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Alzheimer’s Disease – Unraveling the Mystery and Home Safety
Table of Contents

1. Alzheimer’s Disease Unraveling the Mystery Pages 1-80

2. Home Safety for People with Alzheimer’s Disease Pages 1-40

Unraveling the Mystery
National Institute on Aging
National Institutes of HealthALZHEIMERS
Unraveling the Mysteryof
Table Contents
ver the past few lead agency for AD research at nizations around the world, and
decades, Alzheimer’s the National Institutes of Health many private-sector research, 4 INTRODUCTION p a r t 3
disease (AD) has (NIH). NIA launched its AD education, and advocacy groups,
4 AD: A Growing National Problem
O emerged from program in 1978, and since the study of AD is moving NEW ANSWERS
5 About This Book
obscurity. Once considered a then, the study of this disease ahead rapidly. This book explains
36 Looking for the Causes of AD
rare disorder, it is now seen as has become one of NIA’s top what AD is, describes the main
36 Genetic Factors at Work in AD
a major public health problem priorities. Several other NIH in- areas in which researchers are
40 Other Factors at Work in AD
that has a severe impact on mil- stitutes also conduct and sponsor working, and highlights new p a r t 1
lions of older Americans and studies on AD. approaches for helping families 48 New Techniques Help in Diagnosing AD
50 Exciting New Developments in
their families. The National Thanks to the work of NIH and friends care for people
10 Inside the Human Brain
AD Diagnosis
Institute on Aging (NIA) is the institutes, other research orga- with AD.
10 The Main Players
54 The Search for New Treatments
12 Other Crucial Parts
55 Helping People with AD Maintain Their
12 The Brain in Action
Mental Functioning
14 Neurons and Their Jobs
56 Managing Symptoms
Learn the Basics of the Healthy Brain Discover What Happens
14 Communication
57 Slowing, Delaying, or Preventing AD
to the Brain in AD
16 Metabolism
■ The parts of the brain (pages 10-13)
16 Repair
■ The hallmarks of AD (pages 21-26)
■ How neurons work (pages 14-16)
■ The changing brain in AD (pages 27-33)
■ The changing brain in healthy aging
17 The Changing Brain in Healthy Aging
p a r t 4
(pages 17-19)
Explore Cutting-Edge AD Research Learn about Caregiver Support
p a r t 2
64 Research Findings Benefit Caregivers
66 Early-Stage AD Support Groups:
■ Looking for causes (pages 36-47) ■ Who are AD caregivers? (page 63)
A Vital Source of Help
■ Diagnosing AD (pages 48-53) ■ Reducing the personal costs of caregiving
21 The Hallmarks of AD
■ Searching for treatments (pages 54-61) (pages 64-67)
21 Amyloid Plaques
■ Taking care of mom or dad from a distance
25 Neurofibrillary Tangles
(page 68)
26 Loss of Connection Between
Cells and Cell Death
27 The Changing Brain in AD
Visit NIA’s Alzheimer’s Disease Education and Referral Center website at www.nia.nih.gov/Alzheimers.
27 Preclinical AD 74 Information and Support Resources
There, you will find resources to accompany this book, such as downloadable versions of the illustrations
28 Very Early Signs and Symptoms
75 Caregiving Support and Services
and an animation that shows what happens to the changing brain in AD. And while you are there,
30 Mild AD 76 Research and Clinical Trials
explore the ADEAR Center’s many other offerings. These include free publications about AD and AD
31 Moderate AD 76 Recommended Reading
caregiving, clinical trials information, a list of NIA-funded Alzheimer’s Disease Centers, and NIA’s
31 Severe AD
searchable AD Library database of thousands of materials about AD.
2 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 3Introduction
“Never have I loved my husband of 41 years more than I do today....Though he may not know I’m his wife, disease like AD because the number of people begins many years, perhaps even decades,
with the disease doubles for every 5-year age before symptoms emerge. Discovering ways to
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 interval beyond age 65. identify AD in the earliest stages and halt or slow
content when I am with him, though I grieve for the loss of his smile, the sound of my name on his lips.” AD not only affects the people with the disease, its progress will benefit individuals, families, and
of course. The number of AD caregivers—and the Nation as a whole.
their needs—can be expected to rise rapidly as
his excerpt from Lessons Learned: Shared studying AD so that they can find ways to manage, the population ages and as the number of people ABOUT THIS BOOK
Experiences in Coping, by participants treat, and one day prevent this terrible disease. with AD grows. During their years of AD care- Thinking about AD leads to questions such as:
of the Duke University Alzheimer
giving, spouses, relatives, and friends experience What causes it? What can be done to cure it or
TSupport Groups, gives a glimpse into AD: A GROWING NATIONAL PROBLEM great emotional, physical, and financial challenges. prevent it? Will I get it? Scientists ask the same
what a person with Alzheimer’s disease (AD) and For many older adults and their families, AD As the disease runs its course and the abilities of types of questions, and this book describes their
a family caregiver might experience as the disease stands in the way of the “Golden Years.” It also
people with AD steadily decline, family members search for answers. It is written for people with
progresses. The gradual slipping away of mind presents a major problem for our health care system face difficult, and often costly, decisions about the AD, their family members and friends, caregivers,
and memory is frightening and frustrating, both and society as a whole. AD is the most common long-term care of their loved ones. and others interested in AD.
for the person with the disease and for family and cause of dementia among older people. Recent
The growing number of people with AD and This book has four sections:
friends, and can elicit strong feelings of love, grief, estimates of how many people in the United States the costs associated with the disease also put a
■ Part 1 gives readers some basics about the
anger, and exhaustion. currently have AD differ, with numbers ranging heavy economic burden on society. The national
healthy brain. Illustrations and text show what a
AD is an irreversible, progressive brain disease from 2.4 million to 4.5 million, depending on how
direct and indirect costs of caring for people with
healthy brain looks like and how it works.
that slowly destroys memory and thinking skills, AD is measured. But scientists agree that unless AD are estimated to be more than $100 billion a
■ Part 2 focuses on what happens in the brain
eventually even the ability to carry out the simplest the disease can be effectively treated or prevented, year. A 2004 study provided an equally sobering
during AD.
tasks. In most people with AD, symptoms first the numbers will increase significantly if current
picture of the impact of AD. It is estimated that
appear after age 60. AD is caused by a disease that population trends continue. if current AD trends continue, total Federal
affects the brain. In the absence of disease, the Our aging society makes AD an especially criti- Medicare spending to treat beneficiaries with the
Visit the National Institute on Aging
human brain often can function well into the cal issue. A 2005 Census Bureau report on aging disease will increase from $62 billion in 2000 to
(NIA) Alzheimer’s Disease Education
10th decade of life. in the United States notes that the population $189 billion in 2015.
and Referral (ADEAR) Center website
Not so long ago, we were not able to do age 65 and older is expected to double in size to For these reasons, AD is an urgent research
at www.nia.nih.gov/Alzheimers/ADvideo
much for people with AD. Today, that situation about 72 million people within the next 25 years. priority. We need to find ways to manage and treat
to view an animation that helps this part
is changing. Thousands of scientists, voluntary Moreover, the 85 and older age group is now the
AD because of its broad-reaching and devastating
of the book come alive.
organizations, and health care professionals are fastest growing segment of the population. This is impact. We now know that the disease process
all the more important for a neurodegenerative
See the glossary on page 70 for
definitions of boldfaced terms.
4 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 5Introduction
■ Part 3 talks about current research and the A book like this is possible only because of better at diagnosing it early and accurately. Most function in healthy older people and identified
advances that are bringing us closer to ways of the major progress that scientists throughout the important, we now have some promising leads on ways we might lessen normal age-related declines
managing and eventually defeating AD. world have made. Not long ago, we knew very possible treatments. Studies also are beginning in mental function. Most importantly, this accu-
■ Part 4 focuses on issues important to AD little about AD other than some facts about its to focus on preventive strategies by examining mulated research has increased our appreciation
caregivers and families, including current research major characteristics. Today, we are beginning lifestyle factors that might influence a person’s for just how complex AD is. It is now clear that
that is finding ways to improve caregiver support. to understand more about what AD is and who risk of developing AD. many scientific and clinical disciplines need to
gets it, how and why it develops, and what course Since the 1970s, research supported by work together to untangle the genetic, biological,
The end of the book includes a list of publica-
it follows. We are learning about the complex NIA and other organizations has deepened and environmental factors that, over many
tions and resources that people with AD, family
interface between AD and normal age-related our understanding of this devastating disease. years, set a person on a course that ultimately
members, and caregivers may find useful as they
changes in the brain. We also are getting much It also has expanded our knowledge of brain results in AD.
live day to day with the disease.
Then and Now: The Fast Pace of Developments in AD Research
s shown in this timeline, we have learned a lot since Dr. Alzheimer presented the case of his patient, Auguste D.
A The pace of research continues to accelerate as new findings open more and more doors to discovery.

19O6 196Os Scientists start to unravel the biological pathways
■ ■
Scientists discover a link between dementia and ■
Dr. Alois Alzheimer, a German neurologist and that lead to the development of beta-amyloid The FDA approves other AD drugs, including
® ®
psychiatrist, describes the case of a 51-year-old the number of plaques present in the brain. AD is plaques in the brain. rivastigmine (Exelon ), galantamine (Razadyne ),
® ®

woman, Auguste D., who had been admitted to recognized as a distinct disease, not a normal part Abnormal tau protein in tangles is identified.
donepezil (Aricept ), and memantine (Namenda )
of aging.
a hospital 5 years earlier with a cluster of unusual to treat symptoms of AD.

symptoms, including problems with comprehension 199Os Early work on an AD vaccine begins.
■ ■
and memory, an inability to speak, disorientation, 197Os The U.S. Food and Drug Administration (FDA)
Many new AD clinical trials, initiatives, and

Scientists find that levels of acetylcholine, a
behavioral problems, and hallucinations. After her approves tacrine (Cognex ), the first drug used to studies are launched, looking at a broad array of
death, Dr. Alzheimer examined her brain tissue and neurotransmitter important in memory formation, treat AD. This drug has since been replaced by translational, treatment, and prevention issues.

described two of the hallmarks of AD—numerous falls sharply in people with AD. This discovery is other medications.
New transgenic mouse models, including one

one of the first to link AD with biochemical changes
globs of sticky proteins in the spaces between Genetic mutations linked to early-onset and that develops both plaques and tangles, are
neurons (beta-amyloid plaques) and a tangled in the brain. late-onset AD are discovered. developed.
■ ■ ■
bundle of fibrils within neurons (neurofibrillary “Alzheimer’s disease” becomes a common term as The first transgenic mouse model of AD is Pittsburgh Compound B (PiB) is developed, allowing
recognition of AD as a major public health problem
tangles). created. researchers to “see” beta-amyloid plaques in the

grows. Additional diagnostic criteria are developed for AD. brains of living people.

■ ■
191Os – 194Os NIA is established. Characteristics of mild cognitive impairment are The growing sophistication of neuroimaging

Belief persists that “senile dementia” is a normal part described and defined.
techniques, genetics, memory and cognitive

of aging. 198Os NIA launches the Alzheimer’s Disease Education tests, structured interviews, and other technologies

Diagnostic criteria for AD are established. and Referral Center, AD Cooperative Study, and improve our ability to identify people at high

195Os Genetic links to early-onset AD begin to surface. other initiatives to conduct and support AD treatment
risk of AD.
■ ■
Congress mandates NIA as lead Federal agency
Scientists study the biological structure of plaques and prevention clinical trials.
and tangles. for AD research.
6 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 7o understand AD, it is important to
The Brain’s
know a bit about the brain. This part of
Vital Statistics
Unraveling the Mystery gives an inside
Tview of the normal brain, how it works,
and what happens during aging.
about 3 pounds
The brain is a remarkable organ. Seemingly
without effort, it allows us to carry out every
a medium cauliflower
element of our daily lives. It manages many body
functions, such as breathing, blood circulation,
and digestion, without our knowledge or
about 100,000,000,000 (100 billion)
direction. It also directs all the functions we carry
out consciously. We can speak, hear, see, move,
(the gaps between neurons)
remember, feel emotions, and make decisions
about 100,000,000,000,000 (100 trillion)
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 (tiny blood vessels)
about 400,000,000,000 (400 billion)
other cell types. Nerve cells also are called
neurons. The neurons of all animals function in
basically the same way, even though animals can
of the be very different from each other. Neurons survive the brain is only about 2 percent of the body’s
and function with the help and support of glial weight, it receives 20 percent of the body’s blood
cells, the other main type of cell in the brain. Glial supply. Billions of tiny blood vessels, or capillaries,
cells hold neurons in place, provide them with carry oxygen, glucose (the brain’s principal source
nutrients, rid the brain of damaged cells and other of energy), nutrients, and hormones to brain cells
cellular debris, and provide insulation to neurons so they can do their work. Capillaries also carry
in the brain and spinal cord. In fact, the brain away waste products.
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
ALZHEIMER’S DISEASE Unraveling the Mystery 9P A R T The Basics of the Healthy Brain
Inside the
Human Brain
he brain has many parts, each of which ■ The occipital lobe, which is at the back of the
is responsible for particular functions. brain, is concerned with vision.
The following section describes a few ■ The temporal lobe, which runs along the
Tkey structures and what they do. side of the brain under the frontal and pari-
etal lobes, deals with the senses of smell, taste,
THE MAIN PLAYERS and sound, and the formation and storage of
■ Two cerebral hemispheres account for 85 per- memories.
cent of the brain’s weight. The billions of neurons
■ The cerebellum sits above the brain stem and
in the two hemispheres are connected by thick
beneath the occipital lobe. It takes up a little more
bundles of nerve cell fibers called the corpus cal-
than 10 percent of the brain. This part of the
losum. Scientists now think that the two hemi-
brain plays roles in balance and coordination. The
spheres differ not so much in what they do (the
cerebellum has two hemispheres, which receive
“logical versus artistic” notion), but in how they
information from the eyes, ears, and muscles and
process information. The left hemisphere appears
to focus on details (such as recognizing a particular
face in a crowd). The right hemisphere focuses on
Front View of the Brain
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, Side View of the Brain
and movement.
This illustration shows a three-dimensional side
■ The parietal lobe, which sits behind the
view of one of two cerebral hemispheres of the brain.
frontal lobe, deals with the perception and
To help visualize this, imagine looking at the cut side
integration of stimuli from the senses. 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)
10 ALZHEIMER’S DISEASE Unraveling the Mystery and the brain stem.P A R T The Basics of the Healthy Brain
joints about the body’s movements and position. ■ The hippocampus, which is buried in the
Once the cerebellum processes that information, it temporal lobe, is important for learning and
sends instructions to the body through the rest of short-term memory. This part of the brain is
the brain and spinal cord. The cerebellum’s work thought to be the site where short-term
allows us to move smoothly, maintain our balance, memories are converted into long-term
and turn around without even thinking about it. It memories for storage in other brain areas.
also is involved with motor learning and remem- ■ The thalamus, located at the top of the brain
bering how to do things like drive a car or write stem, receives sensory and limbic information,
your name. processes it, and then sends it to the cerebral
■ The brain stem sits at the base of the brain. It cortex.
connects the spinal cord with the rest of the brain. ■ The hypothalamus, a structure under
Even though it is the smallest of the three main the thalamus, monitors activities such as body
players, its functions are crucial to survival. The temperature and food intake. It issues instructions
brain stem controls the functions that happen to correct any imbalances. The hypothalamus also
automatically to keep us alive—our heart rate, controls the body’s internal clock.
blood pressure, and breathing. It also relays
information between the brain and the spinal THE BRAIN IN ACTION
cord, which then sends out messages to the Sophisticated brain-imaging techniques allow
muscles, skin, and other organs. Sleep and scientists to monitor brain function in living
dreaming are also controlled by the brain stem. people and to see how various parts of the brain
are used for different kinds of tasks. This is
OTHER CRUCIAL PARTS opening up worlds of knowledge about brain
Several other essential parts of the brain lie deep function and how it changes with age or disease.
inside the cerebral hemispheres in a network of One of these imaging techniques is called
structures called the limbic system. The limbic positron emission tomography, or PET
system links the brain stem with the higher scanning. Some PET scans measure blood
reasoning elements of the cerebral cortex. It plays flow and glucose metabolism throughout the
a key role in developing and carrying out instinc- brain. (For more on metabolism, see page 16.)
tive behaviors and emotions and also is impor- During a PET scan, a small amount of a radioac- In essence, a PET scan produces a “map” of serotonin. (To learn about exciting developments
tant in perceiving smells and linking them with tive substance is attached to a compound, such the active brain. using one new tracer, see PiB and PET on page
memory, emotion, and instinctive behaviors. The as glucose, and injected into the bloodstream. Scientists can use PET scans to see what hap- 28.) Some of these neurotransmitters are changed
limbic system includes: This tracer substance eventually goes to the brain.
pens in the brain when a person is engaged in with age, disease, and drug therapies.
When nerve cells in a region of the brain become a physical or mental activity, at rest, or even
■ The amygdala, an almond-shaped structure
active, blood flow and glucose metabolism in while sleeping or dreaming. Certain tracers can
involved in processing and remembering strong
that region increase. When colored to reflect track the activity of brain chemicals, for example
emotions such as fear. It is located in the temporal
metabolic activity, increases usually look red neurotransmitters such as dopamine and
lobe just in front of the hippocampus.
and yellow. Shades of blue and black indicate
decreased or no activity within a brain region.
12 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 13P A R T The Basics of the Healthy Brain
Neurons in the Brain
and Their
he human brain is made up of billions to survive and stay healthy. These processes are
of neurons. Each has a cell body, communication, metabolism, and repair.
an axon, and many dendrites. The
Tcell body contains a nucleus, which COMMUNICATION
controls much of the cell’s activities. The cell Imagine the many miles of fiber-optic cables that
body also contains other structures, called run under our streets. Day and night, millions of
organelles, that perform specific tasks. televised and telephonic messages flash at incredible
The axon, which is much narrower than the speeds, letting people strike deals, give instructions,
width of a human hair, extends out from the cell share a laugh, or learn some news. Miniaturize it,
body. Axons transmit messages from neuron to multiply it many-fold, make it much more complex,
neuron. Sometimes, signal transmissions—like and you have the brain. Neurons are the great com-
those from head to toe—have to travel over very municators, always in touch with their neighbors.
long distances. Axons are covered with an insulat- Neurons communicate with each other through
ing layer called myelin (also called white matter their axons and dendrites. When a dendrite re-
because of its whitish color). Myelin, which is ceives an incoming signal (electrical or chemical),
made by a particular kind of glial cell, increases an “action potential,” or nerve impulse, can be
the speed of nerve signal transmissions through generated in the cell body. The action potential
the brain. travels to the end of the axon and once there, the
Dendrites also branch out from the cell body. passage of either electrical current or, more
They receive messages from the axons of other typically, the release of chemical messengers,
neurons. Each neuron is connected to thousands called neurotransmitters, can be triggered. The
of other nerve cells through its axon and dendrites. neurotransmitters are released from the axon
Groups of neurons in the brain have special terminal and move across a tiny gap, or synapse,
jobs. For example, some are involved with to specific receptor sites on the receiving, or post-
thinking, learning, and memory. Others are synaptic, end of dendrites of nearby neurons. A
responsible for receiving information from the typical neuron has thousands of synaptic connec-
sensory organs (such as the eyes and ears) or the tions, mostly on its many dendrites, with other
skin. Still others communicate with muscles, neurons. Cell bodies also have receptor sites for
stimulating them into action. neurotransmitters.
Several processes all have to work smoothly
together for neurons, and the whole organism,
14 ALZHEIMER’S DISEASE Unraveling the MysteryP A R T The Basics of the Healthy Brain
Once the post-synaptic receptors are activated,
they open channels through the cell membrane All cells break down chemicals and nutrients to
into the receiving nerve cell’s interior or start other generate energy and form building blocks that
make new cellular molecules such as proteins.
processes that determine what the receiving nerve
Changing Brain
cell will do. Some neurotransmitters inhibit nerve This process is called metabolism. To maintain
cell function (that is, they make it less likely that metabolism, the brain needs plenty of blood
constantly circulating through its billions of
the nerve cell will send an electrical signal down
its axon). Other neurotransmitters stimulate nerve capillaries to supply neurons and other brain
cells, priming the receiving cell to become active cells with oxygen and glucose. Without oxygen
or send an electrical signal down the axon to more and glucose, neurons will quickly die.
neurons in the pathway. A neuron receives signals n the past several decades, investigators have ■ In some people, structures called plaques and
from many other neurons simultaneously, and the REPAIR learned much about what happens in the tangles develop outside of and inside neurons,
sum of a neuron’s neurotransmitter inputs at any Nerve cells are formed during fetal life and for a brain when people have a neurodegenerative respectively, although in much smaller amounts
short time after birth. Unlike most cells, which
one instant will determine whether it sends a sig- Idisease such as Parkinson’s disease, AD, or than in AD (see The Hallmarks of AD on page 21
nal down its axon to activate or inhibit the action have a fairly short lifespan, neurons in the brain other dementias. Their findings also have revealed for more information on plaques and tangles).
of other neighboring neurons. live a long time. These cells can live for up to 100 much about what happens during healthy aging. ■ Damage by free radicals increases (free radicals
years or longer. To stay healthy, living neurons
During any one moment, millions of these sig- Researchers are investigating a number of changes are a kind of molecule that reacts easily with other
nals are speeding through pathways in the brain, must constantly maintain and repair themselves. related to healthy aging in hopes of learning more molecules; see The Aging Process on page 42 for
allowing the brain to receive and process informa- In an adult, when neurons die because of disease about this process so they can fill gaps in our more on these molecules).
or injury, they are not usually replaced. Research,
tion, make adjustments, and send out instructions knowledge about the early stages of AD. ■ Inflammation increases (inflammation is the
to various parts of the body. however, shows that in a few brain regions, new As a person gets older, changes occur in all parts complex process that occurs when the body
neurons can be generated, even in the old brain. of the body, including the brain: responds to an injury, disease, or abnormal
■ Certain parts of the brain shrink, especially
the prefrontal cortex (an area at the front of the What effects does aging have on mental
frontal lobe) and the hippocampus. Both areas function in healthy older people? Some people
are important to learning, memory, planning, and may notice a modest decline in their ability to
other complex mental activities. learn new things and retrieve information, such
■ Changes in neurons and neurotransmitters as remembering names. They may perform worse
affect communication between neurons. In certain on complex tasks of attention, learning, and
brain regions, communication between neurons memory than would a younger person. However,
can be reduced because white matter (myelin- if given enough time to perform the task, the
covered axons) is degraded or lost. scores of healthy people in their 70s and 80s are
■ Changes in the brain’s blood vessels occur. often similar to those of young adults. In fact, as
Blood flow can be reduced because arteries narrow they age, adults often improve in other cognitive
and less growth of new capillaries occurs. areas, such as vocabulary and other forms of verbal
It also appears that additional brain regions can
be activated in older adults during cognitive tasks,
ALZHEIMER’S DISEASE Unraveling the Mystery 17P A R T The Basics of the Healthy Brain
such as taking a memory test. Researchers do not and unique mix of genetics, environment, and life
ACTIVE Study May Provide Clues to Help Older Adults Stay Mentally Sharp
fully understand why this happens, but one idea is experiences, the balance may tip in favor of a dis-
that the brain engages mechanisms to compensate ease process that will ultimately lead to dementia.
for difficulties that certain regions may be having. For another person, with a different reserve and he phrase “use it or lose it” may make you think ■ After 5 years, people in each group performed
For example, the brain may recruit alternate brain a different mix of genetics, environment, and life Tof your muscles, but scientists who study brain better on tests in their respective areas of training
networks in order to perform a task. These find- experiences, the balance may result in no apparent health in older people have found that it may apply than did people in the control group. The reasoning
ings have led many scientists to believe that major decline in cognitive function with age. to cognitive skills as well. In 2006, scientists funded and processing-speed groups who received booster
declines in mental abilities are not inevitable as Scientists are increasingly interested in the by NIA and the National Institute of Nursing Research training had the greatest benefit.
people age. Growing evidence of the adaptive influence of all these factors on brain health, and completed a study of cognitive training in older adults. The researchers also looked at the training’s effects
(what scientists call “plastic”) capabilities of the studies are revealing some clues about actions This study, the Advanced Cognitive Training for Inde- on participants’ everyday lives. After 5 years, all three
older brain provide hope that people may be able people can take that may help preserve healthy pendent and Vital Elderly (ACTIVE) study, was the first groups who recieved training reported less difficulty
to do things to sustain good brain function as brain aging. Fortunately, these actions also benefit randomized controlled trial to demonstrate long-lasting, than the control group in tasks such as preparing
they age. A variety of interacting factors, such as a person’s overall health. They include: positive effects of brief cognitive training in older adults. meals, managing money, and doing housework.
lifestyle, overall health, environment, and genetics The ACTIVE study included 2,802 healthy adults However, these results were statistically significant for
■ Controlling risk factors for chronic disease,
also may play a role. age 65 and older who were living independently. only the group that had the reasoning training.
such as heart disease and diabetes (for example,
Another question that scientists are asking Participants were randomly assigned to four groups. As they get older, many people worry about their
keeping blood cholesterol and blood pressure at
is why some people remain cognitively healthy Three groups took part in up to 10 computer-based mental skills getting “rusty.” The ACTIVE study offers
healthy levels and maintaining a healthy weight)
as they get older while others develop cognitive training sessions that targeted a specific cognitive hope that cognitive training may be useful because it
■ Enjoying regular exercise and physical activity
impairment or dementia. The concept of ability—memory, reasoning, and speed of processing showed that relatively brief and targeted cognitive
■ Eating a healthy diet that includes plenty of
“cognitive reserve” may provide some insights. (in other words, how fast participants could respond exercises can produce lasting improvements in the
vegetables and fruits
Cognitive reserve refers to the brain’s ability to to prompts on a computer screen). The fourth group skills taught. Next steps for researchers are to deter-
■ Engaging in intellectually stimulating activities
operate effectively even when some function is (the control group) received no cognitive training. Sixty mine ways to generalize the training benefits beyond
and maintaining close social ties with family,
disrupted. It also refers to the amount of damage percent of those who completed the initial training also the specific skills taught in ACTIVE and to find out
friends, and community
that the brain can sustain before changes in took part in 75-minute “booster” sessions 11 months whether cognitive training programs could prevent,
cognition are evident. People vary in the cognitive Vascular Disease on page 43 and Lifestyle later. These sessions were designed to maintain delay, or diminish the effects of AD.
reserve they have, and this variability may be Factors on page 45 provide more information improvements gained from the initial training.
because of differences in genetics, education, about these issues and how they may influence the The investigators tested the participants at the
occupation, lifestyle, leisure activities, or other life risk of developing AD. beginning of the study, after the initial training and booster
experiences. These factors could provide a certain sessions, and once a year for 5 more years. They found
amount of tolerance and ability to adapt to change that the improvements from the training roughly counter-
and damage that occurs during aging. At some acted the degree of decline in cognitive performance
point, depending on a person’s cognitive reserve
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.
18 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 19The
lzheimer’s disease disrupts critical metabolic
processes that keep neurons healthy. These Amyloid plaques are found in the spaces between
disruptions cause nerve cells in the brain the brain’s nerve cells. They were first described
by Dr. Alois Alzheimer in 1906. Plaques consist
A to stop working, lose connections with
other nerve cells, and finally die. The destruction of largely insoluble deposits of an apparently toxic
and death of nerve cells causes the memory failure, protein peptide, or fragment, called beta-amyloid.
We now know that some people develop
personality changes, problems in carrying out
daily activities, and other features of the disease. some plaques in their brain tissue as they age.
The brains of people with AD have an abundance However, the AD brain has many more plaques
What Happens
in particular brain regions. We still do not know
of two abnormal structures—amyloid plaques
and neurofibrillary tangles—that are made of whether amyloid plaques themselves cause AD or
misfolded proteins (see Protein Misfolding on whether they are a by-product of the AD process.
to the
We do know that genetic mutations can increase
page 41 for more information). This is especially
true in certain regions of the brain that are production of beta-amyloid and can cause rare,
important in memory. inherited forms of AD (see Genes and Early-
The third main feature of AD is the loss of Onset Alzheimer’s Disease on page 38 for
connections between cells. This leads to dimin- more on inherited AD).
ished cell function and cell death.
To view a video showing what happens to
the brain in AD, go to www.nia.nih.gov/
ALZHEIMER’S DISEASE Unraveling the Mystery 21P A R T What Happens to the Brain in AD
From APP to Beta-Amyloid Plaques
myloid precursor protein (APP), the starting the APP molecule at one
From APP to Beta-Amyloid Plaque
A point for amyloid plaques, is one of many proteins end of the beta-amyloid
peptide, releasing sAPP β
associated with the cell membrane, the barrier that
encloses the cell. As it is being made inside the cell, from the cell (Figure 3).
APP becomes embedded in the membrane, like a tooth- Gamma-secretase then
cuts the resulting APP
pick stuck through the skin of an orange (Figure 1).
In a number of cell com- fragment, still tethered in
Figure 3
partments, including the the neuron’s membrane,
outermost cell membrane, at the other end of the
specific enzymes snip, or beta-amyloid peptide.
cleave, APP into discrete Following the cleavages
fragments. In 1999 and at each end, the beta-
2000, scientists identified amyloid peptide is
Figure 1
the enzymes responsible released into the space
for cleaving APP. These enzymes are called alpha- outside the neuron and
Figure 4
secretase, beta-secretase, and gamma-secretase. begins to stick to other
In a major breakthrough, scientists then discovered beta-amyloid peptides (Figure 4). These small,
that, depending on which enzyme is involved and soluble aggregates of two, three, four, or even
up to a dozen beta-amyloid peptides are called
the segment of APP where the cleaving occurs, APP
processing can follow one of two pathways that oligomers. Specific sizes of oligomers may
have very different consequences for the cell. be responsible for reacting with receptors on
neighboring cells and synapses, affecting their
In the benign pathway, alpha-secretase cleaves the
APP molecule within the portion that has the potential to ability to function.
become beta-amyloid. This eliminates the production of It is likely that some oligomers are cleared from
the brain. Those that cannot be cleared clump
the beta-amyloid peptide and the potential for plaque
buildup. The cleavage releases from the neuron a frag- together with more beta-amyloid peptides. As the
ment called sAPP α, which has beneficial properties, process continues, oligomers grow larger, becoming
entities called protofibrils and fibrils. Eventually, other
such as promoting neuronal growth and survival. The
remaining APP fragment, still tethered in the neuron’s proteins and cellular material are added, and these
membrane, is then cleaved by gamma-secretase at increasingly insoluble entities combine to become the
well-known plaques that are characteristic of AD.
the end of the beta-amyloid segment. The smaller of
the resulting fragments also is released into the space For many years, scientists thought that plaques
outside the neuron, while might cause all of the damage to neurons that is seen
the larger fragment remains in AD. However, that concept has evolved greatly
within the neuron and in the past few years. Many scientists now think that
interacts with factors in the oligomers may be a major culprit. Many scientists
nucleus (Figure 2). also think that plaques actually may be a late-stage
In the harmful pathway, attempt by the brain to get this harmful beta-amyloid
beta-secretase first cleaves away from neurons.
Figure 2
22 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 23P A R T What Happens to the Brain in AD
Healthy and Diseased Neurons
Inside a
Healthy Neuron
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 neurotransmitter-
containing 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
Inside a Diseased Neuron
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, collaps-
ing the neuron’s internal transport
network. This collapse damages
the ability of neurons to com-
municate with each other.
Formation of T au Tangles
2 24 4 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 2 25 5P A R T What Happens to the Brain in AD
LOSS OF CONNECTION BETWEEN The AD process not only inhibits communi-
CELLS AND CELL DEATH cation between neurons but can also damage
Changing Brain
The third major feature of AD is the gradual
neurons to the point that they cannot function
loss of connections between neurons. Neurons properly and eventually die. As neurons die
live to communicate with each other, and this throughout the brain, affected regions begin to in
vital function takes place at the synapse. Since
shrink in a process called brain atrophy. By the
the 1980s, new knowledge about plaques and final stage of AD, damage is widespread, and
tangles has provided important insights into brain tissue has shrunk significantly.
their possible damage to synapses and on the o one knows exactly what starts severity of cognitive problems at diagnosis.
development of AD. the AD process or why some of the Although the course of the disease is not the same
normal changes associated with in every person with AD, symptoms seem to
Naging become so much more extreme develop over the same general stages.
Loss of Connection
and destructive in people with the disease. We
Between Cells
know a lot, however, about what happens in the PRECLINICAL AD
brain once AD takes hold and about the physical AD begins deep in the brain, in the entorhinal
This illustration shows
the damage caused by AD:
and mental changes that occur over time. The cortex, a brain region that is near the hippocampus
plaques, tangles, and the
time from diagnosis to death varies—as little as and has direct connections to it. Healthy neurons
loss of connection between
3 or 4 years if the person is older than 80 when in this region begin to work less efficiently, lose
diagnosed to as long as 10 or more years if the their ability to communicate, and ultimately die.
person is younger. Several other factors besides This process gradually spreads to the hippocam-
age also affect how long a person will live with pus, the brain region that plays a major role in
AD. These factors include the person’s sex, learning and is involved in converting short-term
the presence of other health problems, and the memories to long-term memories. Affected
regions begin to atrophy. Ventricles, the fluid-
filled spaces inside the brain, begin to enlarge
Preclinical AD
as the process continues.
Scientists believe that these brain changes
begin 10 to 20 years before any clinically
detectable signs or symptoms of forgetful-
ness 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
26 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 27P A R T What Happens to the Brain in AD
PiB and PET Charting the Course from Healthy Aging to AD
magine being able to see deep inside the brain tissue of his chart shows cur-
Amnestic MCI: Cognitive
Ia living person. If you could do that, you could find out Trent thinking about the
AD brain memory problems; decline
whether the AD process was happening many years before evolution from healthy aging
changes start
other cognitive accelerates
symptoms were evident. This knowledge could have a to AD. Researchers view it as decades before functions OK; after AD
symptoms brain compensates diagnosis
profound impact on improving early diagnosis, monitoring a series of events that occur
show for changes
disease progression, and tracking response to treatment. in the brain over many years.
Scientists have stepped closer to this possibility with the This gradual process, which
development of a radiolabeled compound called Pittsburgh results from the combination of
Compound B (PiB). PiB binds to beta-amyloid plaques in the biological, genetic, environ- Normal age-related
memory loss
brain and it can be imaged using PET scans. Initial studies mental, and lifestyle factors,
showed that people with AD take up more PiB in their brains eventually sets some people
Total loss of
than do cognitively healthy older people. Since then, scien- on a course to MCI and
tists have found high levels of PiB in some cognitively healthy possibly AD. Other people,
people, suggesting that the damage from beta-amyloid may In this PET scan, the red and yellow colors whose genetic makeup may
already be underway. The next step will be to follow these indicate that PiB uptake is higher in the brain be the same or different and
Birth 40 60 80 Death
of the person with AD than in the cognitively
cognitively healthy people who have high PiB levels to see who experience a different
Life Course
whether they do, in fact, develop AD over time. healthy person. combination of factors over a
lifetime, continue on a course
Healthy Aging Amnestic MCI Clinically Diagnosed AD
of healthy cognitive aging.
develop drugs or other treatments that will to a substance, the presence of a disease, or the
slow or stop the disease process before significant progression over time of a disease. For example,
impairment occurs (see The Search for New high blood cholesterol is a biomarker for risk of a much higher percentage of them go on to de- AD (see Genetic Factors at Work in AD on
Treatments on page 54 for more information). heart disease. Such tools are critical to helping velop AD than do people without these memory page 36 for more information). And, they have
scientists detect and understand the very early problems. About 8 of every 10 people who fit found that different brain regions appear to
VERY EARLY SIGNS AND SYMPTOMS signs and symptoms of AD. the definition of amnestic MCI go on to develop be activated during certain mental activities in
At some point, the damage occurring in the brain AD within 7 years. In contrast, 1 to 3 percent of cognitively healthy people and those with MCI.
begins to show itself in very early clinical signs and Mild Cognitive Impairment people older than 65 who have normal cognition These changes appear to be related to the early
symptoms. Much research is being done to identify As some people grow older, they develop memory will develop AD in any one year. stages of cognitive impairment.
these early changes, which may be useful in problems greater than those expected for their age. However, researchers are not yet able to say
predicting dementia or AD. An important part of But they do not experience the personality changes definitively why some people with amnestic MCI Other Signs of Early AD Development
this research effort is the development of increas- or other problems that are characteristic of AD. do not progress to AD, nor can they say who As scientists have sharpened their focus on the
ingly sophisticated neuroimaging techniques (see These people may have a condition called mild will or will not go on to develop AD. This raises early stages of AD, they have begun to see hints of
Exciting New Developments in AD Diagnosis cognitive impairment (MCI). MCI has several pressing questions, such as: In cases when MCI other changes that may signal a developing disease
on page 50 for more on neuroimaging) and the use subtypes. The type most associated with memory progresses to AD, what was happening in the brain process. For example, in the Religious Orders Study,
of biomarkers. Biomarkers are indicators, such as loss is called amnestic MCI. People with MCI are that made that transition possible? Can MCI be a large AD research effort that involves older nuns,
changes in sensory abilities, or substances that ap- a critically important group for research because prevented or its progress to AD delayed? priests, and religious brothers, investigators have
pear in body fluids, such as blood, cerebrospinal Scientists also have found that genetic
fluid, or urine. Biomarkers can indicate exposure factors may play a role in MCI, as they do in
28 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 29P A R T What Happens to the Brain in AD
Mild to Moderate AD
explored whether changes in older adults’ ability to Accepting these signs as something other than ■ Hallucinations, delusions, suspiciousness or
move about and use their bodies might be a sign of normal and deciding to go for diagnostic tests can paranoia, irritability
early AD. The researchers found that participants be a big hurdle for people and families. Once this ■ Loss of impulse control (shown through
with MCI had more movement difficulties than the hurdle is overcome, many families are relieved to undressing at inappropriate times or places
cognitively healthy participants but less than those know what is causing the problems. They also can or vulgar language)
with AD. Moreover, those with MCI who had lots take comfort in the fact that despite a diagnosis ■ An inability to carry out activities that involve
of trouble moving their legs and feet were more of MCI or early AD, a person can still make multiple steps in sequence, such as dressing,
than twice as likely to develop AD as those with meaningful contributions to his or her family making a pot of coffee, or setting the table
good lower body function. and to society for a time.
Behavior is the result of complex brain
It is not yet clear why people with MCI might
processes, all of which take place in a fraction of
have these motor function problems, but the MODERATE AD
a second in the healthy brain. In AD, many of
scientists who conducted the study speculate that By this stage, AD damage has spread to the areas
those processes are disturbed, and these disrupted
they may be a sign that damage to blood vessels in of the cerebral cortex that control language,
communications between neurons are the basis
the brain or damage from AD is accumulating in reasoning, sensory processing, and conscious
for many distressing or inappropriate behaviors.
areas of the brain responsible for motor function. thought. Affected regions continue to shrink,
For example, a person may angrily refuse to take
If further research shows that some people with ventricles enlarge, and signs and symptoms of the
a bath or get dressed because he does not under-
MCI do have motor function problems in addi- disease become more pronounced and widespread.
stand what his caregiver has asked him to do. If
tion to memory problems, the degree of difficulty, As AD spreads through the brain, the number of Behavioral problems, such as wandering and
he does understand, he may not remember how
especially with walking, may help identify those at plaques and tangles grows, shrinkage progresses, agitation, can occur. More intensive supervision
to do it. The anger can be a mask for his confu-
and more and more of the cerebral cortex is
risk of progressing to AD. and care become necessary, which can be
sion and anxiety. Or, a person with AD may
Other scientists have focused on changes in affected. Memory loss continues and changes difficult for many spouses and families. The
constantly follow her husband or caregiver and
sensory abilities as possible indicators of early in other cognitive abilities begin to emerge. The symptoms of this stage can include:
fret when the person is out of sight. To a person
clinical diagnosis of AD is usually made during
cognitive problems. For example, in one study they
■ Increasing memory loss and confusion who cannot remember the past or anticipate the
found associations between a decline in the ability this stage. Signs of mild AD can include:
■ Shortened attention span future, the world can be strange and frightening.
to detect odors and cognitive problems or dementia.
■ Memory loss ■ Inappropriate outbursts of anger Sticking close to a trusted and familiar caregiver
These findings are tentative, but they are
■ Confusion about the location of familiar places
■ Problems recognizing friends and family members may be the only thing that makes sense and
promising because they suggest that, some day, it
(getting lost begins to occur) ■ Difficulty with language and problems with provides security.
may be possible to develop ways to improve early
■ Taking longer than before to accomplish reading, writing, and working with numbers
detection of MCI or AD. These tools also will help
normal daily tasks
■ Difficulty organizing thoughts and thinking SEVERE AD
scientists answer questions about causes and very
■ Trouble handling money and paying bills logically In the last stage of AD, plaques and tangles are
early development of AD, track changes in brain
■ Poor judgment leading to bad decisions ■ Inability to learn new things or to cope with widespread throughout the brain, most areas of
and cognitive function over time, and ultimately
■ Loss of spontaneity and sense of initiative
new or unexpected situations the brain have shrunk further, and ventricles have
track a person’s response to treatment for AD.
■ Mood and personality changes, increased ■ Restlessness, agitation, anxiety, tearfulness, enlarged even more. People with AD cannot
anxiety and/or aggression wandering—especially in the late afternoon or recognize family and loved ones or communicate
at night in any way. They are completely dependent on
In mild AD, a person may seem to be healthy
■ Repetitive statements or movement, occasional others for care. Other symptoms can include:
but is actually having more and more trouble
muscle twitches
making sense of the world around him or her. The ■ Weight loss
realization that something is wrong often comes
■ Seizures
gradually to the person and his or her family. ■ Skin infections
■ Difficulty swallowing
30 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 31P A R T What Happens to the Brain in AD
AD Spreads Through the Brain
■ Groaning, moaning, or grunting
The Buddy Program at Northwestern University
■ Increased sleeping
■ Lack of bladder and bowel control
he medical school curriculum
The Buddy Program at Northwestern University
Near the end, the person may be in bed much or Tdemands that students spend
all of the time. The most frequent cause of death for enormous amounts of time in the
people with AD is aspiration pneumonia. This type classroom and clinic learning the
of pneumonia develops when a person is not able to information and skills necessary
swallow properly and takes food or liquids into the for a career in medicine. How-
lungs instead of air. ever, little or no time is set aside
for students to be with patients
outside the hospital or clinic
Severe AD
setting. As a result, it is hard for
medical students to get to know
the human side of the diseases
they are learning about.
The Buddy Program pairs medical students and people with AD
A program at Northwestern
to spend time with—and learn from—each other.
University’s Cognitive Neurology
and Alzheimer’s Disease Center museums, exercising together, or hands-on way to learn about AD
is adding just that element to its even just sharing a coffee or a and related dementias, and it
medical education. The Buddy meal. The students also are able helps him or her understand the
Program, begun in 1998, to observe their buddies’ clinical daily realities and issues involved
matches first-year medical evaluations at the Center. Other in caring for and supporting
students with people diagnosed medical schools have started people with AD and their
with AD or another form of similar programs. families. It also introduces them
dementia. About 10 to 15 The people with AD and to the career path of research
medical students participate their families are selected from and clinical practice in AD and
every year. They first take a Northwestern’s Alzheimer’s related dementias. For the person
3-hour orientation course on AD, Disease Center and other with AD, participation in the
family issues, and communication related programs at the university. program provides an opportunity
skills. Then, for the next year, they Families are contacted about for friendship and socializing
spend at least 4 hours a month participating, and the people and an outlet for sharing their
with a person with dementia in with AD are selected based on experiences with a sympathetic
addition to monthly meetings their ability to understand the listener.
with the program coordinators. nature of the program and their For many of the students, the
Together with the person’s willingness to spend time every program is a transformative
caregiver and the program’s month with the student buddy. experience. They become very
professional staff, students and The program has clear ben- close to their buddies and family
their “buddies” choose activities efits for both the medical student caregivers during their year
for their visits together. Activities and the person with AD. For the together, and continue the friend-
can include shopping, visiting medical student, it provides a ship even after the year is over.
32 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 33cientists have studied AD from many drug treatments. Findings from current research
angles. They have looked at populations are pointing scientists in promising directions for
to see how many cases of AD occur the future. They are also helping researchers to
S every year and whether there might ask better questions about the issues that are still
be links between the disease and lifestyles or unclear.
genetic backgrounds. They also have conducted Part 3 of Unraveling the Mystery describes what
clinical studies with healthy older people and scientists are learning from their search for:
those at various stages of AD. They have done
■ The causes of AD
many studies with laboratory animals. They
■ New techniques to help in diagnosis
have begun to look at neuronal circuits and
■ New treatments
networks of cells to learn how AD pathology
develops and spreads. They even have examined Results from this research will bring us closer
individual nerve cells to see how beta-amyloid, to the day when we will be able to delay the onset
tau, and other molecules affect the ability of of, prevent, or cure the devastating disease that
cells to function normally. robs our older relatives and friends of their most
These studies have led to a fuller under- precious possession—their minds.
standing of many aspects of the disease, improved
diagnostic tests, new ways to manage behavioral
aspects of AD, and a growing number of possible
ALZHEIMER’S DISEASE Unraveling the Mystery 35P A R T AD Research: Better Questions, New Answers
DNA, Chromosomes, and Genes: The Body’s Amazing Control Center
he nucleus of almost
for the
Tevery human cell contains
an encrypted “blueprint,” along
Causes AD
with the means to decipher it. This
blueprint, accumulated over eons
of genetic trial and error, carries all
ne of the most important parts of person’s risk, such as the age at which the disease
the instructions a cell needs to do
unraveling the AD mystery is begins. Slow and careful detective work by scientists
its job. The blueprint is made up of
finding out what causes the disease. has paid off in discoveries of genetic links to the two
DNA, which exists as two long,
O What makes the disease process begin main types of AD.
intertwined, thread-like strands
in the first place? What makes it worse over time? One type is the rare, early-onset Alzheimer’s
called chromosomes. Each cell
Why does the number of people with the disease disease. It usually affects people aged 30 to 60.
has 46 chromosomes in 23 pairs.
increase with age? Why does one person develop Some cases of early-onset disease are inherited and
The DNA in chromosomes is made
AD while another remains healthy? are called familial AD (FAD). The other is
up of four chemicals, or bases,
Some diseases, such as measles or pneumonia, late-onset Alzheimer’s disease. It is by far the
strung together in various sequence
have clear-cut causes. They can be prevented with more common form and occurs in those 60 and
patterns. The DNA in nearly all
vaccines or cured with antibiotics. Others, such as older. Gaining insight into the genetic factors
cells of an individual is identical.
diabetes or arthritis, develop when genetic, lifestyle, associated with both forms of AD is important
Each chromosome contains
and environmental factors work together to start because identifying genes that either cause the
many thousands of segments,
a disease process. The role that any or all of these disease or influence a person’s risk of developing it
called genes. People inherit two
factors play may be different for each individual. improves our ability to understand how and why
copies of each gene from their
AD fits into the second group of diseases. the disease starts and progresses.
parents, except for genes on the
We do not yet fully understand what causes AD,
X and Y chromosomes, which are construction, operation, and repair. DNA that causes a disease is
but we believe it develops because of a complex
chromosomes that, among other Even though all genes are present called a mutation. Mutations
series of events that take place in the brain over a
functions, determine a person’s sex. in most cells, the pattern in which also can change the activation
long period of time. Many studies are exploring
Each person normally has one pair they are activated varies from cell of a particular gene. Other more
the factors involved in the cause and develop-
of sex chromosomes (females are to cell, and gives each cell type common (or frequent) changes in
ment of AD.
XX and males are XY). The its distinctive character. Even slight a gene’s sequence of bases do not
sequence of bases in a gene tells alterations in a gene can produce automatically cause disease, but
the cell how to make specific
an abnormal protein, which, in turn, they can increase the chances that
Genetic studies of complex neurodegenera-
proteins. Proteins in large part deter- may lead to cell malfunction and, a person will develop a particular
tive diseases such as AD focus on two main
mine the different kinds of cells that eventually, to disease. disease. When this happens,
issues—whether a gene might influence
make up an organism and direct
Any permanent change in the the changed gene is called a
a person’s overall risk of developing
almost every aspect of the cell’s sequence of bases in a gene’s genetic risk factor.
a disease and whether a gene might
influence some particular aspect of a
ALZHEIMER’S DISEASE Unraveling the Mystery 37P A R T AD Research: Better Questions, New Answers
Genes and Early-Onset A Different Genetic Story in
The Hunt for New AD Genes
Alzheimer’s Disease Late-Onset Alzheimer’s Disease
In the early days of AD genetics research, scientists While some scientists were studying the role of
or some time, scientists have In 2003, NIA launched the
realized that some cases, particularly of the rare chromosomes 21, 14, and 1 in early-onset AD,
Fsuspected that, in addition Alzheimer’s Disease Genetics
early-onset AD, ran in families. This led them to others were looking elsewhere to see if they could
to APOE ε4, as many as half a Study to identify at least 1,000
examine DNA samples from these families to see find genetic clues for the late-onset form. By 1992,
dozen other risk-factor genes exist families with members who have
whether they had some genetic trait in common. investigators had narrowed their search to a region
for late-onset AD, but they have late-onset AD as well as members
Chromosomes 21, 14, and 1 became the focus of of chromosome 19. They found a gene on
been unable to find them. In 2007, who do not have the disease. All
attention. The scientists found that some families chromosome 19 that they were able to link to
scientists unveiled their discovery of of these family members provide
have a mutation in selected genes on these chromo- late-onset AD.
one new AD risk-factor gene. blood samples and other clinical
somes. On chromosome 21, the mutation causes an This gene, called APOE, produces a protein
This AD risk-factor gene is data for the initiative. The material
abnormal amyloid precursor protein to be produced called apolipoprotein E. APOE comes in several
called SORL1. It is involved in collected allows investigators to
(see page 22 for more on APP). On chromosome forms, or alleles— ε2, ε3, and ε4:
recycling APP from the surface of create and maintain “immortalized”
14, the mutation causes an abnormal protein called
■ The APOE ε2 allele is relatively rare and may
cells, and its association with AD cell lines—cells that are continu-
presenilin 1 to be produced. On chromosome 1,
provide some protection against the disease. If AD was identified and confirmed in ously regenerated in the laboratory.
the mutation causes another abnormal protein to be
does occur in a person with this allele, it develops three separate studies. Research- These cell lines are crucial for the
produced. This protein, called presenilin 2, is very
later in life than in those with an APOE ε4 allele.
ers found that when SORL1 is exhaustive DNA analysis studies
similar to presenilin 1. Even if only one of these
■ APOE ε3 is the most common allele. Research-
expressed at low levels or in a needed to identify risk-factor genes, be drawn from existing samples
genes that are inherited from a parent contains a
ers think it plays a neutral role in AD. variant form, harmful beta-amyloid each of which may have relatively of blood and tissue; other genetic
mutation, the person will almost inevitably develop
■ APOE ε4 occurs in about 40 percent of all
levels increase, perhaps by small effects on AD development. material will be collected from new
early-onset AD. This means that in these families,
people who develop late-onset AD and is present
deflecting APP away from its More than 4,000 new cell lines participants.
children have about a 50-50 chance of developing
in about 25 to 30 percent of the population. Peo- normal pathways and forcing it are now available for researchers New AD genetics discoveries
the disease if one of their parents has it.
ple with AD are more likely to have an APOE ε4
into cellular compartments that to study risk-factor genes for late- are possible largely because
Early-onset AD is very rare, and mutations in
allele than people who do not have AD. However,
generate beta-amyloid. onset AD. of close collaboration among
these three genes do not play a role in the more
at least one-third of people with AD do not have As AD genetics research has A new initiative, the Alzheimer’s scientists, participation of volunteer
common late-onset AD. However, these findings
an APOE ε4 allele. Dozens of studies have con-
intensified, it has become increas- Disease Genetics Consortium, families, new genetics tech-
were crucial because they showed that genetics was
firmed that the APOE ε4 allele increases the risk
ingly clear that scientists need was launched in 2007 to acceler- nologies, statistical and analytic
indeed a factor in AD, and they helped to identify
of developing AD, but how that happens is not many different samples of genetic ate the application of genetics advances, and rapid data sharing.
some key cell pathways involved in the AD disease
yet understood. These studies also have helped to
material if they are to continue technologies to late-onset AD For example, the SORL1 studies
process. They showed that mutations in APP can
explain some of the variation in the age at which
making progress in identifying new through collaborations among most involved 14 scientific institutions in
cause AD, highlighting the presumed key role of
AD develops, as people who inherit one or two risk-factor genes. Genetic material of the leading researchers in AD North America, Europe, and Asia
beta-amyloid in the disease. Mutations in pre-
APOE ε4 alleles tend to develop AD at an earlier is also essential for identifying genetics. The ultimate goal of this and the participation of more than
senilin 1 and 2 also cause an increased amount of
age than those who do not. However, inheriting
associated environmental factors effort is to obtain genetic material 6,000 people who donated blood
the damaging beta-amyloid to be made in the brain.
an APOE ε4 allele does not mean that a person and understanding the interactions from 10,000 people with AD and and tissue for genetic typing. An
will definitely develop AD. Some people with one of genes and the environment. 10,000 cognitively healthy people important part of NIA’s efforts to
or two APOE ε4 alleles never get the disease, and
These advances ultimately will to comprehensively scan the whole promote and accelerate AD
others who do develop AD do not have any APOE allow investigators to identify people genome for the remaining AD genetics research is to make
ε4 alleles. at high risk of developing AD and risk-factor genes, as well as those biological samples and data
help them focus on new pathways for age-related cognitive decline. publicly available to approved
for prevention or treatment. Some of the genetic material will researchers.
38 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 39P A R T AD Research: Better Questions, New Answers
refined antibody approaches are now being tested scientists now speculate that one reason tau may Protein Misfolding
Genetics explains some of what might cause AD, in clinical trials, and additional research on new damage and kill neurons is because it upsets Researchers have found that a number of devastat-
but it does not explain everything. So, researchers ways of harnessing the antibody response contin- the normal activity of the cell, in addition to
ing neurodegenerative diseases (for example, AD,
continue to investigate other possibilities that may
ues in the lab. forming neurofibrillary tangles. Parkinson’s disease, dementia with Lewy bodies,
explain how the AD process starts and develops. Another important area of research is how Other studies of mutant tau in mice suggest that frontotemporal lobar degeneration, Huntington’s
beta-amyloid may disrupt cellular communication the accumulation of tau in tangles may not even be the
disease, and prion diseases) share a key
well before plaques form. One recent study culprit in memory loss. Rather, as with beta-amyloid, characteristic—protein misfolding.
We now know a great deal about how beta-
described how beta-amyloid oligomers target it may be that an earlier and more soluble abnormal When a protein is formed, it “folds” into a
amyloid is formed and the steps by which
specific synaptic connections between neurons, form of the protein causes the damage to neurons. unique three-dimensional shape that helps it
beta-amyloid fragments stick together in small causing them to deteriorate. Other scientists are
aggregates (oligomers), and then gradually form
studying other potentially toxic effects that plaques
Researchers Explore Neurodegenerative “Cousins”
into plaques (see page 22 in The Hallmarks of
have on neurons and in cellular communication.
AD for more on this process). Armed with this Understanding more about these processes may
eurodegenerative diseases like AD, Parkinson’s a combination of genetic, lifestyle, and environmental
knowledge, investigators are intensely interested
allow scientists to develop specific therapies to
Ndisease, amyotrophic lateral sclerosis (ALS), causes and they develop over many years.
in the toxic effects that beta-amyloid, oligomers,
block the toxic effects.
and dementia with Lewy bodies share more than the This graphic shows one way of thinking about
and plaques have on neurons. This research is
basic characteristic of misfolded proteins. They also how these diseases may be linked as well as what
possible in part because scientists have been able T au
share clinical characteristics. For example, people makes them unique. By investigating the unique
to develop transgenic animal models of AD.
Tau, the chief component of neurofibrillary tangles
with AD have trouble moving, a characteristic of characteristics of these diseases as well as the
Transgenics are animals that have been specially (see page 25 in The Hallmarks of AD for more
Parkinson’s disease. Sleep-wake disorders, delusions, characteristics they share, scientists hope to learn
bred to develop AD-like features, such as on tau), is generating new excitement as an area
psychiatric disturbances, and memory loss occur in even more than they would if they focused on each
beta-amyloid plaques.
of study. The recent focus on tau has been spurred
all of these diseases. These diseases also result from disease by itself.
Beta-amyloid studies have moved forward to by the finding that a mutant form of the protein
the point that scientists are now carrying out is responsible for one form of frontotemporal
preliminary tests in humans of potential therapies
dementia, the third most common cause of late-life
Damaging Processes
aimed at removing beta-amyloid, halting its dementia, after AD and vascular dementia. This Lifetime Occurring Before Neurodegenerative
Influences Symptoms Appear Early Symptoms Diseases*
formation, or breaking down early forms before form is known as frontotemporal dementia with
they can become harmful. parkinsonism linked to chromosome 17 (FTDP-
For example, one line of research by a pharma- 17). Finding this mutant protein was important
ceutical company started with the observation that because it suggested that abnormalities in the tau
Memory loss
Amyloid plaques
injecting beta-amyloid into AD transgenic mice protein itself can cause dementia. AD
Executive function
T au tangles PD
caused them to form antibodies to the beta- New transgenic mouse models of AD have
Other abnormal
Movement problems
amyloid and reduced the number of amyloid helped tau research make rapid progress. For VaD
protein deposits
Gait and balance problems
plaques in the brain. This exciting finding led to example, a recent model, the “triple transgenic”
Reduced oxygen
factors Sleep-wake disorders
flow to tissues
other studies and ultimately to clinical trials in
mouse, forms plaques and tangles over time in
Toxic processes
which human participants were immunized with brain regions similar to those in human AD.
beta-amyloid. These studies had to be stopped Another recent transgenic mouse model, which
because some of the participants developed
contains only human tau, forms clumps of
harmful side effects, but the investigators did damaging tau filaments also in a region-specific
* AD = Alzheimer’s disease, AD/PD = AD with parkinsonism, ALS = amyotrophic lateral sclerosis, DLB = dementia with Lewy bodies,
not give up hope. Rather, they went back to the fashion similar to AD in humans.
FTLD = frontotemporal lobar degeneration, VaD = vascular dementia (includes multi-infarct dementia), PD = Parkinson’s disease,
drawing board to rethink their strategy. More
These studies of tau also have suggested a
PDD = Parkinson’s disease with dementia
mechanism for tau damage that is different from Adapted from an Emory University illustration
that previously suspected. With these new insights,
40 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 41P A R T AD Research: Better Questions, New Answers
The Brain’s Vascular System
perform its specific function. This crucial process Scientists do not know exactly why or how
can go wrong for various reasons, and more these processes occur, but research into the unique
This image shows the complexity of the human brain’s
commonly does go wrong in aging cells. As a characteristics and actions of various misfolded
vascular system, particularly large and small arteries
result, the protein folds into an abnormal shape— proteins is helping investigators learn more about
that carry oxygen from the lungs to the brain. Although
it is misfolded. In AD, the misfolded proteins are the similarities and differences across age-related
many blood vessels are visible here, this image shows
beta-amyloid (the cleaved product of APP; see neurodegenerative diseases. This knowledge may fewer than half of the total number in the brain.
From APP to Beta-Amyloid Plaques on page 22 someday lead to therapies.
for more on the formation of beta-amyloid) out its functions. Energy for the cell is produced
and a cleaved product of tau. The Aging Process in an efficient metabolic process. In this process,
Normally, cells repair or degrade misfolded Another set of insights about the cause of AD free radicals are produced. Free radicals can help
proteins, but if many of them are formed as part comes from the most basic of all risk factors— cells in certain ways, such as fighting infection.
of age-related changes, the body’s repair and aging itself. Age-related changes, such as inflam- However, because they are very active and combine
clearance process can be overwhelmed. Misfolded mation, may make AD damage in the brain worse. easily with other molecules, free radicals also can
proteins can begin to stick together with other Because cells and compounds that are known to be damage the neuron’s cell membrane or its DNA.
misfolded proteins to form insoluble aggregates. involved in inflammation are found in AD plaques, The production of free radicals can set off a chain
As a result, these aggregates can build up, leading some researchers think that components of the reaction, releasing even more free radicals that
to disruption of cellular communication, and inflammatory process may play a role in AD. can further damage neurons (see illustration on Vascular Disease
metabolism, and even to cell death. These Other players in the aging process that may page 42). This kind of damage is called oxidative For some time now, hints have been emerging
effects may predispose a person to AD or other be important in AD are free radicals, which are damage. The brain’s unique characteristics, includ-
that the body’s vast network of small and large
neurodegenerative diseases. oxygen or nitrogen molecules that combine easily ing its high rate of metabolism and its long-lived blood vessels—the vascular system—may make
with other molecules (scientists cells, may make it especially vulnerable to oxida- an important contribution in the development of
call them “highly reactive”). Free tive damage over the lifespan. The discovery that
dementia and the clinical symptoms of AD. Some
radicals are generated beta-amyloid generates free radicals in some AD scientists are focusing on what happens with the
in mitochondria, which are plaques is a potentially significant finding in the brain’s blood vessels in aging and AD. Others are
structures found in all cells, quest for better understanding of AD as well as for
looking at the relationship between AD and vascu-
including neurons. other neurodegenerative disorders and unhealthy lar problems in other parts of the body.
Mitochondria are the cell’s brain aging.
power plant, providing the Researchers also are studying age-related
AD and Vascular Problems in the Brain
energy a cell needs to maintain changes in the working ability of synapses in The brain requires a constant and dependable flow
its structure, divide, and carry certain areas of the brain. These changes may of oxygen and glucose to survive and flourish. The
reduce the ability of neurons to communicate brain’s blood vessels provide the highways to deliver
with each other, leading to increased neuronal
these vital elements to neurons and glial cells.
Mitochondria and
vulnerability in regions of the brain important Aging brings changes in the brain’s blood
Free Radicals
in AD. Age-related reductions in levels of vessels—arteries can narrow and growth of new
Any given cell has hundreds of particular growth factors, such as nerve growth
capillaries slows down. In AD, whole areas of
mitochondria. This illustration
factor and brain-derived neurotrophic factor, nervous tissue, including the capillaries that supply
shows two—a healthy mitochon-
also may cause important cell populations to be
drion and an oxidatively stressed
compromised. Many studies are underway to tease
and damaged one. The arrows
out the possible effects of the aging process on the
indicate the movement of free
development of AD.
radicals, which can spread easily
from damaged mitochondria to
other parts of the cell.
42 ALZHEIMER’S DISEASE Unraveling the Mystery ALZHEIMER’S DISEASE Unraveling the Mystery 43P A R T AD Research: Better Questions, New Answers
and drain it, also are lost. Blood flow to and from studies). These studies have found, for example, Lifestyle Factors
various parts of the brain can be affected, and the that heart disease and stroke may contribute to the We know that physical activity and a nutritious diet
brain may be less able to compensate for damage development of AD, the severity of AD, or the de-
can help people stay healthy as they grow older. A
that accumulates as the disease progresses. velopment of other types of dementia. Studies also healthy diet and exercise can reduce obesity, lower
For some time now, study of the brain’s blood show that high blood pressure that develops dur- blood cholesterol and high blood pressure, and
vessel system in AD has been a productive line of ing middle age is correlated with cognitive decline
improve insulin action. In addition, association
inquiry. One important finding has been that the and dementia in later life. studies suggest that pursuing intellectually
brain’s ability to rid itself of toxic beta-amyloid by Another focus of AD vascular research is the stimulating activities and maintaining active
sending it out into the body’s blood circulation metabolic syndrome, a constellation of factors that contacts with friends and family may contribute
is lessened. Some scientists now think that poor increases the risk of heart disease, stroke, and type
to healthy aging. A growing body of evidence now
clearance of beta-amyloid from the brain, com- 2 diabetes. Metabolic syndrome includes obesity suggests that these lifestyle factors may be related ■ Epidemiologic studies show that higher levels
bined with a diminished ability to develop new (especially around the waist), high triglyceride to cognitive decline and AD. Researchers who of physical activity or exercise in older people are
capillaries and abnormal aging of the brain’s blood levels, low HDL (“good cholesterol”) levels, high associated with reduced risk of cognitive decline
are interested in discovering the causes of AD are
vessel system, can lead to chemical imbalances in blood pressure, and insulin resistance (a condition intensively studying these issues, too. and reduced risk of dementia. Even moderate
the brain and damage neurons’ ability to function in which insulin does not regulate blood sugar exercise, such as brisk walking, is associated with
and communicate with each other. These findings levels very well). Evidence from epidemiologic Physical Activity and Exercise reduced risk.
are exciting because they may help to explain part studies now suggests that people with the meta- Exercise has many benefits. It strengthens muscles, ■ Clinical trials show some evidence of short-term
of what happens in the brain during the develop- bolic syndrome have increased risk of cognitive improves heart and lung function, helps prevent positive effects of exercise on cognitive function,
ment of AD. These findings also suggest several impairment and accelerated cognitive decline. osteoporosis, and improves mood and overall well- especially executive function (cognitive abilities
new targets for potential AD therapies. Nearly one in five Americans older than age 60 being. So it is not surprising that AD investigators involved in planning, organizing, and decision
has type 2 diabetes, and epidemiologic studies began to think that if exercise helps every part of making). One trial showed that older adults who
AD and Vascular Problems in suggest that people with this disease may be the body from the neck down, then it might help participated in a 6-month program of brisk
Other Parts of the Body at increased risk of cognitive problems, including the brain as well. walking showed increased activity of neurons in
Research also has begun to tease out some MCI and AD, as they age. The higher risk Epidemiologic studies, animal studies, and key parts of the brain.
relationships between AD and other vascular associated with diabetes may be the result of high human clinical trials are assessing the influence More clinical trials are underway to expand
of exercise on cognitive function. Here are a few
diseases, such as heart disease, stroke, and type 2 levels of blood sugar, or it may be due to other our knowledge about the relationship of exercise
diabetes. It is important to sort out the various conditions associated with diabetes (obesity, high things these studies have found: to healthy brain aging, reduced risk of cognitive
effects on the brain of these diseases because they blood pressure, abnormal blood cholesterol levels, decline, and development of AD. (See Partici-
■ Animal studies have shown that exercise in-
are major causes of illness and death in the United progressive atherosclerosis, or too much insulin pating in a Clinical Trial on page 59 for more
creases the number of capillaries that supply blood
States today. in the blood). These findings about diabetes information).
to the brain and improves learning and memory in
Much of this evidence comes from epidemio- have spurred research on a number of fronts—