skills training, stress-management techniques, and 

telephone support groups. Caregivers reported 

that taking part in REACH helped them feel 

more confident in working with their loved 

■

■

ones, made life easier for them, improved their 

caregiving ability, improved the care recipient’s 

life, and helped them keep their loved one at 

home. 

Developing ways to help caregivers become 

educated about AD, improve flexibility in 

responding to caregiving demands, and learn a 

variety of practical strategies can help. Studies 

are teaching caregivers how to read the emotional 

and physical cues of the person with AD and to 

understand the sequence of events that often 

leads to inappropriate behaviors. They are also 

helping caregivers respond to the needs of the 

person with AD in a variety of creative ways, 

such as maintaining flexibility in the face of 

many demands, becoming educated about the 

disease, learning practical strategies, using available 

■

A

lthough research on family caregiver 

 support is still in its early days, we have 

 already learned much about the unique 

 aspects of caregivers’ personalities and 

situations. For example, it is well established that 

AD caregivers often experience stress, anxiety, 

depression, and other mental health problems as a 

result of the continuing and demanding nature of 

AD care. This chronic stress can have detrimental 

effects on the physical health of caregivers. The 

physical and emotional effects of AD caregiving 

can last a long time, even after the death of the 

person with AD. 

On the other hand, research also has shown 

that caregiving can have important positive effects, 

including:

A new sense of purpose or meaning in life

Fulfillment of a lifelong commitment to a spouse

 An opportunity to give back to a parent some 

of what the parent has given to them

Renewal of religious faith

 Closer ties with people through new relationships or stronger existing relationships

■

■

■

■

■

AD caregivers do not all have the same 

psychological and physical response to caregiving. 

For example, caregivers who have strong support 

systems and well-developed coping skills may be 

able to weather the stresses of caring for a loved 

one with AD. Others who have few breaks from 

caregiving responsibilities and/or have preexisting 

illnesses may be more vulnerable to the physical 

and emotional stresses associated with dementia 

care. Caregiver research is beginning to discover 

effective ways to ease the burden of caregiving. 

Researchers have learned that:

The information and problem-solving needs 

of caregivers evolve over time as AD progresses. 

Therefore, support programs should be tailored 

to the needs of the caregiver at various stages of 

caregiving. Programs can respond by offering 

■

P A R T 4

Caregivers Research FindingsBenefit

Improving Support for Families and Other Caregivers

Where Are People with 

Alzheimer’s Disease Cared For? 

Home

Assisted living facilities (those in the early stages) 

Adult day care centers

Nursing homes

Special care units

■

■

■

■

■

For Information About AD Support Groups

To find out whether an AD support group is operating in your area, contact:

 NIA’s Alzheimer’s Disease Education and Referral (ADEAR) Center at 800-438-4380 or 

visit www.nia.nih.gov/Alzheimers/ResearchInformation/ResearchCenters

 Alzheimer’s Association at 800-272-3900 or visit www.alz.org

■

■
What Happens Next?

It is a question many people and their families ask when AD is first diagnosed. 

Members of an early-stage support group at the Northwestern University Alzheimer’s 

Disease Center in Chicago wrote What Happens Next? to help people with earlystage dementia cope with their feelings and the practical aspects of everyday life. 

For a free copy, call the Alzheimer’s Disease Education and Referral (ADEAR) 

Center at 800-438-4380 or visit www.nia.nih.gov/Alzheimers/Publications/

 WhatHappensNext.htm.

66 ALZHE IMER’S D ISEASE Unraveling the Mystery ALZHE IMER’S D ISEASE Unraveling the Mystery 67

resources, involving other family members and 

friends, and balancing the needs of the person 

with their own needs.

Helping caregivers deal with the complicated 

issue of whether and when to place a loved one 

in a nursing home is an important aspect of 

caregiver support. People with dementia are 

at much greater risk of nursing home placement 

than are other older people of the same age. 

Placing a loved one in a nursing home may relieve 

some of the burden of caregiving, but it does not 

necessarily reduce caregiver stress or emotional 

distress. Moreover, nursing home costs now 

average more than $70,000 per year. 

One clinical trial tested the effects of an 

enhanced counseling and support program on 

nursing home placement and caregiver health. 

This program for caregivers consisted of six sessions 

of individual and family counseling, support 

group participation, and on-demand telephone 

counseling. Participants in the program were able 

to delay placement of their loved ones in nursing 

homes by about 18 months. Researchers attributed 

the effects of the program to greater tolerance for 

memory and behavior problems in the person with 

AD, improved satisfaction with the support 

provided by family and friends, and fewer 

symptoms of depression. Moreover, it appears 

that the extra time at home did not come at the 

expense of the caregivers’ sense of well-being. 

■

Helping caregivers stay physically active has 

big benefits. Researchers have found that regular 

moderate exercise is an important stress reliever for 

caregivers. Exercise helps to reduce blood pressure 

increases due to stress, improves sleep quality, and 

reduces psychological distress and depression.

EARLY-STAGE AD SUPPORT GROUPS: 

A VITAL SOURCE OF HELP 

For families and friends who care for a person with 

AD, talking with others who are going through the 

same experience can be a vital lifeline. AD support 

groups provide a place where caregivers can seek 

respite, express concerns, share experiences, get 

tips, and receive emotional comfort. NIA-funded 

Alzheimer’s Disease Centers, the Alzheimer’s 

Association, and many other organizations sponsor 

in-person and online AD support groups all 

around the country. 

Improved diagnostic tests and increasing awareness of AD mean that more and more people are 

now being diagnosed at early stages of AD. People 

■

P A R T 4 Improving Support for Families and Other Caregivers

in the early stages often still have good coping 

skills and are intensely aware of themselves and 

their symptoms. They also may feel considerable 

distress, embarrassment, and isolation because of a 

perceived stigma associated with the disease. As a 

result, a growing number of people with early-stage 

AD and their family members are looking for coping strategies, meaningful activities, and mental 

stimulation. They are eager to educate themselves 

about AD, share common experiences, and break 

the potential barriers and isolation caused by their 

diagnosis. This has led to the formation of earlystage support groups specifically designed to meet 

their needs.

Some early-stage support groups follow a 

structured model, with 1- to 2-hour sessions 

scheduled over 6 to 8 weeks. The sessions are 

led by a facilitator and discussion topics are 

determined in advance. Guest speakers provide 

information and help on specific topics such as 

legal and financial planning. In some programs, 

the person with AD and the caregiver meet in 

separate groups; in others, people with AD and 

their caregivers are together for part of the session 

and apart for the remainder. 

Other types of early-stage support groups are 

less structured. Members discuss topics of their 

own choosing, and the groups meet regularly over 

an extended time. Members with AD may stay in 

the group as long as they are able to meaningfully 

take part in the discussion and activities.

Early-stage support groups are not for everyone. 

Some people with early AD and their families may 

not benefit because of family conflict, denial, cognitive impairment, or discomfort with the intimacy 

of a group experience. However, most participants 

report positive outcomes, such as a greater sense 

of control over their lives and feelings that they 

are not alone. Many participants find early-stage 

support groups helpful because they instill a spirit 

of camaraderie, build coping skills, and forge 

relationships and emotional support that continue 

to help the person with AD and the caregiver even 

after the sessions end. 
P A R T 4 Improving Support for Families and Other Caregivers

68 ALZHE IMER’S D ISEASE Unraveling the Mystery

Taking Care of Mom or Dad at a Distance

Taking care of a parent with AD who lives 

hundreds of miles away is a real worry facing 

many adults. “How can we make sure Mom gets the 

best care possible if we’re not there all the time?” 

“What can I do to help Dad live at home for as long 

as possible?”

That was the dilemma facing Ken Nixon and his 

two brothers in 2001. Their mother lived in an Arkansas farming community and wanted to stay there. Ken 

and his brothers lived 3 to 5 hours away—close, but 

not close enough.

With funding from NIA, Ken and his brothers 

created a multi-purpose, Internet-based system called 

AttentiveCare that is currently available to others faced 

with the same long-distance caregiving challenges. 

Back in 2001, broadband Internet service had just 

become available in their mother’s community, so the 

brothers decided to see whether videoconferencing 

could be a way to keep in touch with her. They installed a computer with a video camera in her home so 

they could check on her daily, helping fulfill her wish to 

continue living independently on the family farm while 

assuring themselves that she was faring well.

“We had a need, and we patched the system 

together at first,” says Ken. “It exceeded our 

expectations in being able to keep our mother 

independent and connected to the family. We could 

call and have coffee with her every morning, and it 

got her day started off right. She had something to 

look forward to every day—one or two of her boys 

was going to visit.”

After 6 months of using the home-grown system, 

Nixon decided to develop it to help other caregivers. 

In 2003, he applied for and received a grant from 

NIA to refine the AttentiveCare prototype and test its 

feasibility in providing informal, long-distance care to 

people with AD. 

He later received another grant to evaluate the 

software, services, and caregiver usage and benefits 

of the system in a variety of caregiving situations. The 

participants in this study are distance caregivers of 

persons with early- to moderate-stage AD who had 

the AttentiveCare system installed in their own homes 

and the homes of their family members with AD. 

AttentiveCare now features videoconferencing, 

multimedia reminders to help care recipients function 

independently, and slide shows to keep care recipients connected with family. The system’s journal and 

data logging capability also allows family caregivers 

to maintain and share information about the care 

recipient’s health and well-being, whether they are 

across the street or thousands of miles away. 

The future builds upon the events and 

experiences of the past. That’s certainly true 

of AD research. Our knowledge of AD is 

advancing rapidly, and we have much to 

celebrate in our scientific successes.

At the same time, we cannot forget that AD remains 

an urgent problem for our Nation. The challenge is 

to continue building on these discoveries so that we 

can create a brighter future in which the potential of 

successfully managing AD or even preventing this 

terrible disease can become a reality.

Conclusion

Ken Nixon and his grandson use AttentiveCare to 

check in with Ken’s mother.
ALZHE IMER’S D ISEASE Unraveling the Mystery 71

Cerebrospinal fluid—the fluid found in 

and around the brain and spinal cord. It protects 

these organs by acting like a liquid cushion and 

by providing nutrients. 

Chromosome—a threadlike structure in 

the nucleus of a cell that contains DNA. DNA 

sequences make up genes. Most human cells 

have 23 pairs of chromosomes containing 

approximately 30,000 genes.

Clinical trial—a research study involving 

humans that rigorously tests safety, side effects, 

and how well a medication or behavioral 

treatment works.

Cognitive functions—all aspects of conscious 

thought and mental activity, including learning, 

perceiving, making decisions, and remembering.

Computed tomography (CT) scan—

a diagnostic procedure that uses special x-ray 

equipment and computers to create cross-sectional 

pictures of the body.

Corpus callosum—thick bundles of nerve cell 

fibers that connect the two cerebral hemispheres.

Dementia—a broad term referring to a decline 

in cognitive function to the extent that it interferes 

with daily life and activities.

Dendrite—a branch-like extension of a neuron 

that receives messages from other neurons.

DNA (deoxyribonucleic acid)—a long, 

double-stranded molecule within the nucleus of 

the cell that forms chromosomes and genes.

Early-onset Alzheimer’s disease—a rare 

form of AD that usually affects people between 

ages 30 and 60. It is called familial AD (FAD) if it 

runs in the family.

Entorhinal cortex—an area deep within the 

brain where damage from AD often begins.

Enzyme—a protein that causes or speeds up a 

biochemical reaction.

Free radical—a highly reactive molecule 

(typically oxygen or nitrogen) that combines 

easily with other molecules because it contains an 

unpaired electron. The combination with other 

molecules sometimes damages cells. 

Gene—the biologic unit of heredity passed from 

parent to child. Genes are segments of DNA and 

contain instructions that tell a cell how to make 

specific proteins.

Genetic risk factor—a variant in a cell’s 

DNA that does not cause a disease by itself but 

may increase the chance that a person will 

develop a disease.

70 ALZHE IMER’S D ISEASE Unraveling the Mystery

Acetylcholine—a neurotransmitter that plays 

an important role in many neurological functions, 

including learning and memory.

Amygdala—an almond-shaped structure 

involved in processing and remembering strong 

emotions such as fear. It is part of the limbic 

system and located deep inside the brain. 

Amyloid plaque—a largely insoluble 

deposit found in the space between nerve cells 

in the brain. Plaques are made of beta-amyloid, 

other molecules, and different kinds of nerve 

and non-nerve cells.

Amyloid precursor protein (APP)—the 

larger protein from which beta-amyloid is formed.

Apolipoprotein E—a protein that carries 

cholesterol in blood and that appears to play some 

role in brain function. The gene that produces this 

protein comes in several forms, or alleles: ε2, ε3, 

and ε4. The APOE ε2 allele is relatively rare and 

may provide some protection against AD (but it 

may increase risk of early heart disease). APOE 

ε3 is the most common allele and appears to play 

a neutral role in AD. APOE ε4 occurs in about 

40 percent of all people with AD who develop 

the disease in later life; it increases the risk of 

developing AD.

Axon—the long extension from a neuron that 

transmits outgoing signals to other cells.

Beta-amyloid—a part of the amyloid precursor 

protein found in plaques, the insoluble deposits 

outside neurons.

Brain-derived neurotrophic factor 

(BDNF)—a growth factor that stimulates survival, 

growth, and adaptability of some neurons.

Brain stem—the portion of the brain that 

connects to the spinal cord and controls automatic 

body functions, such as breathing, heart rate, and 

blood pressure.

Capillary—a tiny blood vessel. The brain has 

billions of capillaries that carry oxygen, glucose 

(the brain’s principal source of energy), nutrients, 

and hormones to brain cells so they can do their 

work. Capillaries also carry away carbon dioxide 

and cell waste products. 

Cerebellum—the part of the brain 

responsible for maintaining the body’s balance 

and coordination.

Cerebral cortex—the outer layer of nerve cells 

surrounding the cerebral hemispheres.

Cerebral hemispheres—the largest 

portion of the brain, composed of billions of 

nerve cells in two structures connected by the 

corpus callosum. The cerebral hemispheres control 

conscious thought, language, decision making, 

emotions, movement, and sensory functions.

Glossary
ALZHE IMER’S D ISEASE Unraveling the Mystery 73

Neurofibrillary tangle—a filamentous 

collection of twisted and hyperphosphorylated tau

found in the cell body of a neuron in AD.

Neuron—a nerve cell.

Neurotransmitter—a chemical messenger 

between neurons. These substances are released by 

the axon on one neuron and excite or inhibit 

activity in a neighboring neuron.

Nucleus—the structure within a cell that 

contains the chromosomes and controls many 

of its activities.

Oxidative damage—damage that can occur 

to cells when they are exposed to too many free 

radicals. 

Positron emission tomography (PET)—

an imaging technique using radioisotopes that 

allows researchers to observe and measure activity 

in different parts of the brain by monitoring blood 

flow and concentrations of substances such as 

oxygen and glucose, as well as other specific 

constituents of brain tissues.

Single photon emission computed 

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 helps to maintain the 

structure of microtubules in normal nerve cells. 

Abnormal tau is a principal component of the 

paired helical filaments in neurofibrillary tangles.

Thalamus—a small structure in the front of the 

cerebral hemispheres that serves as a way station 

that receives sensory information of all kinds and 

relays it to the cortex; it also receives information 

from the cortex.

Transgenic—an animal that has had a gene 

(like human APP) inserted into its chromosomes. 

Mice carrying the mutated human APP gene often 

develop plaques in their brains as they age.

Ventricle—a cavity within the brain that is 

filled with cerebrospinal fluid.

Vesicle—a small container for transporting 

neurotransmitters and other molecules from one 

part of the neuron to another.

72 ALZHE IMER’S D ISEASE Unraveling the Mystery

Glial cell—a specialized cell that supports, 

protects, or nourishes nerve cells.

Hippocampus—a structure in the brain that 

plays a major role in learning and memory and is 

involved in converting short-term to long-term 

memory.

Hypothalamus—a structure in the brain 

under the thalamus that monitors activities such 

as body temperature and food intake.

Late-onset Alzheimer’s disease—the 

most common form of AD. It occurs in people 

aged 60 and older.

Limbic system—a brain region that links 

the brain stem with the higher reasoning elements 

of the cerebral cortex. It controls emotions, 

instinctive behavior, and the sense of smell.

Magnetic resonance imaging (MRI)—

a diagnostic and research technique that uses 

magnetic fields to generate a computer image of 

internal structures in the body. MRIs are very clear 

and are particularly good for imaging the brain 

and soft tissues.

Metabolism—all of the chemical processes 

that take place inside the body. In some metabolic 

reactions, complex molecules are broken down to 

release energy. In others, the cells use energy to 

make complex compounds out of simpler ones 

(like making proteins from amino acids).

Microtubule—an internal support structure for 

a neuron that guides nutrients and molecules from 

the body of the cell to the end of the axon.

Mild cognitive impairment (MCI)—

a condition in which a person has memory 

problems greater than those expected for his or 

her age, but not the personality or cognitive 

problems that characterize AD.

Mutation—a permanent change in a cell’s DNA 

that can cause a disease.

Myelin—a whitish, fatty layer surrounding 

an axon that helps the axon rapidly transmit 

electrical messages from the cell body to the 

synapse.

Nerve growth factor (NGF)—a substance 

that maintains the health of nerve cells. NGF also 

promotes the growth of axons and dendrites, the 

parts of the nerve cell that are essential to its ability 

to communicate with other nerve cells.

Neurodegenerative disease—a disease 

characterized by a progressive decline in the 

structure, activity, and function of brain tissue. 

These diseases include AD, Parkinson’s disease, 

frontotemporal lobar degeneration, and dementia 

with Lewy bodies. They are usually more 

common in older people.

Glossary
ALZHE IMER’S D ISEASE Unraveling the Mystery 75

CAREGIVING SUPPORT AND SERVICES

Children of Aging Parents 

P.O. Box 167

Richboro, PA 18954-0167

800-227-7294 (toll-free)

www.caps4caregivers.org

This nonprofit organization provides information 

and referrals for nursing homes, retirement 

communities, elder-law attorneys, adult day-care 

centers, insurance providers, respite care, assisted 

living centers, support groups, and State and 

county agencies. It also offers fact sheets, a newsletter, and conferences and workshops.

Eldercare Locator

800-677-1116 (toll-free)

www.eldercare.gov

Eldercare Locator is a nationwide, directoryassistance service helping older people and their 

caregivers locate local support and resources. It is 

funded by the U.S. Administration on Aging, whose 

website at www.aoa.gov also features AD information 

for families, caregivers, and health professionals.

Family Caregiver Alliance

180 Montgomery Street, Suite 1100

San Francisco, CA 94104

800-445-8106 (toll-free)

www.caregiver.org

The Family Caregiver Alliance is a nonprofit 

organization that offers support services and 

information for people caring for adults with 

AD, stroke, traumatic brain injuries, and 

other cognitive disorders. 

National Family 

Caregivers Association

10400 Connecticut Avenue, Suite 500

Kensington, MD 20895-3944

800-896-3650 (toll-free)

301-942-6430

www.thefamilycaregiver.org

The National Family Caregivers Association helps 

educate and support people who care for loved 

ones with chronic illness, disability, or the frailties 

of old age. The Association offers an online library 

of information and educational materials, workshops, and other resources.

National Hospice and 

Palliative Care Organization

1700 Diagonal Road, Suite 625 

Alexandria, VA 22314

800-658-8898 (toll-free) 

www.nhpco.org

This nonprofit organization works to enhance the 

quality of life for people who are terminally ill. It 

provides information, resources, and referrals to 

local hospice services, and offers publications and 

online resources.

Well Spouse Association 

63 West Main Street, Suite H

Freehold, NJ 07728

800-838-0879 (toll-free)

www.wellspouse.org

The nonprofit Well Spouse Association gives 

support to spouses and partners of people who are 

chronically ill and/or disabled. It offers support 

groups and a newsletter.

74 ALZHE IMER’S D ISEASE Unraveling the Mystery

INFORMATION AND 

SUPPORT RESOURCES

Alzheimer’s Disease Education 

and Referral (ADEAR) Center 

P.O. Box 8250

Silver Spring, MD 20907-8250

800-438-4380 (toll-free)

www.nia.nih.gov/Alzheimers

This service of the National Institute on Aging 

(NIA) offers information and publications on 

diagnosis, treatment, patient care, caregiver 

needs, long-term care, education and training, 

and research related to Alzheimer’s disease. Staff 

members answer telephone, email, and written 

requests and make referrals to local and national 

resources. The ADEAR website offers free, online 

publications in English and Spanish; email alerts 

and online Connections newsletter registration; 

an AD clinical trials database; the AD Library 

database; and more. 

Alzheimer’s Association

225 North Michigan Avenue, Suite 1700

Chicago, IL 60601-7633

800-272-3900 (toll-free)

www.alz.org

The Alzheimer’s Association is a national, 

non-profit organization with a network of 

local chapters that provide education and 

support for people diagnosed with AD, their 

families, and caregivers. Chapters offer 

referrals to local resources and services and sponsor support groups and educational programs. 

Online and print publications are also available. 

The Association also funds AD research.

Alzheimer’s Foundation of America

322 Eighth Avenue, 7th Floor

New York, NY 10001

866-232-8484 (toll-free)

www.alzfdn.org

The Alzheimer’s Foundation of America provides 

care and services to individuals confronting 

dementia and to their caregivers and families, 

through member organizations dedicated to 

improving quality of life. Services include a 

toll-free hotline, consumer publications and 

other educational materials, and conferences and 

workshops.

Dana Alliance for Brain Initiatives

745 Fifth Avenue, Suite 900

New York, NY 10151

212-223-4040

www.dana.org/danaalliances

The Dana Alliance for Brain Initiatives, a nonprofit organization of more than 265 leading 

neuroscientists, helps advance public awareness 

about the progress and promise of brain research 

and disseminates information about the brain.

More Information

For
ALZHE IMER’S D ISEASE Unraveling the Mystery 77

of AD and the available options for coping 

with and managing this illness. Sixteen chapters 

answer questions about topics such as the 

definition of AD and dementia, AD versus other 

causes of dementia, treatments for behavioral 

symptoms and other complications of AD, 

and practical issues for the patient and family. 

Illustrations, a glossary, and a list of resources 

are also included. 

Doraiswamy, P.M., & Gwyther, L., with Adler, 

T. The Alzheimer’s Action Plan: The Experts’ 

Guide to the Best Diagnosis and Treatment for 

Memory Problems. New York: St. Martin’s Press, 

2008.

This book, by a physician and social worker at 

Duke University, offers information about how to 

get an early and accurate AD diagnosis and why 

it matters, life after the diagnosis, state-of-the-art 

treatments, coping with behavioral and emotional 

changes through the early and middle stages of 

AD, accessing the latest clinical trials, and 

understanding the future of AD.

Kuhn, D., & Bennett, D.A. Alzheimer’s Early 

Stages: First Steps for Family, Friends and 

Caregivers, 2nd ed. Alameda, CA: Hunter House 

Publishers, 2003.

With increased awareness of the symptoms of AD 

and improved diagnostic techniques, more people 

are learning that they or a family member have a 

memory disorder. This book, written by experts 

at Rush University Alzheimer’s Disease Center in 

Chicago, helps readers understand and find ways 

to cope with the early stages of the disease. It also 

includes an extensive resource list of websites, 

organizations, and references to consumer and 

professional literature.

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

A Family Guide to Caring for People With 

Alzheimer’s Disease, Other Dementias, and 

Memory Loss in Later Life, 4th ed. Baltimore: 

Johns Hopkins University Press, 2006. 

This book offers guidance and comfort for families 

caring for loved ones with AD, other dementias, 

and memory loss in later life. The fourth edition 

includes chapters on topics such as getting 

medical help for the person with dementia, 

behavioral symptoms of dementia, nursing homes 

and other living arrangements, and research in 

dementia. New information discusses diagnostic 

evaluation, caregiver resources, legal and 

financial information, nursing homes and other 

communal living arrangements, and the latest 

updates on research, medications, and the 

biological causes and effects of dementia. 

Available in a large-print version. 

Messer, M. Pressure Points: Alzheimer’s and 

Anger. Durham, NC: Duke Family Support 

Program, 2000. Available for $12.50 from the 

ADEAR Center, P.O. Box 8250, Silver Spring, 

MD 20907-8250; 800-438-4380; www.nia.nih.

gov/Alzheimers.

In simple, easy-to-read language, this book 

addresses issues such as setting boundaries, 

managing anger positively, and risk factors for 

anger in AD care. It offers tangible action steps for 

responding appropriately, rather than abusively, 

76 ALZHE IMER’S D ISEASE Unraveling the Mystery

RESEARCH AND CLINICAL TRIALS

Alzheimer’s Disease Cooperative Study 

University of California, San Diego

9500 Gilman Drive 

La Jolla, CA 92093-0949

858-622-5880

www.adcs.org 

The Alzheimer’s Disease Cooperative Study 

(ADCS) is a cooperative agreement between NIA 

and the University of California, San Diego, to 

advance research in the development of drugs to 

treat AD. The ADCS is a consortium of medical 

research centers and clinics working to develop 

clinical trials of medicines to treat behavioral 

symptoms of AD, improve cognition, slow the rate 

of decline caused by AD, delay the onset of AD, 

or prevent the disease altogether. The ADCS also 

develops new and more reliable ways to evaluate 

patients enrolled in clinical trials.

Alzheimer Research Forum

www.alzforum.org

The Alzheimer Research Forum, an online community and resource center, offers professionals and 

the general public access to an annotated index of 

scientific papers, research news, moderated discussions on scientific topics, libraries of animal models 

and antibodies, and directories of clinical trials, 

conferences, jobs, and research-funding sources. 

ClinicalTrials.gov

www.ClinicalTrials.gov

ClinicalTrials.gov is a registry of federally and 

privately supported clinical trials conducted in the 

United States and around the world. Users can 

search for clinical trials and find information 

about each trial’s purpose, who may participate, 

locations, and phone numbers for more details.

RECOMMENDED READING

The ADEAR Center offers fact sheets; easy-toread materials; booklets about topics such as being 

diagnosed with early-stage AD, caregiving, home 

safety, and comfort and care at the end of life; 

and more. See the ADEAR Center listing under 

“Information and Support Resources” above for 

contact information. 

Consumers and professionals interested in AD also 

may wish to refer to the following materials: 

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

Shared Experiences in Coping. Durham, NC: 

The Duke Family Support Program, 1999. 

Available for $7 from the ADEAR Center, 

P.O. Box 8250, Silver Spring, MD 20907-8250; 

800-438-4380; www.nia.nih.gov/Alzheimers.

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.

Dash, P., & Villemarette-Pittman, N. Alzheimer’s 

Disease. New York: American Academy of 

Neurology, 2005.

This concise volume provides an overview of 

recent findings regarding the causes, diagnosis, and 

treatment of AD. It is designed to help caregivers 

and family members gain a better understanding 

More Information

For
ALZHE IMER’S D ISEASE Unraveling the Mystery 79

Restak, R. The Secret Life of the Brain. 

Washington, DC: Joseph Henry Press, 2001.

This companion to the PBS documentary takes 

the reader on a fascinating journey through the 

developing brain, from infancy and childhood 

through adulthood and old age. The author examines brain disorders and mechanisms of brain 

repair and healing.

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

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

2003.

An eloquent and moving description of AD, The 

Forgetting is an exploration of, and meditation on, 

the nature of memory and perceptions of self. It 

is a readable, accessible description of the history 

of AD, research, and the human impact of the 

disease. Calling AD a “death by a thousand 

subtractions,” the author describes the science 

of AD in clear and easy-to-understand terms. 

Snowdon, D. Aging With Grace: What the 

Nun Study Teaches Us About Leading Longer, 

Healthier, and More Meaningful Lives. New 

York: Random House, Inc., 2002. 

This book describes the participants and findings 

from the Nun Study, a long-term project examining aging and AD in a unique population of 678 

Catholic sisters. The nuns gave Dr. Snowdon 

access to their medical and personal records and 

agreed to donate their brains upon death. The 

book discusses the relationship of early linguistic 

ability to risk of AD, the association of stroke and 

depression with AD, and the role of heredity and 

lifestyle in healthy aging.

Tanzi, R.E., & Sisodia, S.S. Alzheimer’s Disease: 

Advances in Genetics, Molecular and Cellular 

Biology. New York: Springer Publishing Company, 

2006. 

This book examines every major aspect of AD—

clinical, epidemiologic, structural, chemical, 

genetic, molecular, and therapeutic. This edition 

includes expanded coverage of related dementing 

disorders, including prion diseases, Pick’s disease, 

frontotemporal disorders, an in-depth discussion 

of transgenic models, and the biochemistry 

of presenilins. It also discusses treatment of 

symptoms with therapeutic drugs and AD clinical trials. The broad coverage of AD in this book 

will be of special interest to clinicians, educators, 

investigators, and health administrators.

Uetz, D., & Lindsay, A. Into the Mist: 

When Someone You Love Has Alzheimer’s. 

Philadelphia: Xlibris Corporation, 2005.

This book combines information from 

researchers, experts, and families in a 

comprehensive guide for AD caregivers. It 

offers personal accounts of three families caring 

for a loved one from the earliest stages to the 

last stages, illustrating the commonalities and 

differences among AD patients and the ways their 

families handle the most difficult challenges. It 

also provides information to help families cope 

with the psychological aspects of AD, behavior 

problems, and communication difficulties. The 

book covers such topics as the stages of AD, 

Medicare, Medicaid, long-term care insurance, 

geriatric care management, the diagnosis of AD, 

causes and prevention, and drug treatments. 

78 ALZHE IMER’S D ISEASE Unraveling the Mystery

when feeling angry. Participants in Alzheimer’s 

support groups share helpful techniques and 

coping mechanisms, as well as enlightening 

anecdotes about caring for a loved one with AD. 

Caregivers, family members of AD patients, 

clergy, and health professionals all may benefit 

from this publication. Two companion 

booklets are also available from the ADEAR 

Center: “Hit Pause”: Helping Dementia Families 

Deal with Anger (for health professionals; $3.00) 

and Wait a Minute! When Anger Gets Too Much 

(for families and caregivers; $2.00).

Perry, G., ed., Alzheimer’s Disease: A Century 

of Scientific and Clinical Research. Journal of 

Alzheimer’s Disease, book edition, Fairfax, VA: IOS 

Press, Inc., 2006. 

This volume brings together the important 

discoveries in the AD field since the disease’s 

original description by Dr. Alois Alzheimer a 

century ago. It traces how the importance of AD 

as the major cause of late-life dementia came to 

light and narrates the evolution of the concepts 

related to AD throughout the years. Fifty papers 

are organized into sections on historical 

perspective, neuropathology, synaptic changes, 

amyloid, tau, disease mechanisms, genetics, and 

diagnosis and treatment. 

Petersen, R., ed. Mayo Clinic Guide to 

Alzheimer’s Disease: The Essential Resource for 

Treatment, Coping and Caregiving. Rochester, 

MN: Mayo Clinic Health Solutions, 2006. 

This guide is designed to help nonprofessionals 

understand dementia and its effects on the mind, 

the differences between dementia and changes 

associated with normal aging, and how to improve 

memory and maintain good mental function. It 

includes information about changes that occur in 

normal aging; the process of diagnosing dementia; 

non-AD forms of dementia; how AD develops, 

and AD stages, diagnosis, and treatment. New 

information about mild cognitive impairment, 

ways to stay mentally sharp, and research trends, 

along with an action guide for caregivers, are 

also included. 

More Information

For
80 ALZHE IMER’S D ISEASE Unraveling the Mystery

For additional copies of this 

report or further information about 

Alzheimer’s disease, please contact:

Alzheimer’s Disease Education 

and Referral (ADEAR) Center

P.O. Box 8250

Silver Spring, MD 20907-8250

Phone:

800-438-4380

Email:

adear@nia.nih.gov

Website:

www.nia.nih.gov/Alzheimers

Writer

Anne Brown Rodgers

Medical Illustrator

Stacy Jannis

Jannis Productions

3D Modeling

Bill Dempsey

Rebekah Fredenburg

Graphic Design

Fatima Ameen and Jeffrey Dever

Dever Designs

Project Coordinator 

Susan R. Farrer

JBS International, Inc.

Special Thanks 

NIA appreciates the extraordinary contributions 

of the following people to the vision and creation 

of this book:

Marcelle Morrison-Bogorad, Ph.D., and the staff 

of the NIA Division of Neuroscience

Patricia D. Lynch, former senior public affairs 

specialist, NIA Office of Communications and 

Public Liaison

David M. Burton, JBS International, Inc.

Photography

Front Cover – Doug Sanford, Photogroup

Inside front cover, page 8, 55 – Blend Images

Page 1 – Blend Stock

Pages 9, 19, 39, 61 – Photodisc 

Page 13 – Dynamic Graphics; scans on computer 

screen courtesy of William Jagust, M.D., University of 

California, Berkeley

Page 16 – Fancy Photography

Page 20 – Comstock

Page 28 – University of Pittsburgh

Page 33 – Cognitive Neurology and Alzheimer’s Disease 

Center, Northwestern University

Page 34, back cover – Thinkstock

Pages 36, 62 – Corbis

Page 43 – Berislav Zlokovic, M.D., Ph.D., University of 

Rochester, and Stacy Jannis, Jannis Productions

Page 45 – Pixland Stock

Page 46, inside back cover – Brand X Pictures

Page 51 – Jeff Miller, University of Wisconsin-Madison

Page 53 – Oregon Center for Aging and Technology, 

Oregon Health & Science University

Page 57 – Plainpicture Photography

Page 58 – Digital Vision

Page 64 – Alloy Photography

Page 66 – Marty Katz

Page 68 – Caregiver Technologies, Inc.

Page 69 – Flirt Photography

Page 78 – Stockbyte

Credits
U.S. Department of 

Health and Human Services

NIH Publication Number: 08-3782

September 2008