Alzheimer's Disease Unraveling The Mystery
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Alzheimer's Disease Unraveling The Mystery Alzheimer's Disease Unraveling The Mystery Document Transcript

  • ALZHEIMERS DISEASE Unraveling the Mystery National Institute on Aging National Institutes of Health
  • ALZHEIMERS DISEASE Unraveling the Mystery
  • Preface Table of Contents O 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 34 AD RESEARCH: BETTER QUESTIONS, emerged from program in 1978, and since the study of AD is moving 5 About This Book NEW ANSWERS 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 8 THE BASICS OF THE HEALTHY BRAIN 48 New Techniques Help in Diagnosing AD their families. The National Thanks to the work of NIH and friends care for people 50 Exciting New Developments in 10 Inside the Human Brain AD Diagnosis Institute on Aging (NIA) is the institutes, other research orga- with AD. 10 The Main Players 12 Other Crucial Parts 54 The Search for New Treatments 12 The Brain in Action 55 Helping People with AD Maintain Their TO GET THE MOST OUT OF THIS BOOK 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) The hallmarks of AD (pages 21-26) 16 Repair ■ How neurons work (pages 14-16) ■ ■ The changing brain in healthy aging ■ The changing brain in AD (pages 27-33) 17 The Changing Brain in Healthy Aging (pages 17-19) p a r t 4 62 IMPROVING SUPPORT FOR FAMILIES AND OTHER CAREGIVERS Explore Cutting-Edge AD Research Learn about Caregiver Support p a r t 2 64 Research Findings Benefit Caregivers ■ Looking for causes (pages 36-47) ■ Who are AD caregivers? (page 63) 20 WHAT HAPPENS TO THE BRAIN IN AD 66 Early-Stage AD Support Groups: 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 69 CONCLUSION ■ 25 Neurofibrillary Tangles (page 68) 26 Loss of Connection Between 70 GLOSSARY Cells and Cell Death TO LEARN EVEN MORE 27 The Changing Brain in AD 74 FOR MORE INFORMATION 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 27 Preclinical AD 74 Information and Support Resources and an animation that shows what happens to the changing brain in AD. And while you are there, 28 Very Early Signs and Symptoms 75 Caregiving Support and Services explore the ADEAR Center’s many other offerings. These include free publications about AD and AD 30 Mild AD 76 Research and Clinical Trials caregiving, clinical trials information, a list of NIA-funded Alzheimer’s Disease Centers, and NIA’s 31 Moderate AD 76 Recommended Reading searchable AD Library database of thousands of materials about AD. 31 Severe AD2 ALZHEIMER’S DISEASE Unraveling the Mystery A LZ HE IME R’ S D IS EA SE Unraveling the Mystery 3
  • Introduction “Never have I loved my husband of 41 years more than I do today....Though he may not know I’m his wife, disease like AD because the number of people begins many years, perhaps even decades, he does know that my presence means his favorite foods and drinks are near at hand....I wonder why I can with the disease doubles for every 5-year age before symptoms emerge. Discovering ways to 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 T 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 Support 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 A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 5
  • Introduction ■ 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 A s shown in this timeline, we have learned a lot since Dr. Alzheimer presented the case of his patient, Auguste D. The pace of research continues to accelerate as new findings open more and more doors to discovery. 19O6 196Os ■ Scientists start to unravel the biological pathways 2OOOs ■ Dr. Alois Alzheimer, a German neurologist and ■ Scientists discover a link between dementia 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®) a hospital 5 years earlier with a cluster of unusual of aging. 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 behavioral problems, and hallucinations. After her ■ Scientists find that levels of acetylcholine, a 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 globs of sticky proteins in the spaces between one of the first to link AD with biochemical changes ■ 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 tangles). recognition of AD as a major public health problem 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. ■ Scientists study the biological structure of plaques ■ Congress mandates NIA as lead Federal agency and prevention clinical trials. and tangles. for AD research.6 ALZ H EI MER’ S D ISE ASE Unraveling the Mystery A L Z H E I ME R’ S D I SE A SE Unraveling the Mystery 7
  • T o 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 view of the normal brain, how it works, A D U LT W E I G H T and what happens during aging. about 3 pounds The brain is a remarkable organ. Seemingly without effort, it allows us to carry out every 1 A D U LT S I Z E element of our daily lives. It manages many body a medium cauliflower functions, such as breathing, blood circulation, N U M B E R O F N E U RO NS PART and digestion, without our knowledge or direction. It also directs all the functions we carry about 100,000,000,000 (100 billion) N U M B E R O F S Y N APS ES out consciously. We can speak, hear, see, move, Basics remember, feel emotions, and make decisions (the gaps between neurons) because of the complicated mix of chemical and about 100,000,000,000,000 (100 trillion)The 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 N U M B E R O F C A P I L LARI ES (tiny blood vessels) about 400,000,000,000 (400 billion) neurons. The neurons of all animals function in of the Healthy basically the same way, even though animals can 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 Brain 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 A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 9
  • P A R T 1 The Basics of the Healthy Brain Inside the Human Brain T he brain has many parts, each of which ■ 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 key 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 1 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 A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 13
  • P A R T 1 The Basics of the Healthy Brain Neurons in the Brain Neurons and Their Jobs T 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 cell 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 Mystery
  • P A R T 1 The Basics of the Healthy Brain The Once the post-synaptic receptors are activated, METABOLISM Changing Brainthey open channels through the cell membrane All cells break down chemicals and nutrients tointo the receiving nerve cell’s interior or start other generate energy and form building blocks thatprocesses that determine what the receiving nerve make new cellular molecules such as proteins. HealthyAgingcell will do. Some neurotransmitters inhibit nerve This process is called metabolism. To maintaincell function (that is, they make it less likely thatthe nerve cell will send an electrical signal down metabolism, the brain needs plenty of blood constantly circulating through its billions of inits axon). Other neurotransmitters stimulate nerve capillaries to supply neurons and other braincells, priming the receiving cell to become active cells with oxygen and glucose. Without oxygenor send an electrical signal down the axon to more and glucose, neurons will quickly die. Ineurons in the pathway. A neuron receives signals n the past several decades, investigators have ■ In some people, structures called plaques andfrom 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 amountsone instant will determine whether it sends a sig- short time after birth. Unlike most cells, which disease such as Parkinson’s disease, AD, or than in AD (see The Hallmarks of AD on page 21nal 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 During any one moment, millions of these sig- years or longer. To stay healthy, living neurons Researchers are investigating a number of changes are a kind of molecule that reacts easily with othernals 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 forallowing 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).tion, make adjustments, and send out instructions or injury, they are not usually replaced. Research, knowledge about the early stages of AD. ■ Inflammation increases (inflammation is theto 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 situation). ■ 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 knowledge. It also appears that additional brain regions can be activated in older adults during cognitive tasks, A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 17
  • P A R T 1 The Basics of the Healthy Brain such as taking a memory test. Researchers do not and unique mix of genetics, environment, and life fully understand why this happens, but one idea is experiences, the balance may tip in favor of a dis- ACTIVE Study May Provide Clues to Help Older Adults Stay Mentally Sharp that the brain engages mechanisms to compensate ease process that will ultimately lead to dementia. for difficulties that certain regions may be having. For example, the brain may recruit alternate brain networks in order to perform a task. These find- For another person, with a different reserve and a different mix of genetics, environment, and life experiences, the balance may result in no apparent T he phrase “use it or lose it” may make you think of your muscles, but scientists who study brain health in older people have found that it may apply ■ 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 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 A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 19
  • The Hallmarks of AD A lzheimer’s disease disrupts critical metabolic AMYLOID PLAQUES 2 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 PART to stop working, lose connections with other nerve cells, and finally die. The destruction by Dr. Alois Alzheimer in 1906. Plaques consist of largely insoluble deposits of an apparently toxic and death of nerve cells causes the memory failure, protein peptide, or fragment, called beta-amyloid. personality changes, problems in carrying out We now know that some people develop daily activities, and other features of the disease. some plaques in their brain tissue as they age.What Happens The brains of people with AD have an abundance However, the AD brain has many more plaques Brain of two abnormal structures—amyloid plaques in particular brain regions. We still do not know to the and neurofibrillary tangles—that are made of misfolded proteins (see Protein Misfolding on page 41 for more information). This is especially 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 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). AD ished cell function and cell death. in To view a video showing what happens to the brain in AD, go to www.nia.nih.gov/ Alzheimers/ADvideo. A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 21
  • P A R T 2 What Happens to the Brain in AD From APP to Beta-Amyloid Plaques A myloid precursor protein (APP), the starting point for amyloid plaques, is one of many proteins associated with the cell membrane, the barrier that the APP molecule at one end of the beta-amyloid peptide, releasing sAPPβ From APP to Beta-Amyloid Plaque 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 pick stuck through the skin of an orange (Figure 1). cuts the resulting APP 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- Figure 4 outside the neuron and 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 the segment of APP where the cleaving occurs, APP up to a dozen beta-amyloid peptides are called 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 In the benign pathway, alpha-secretase cleaves the neighboring cells and synapses, affecting their 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 beta-amyloid peptide and the potential for plaque the brain. Those that cannot be cleared clump buildup. The cleavage releases from the neuron a frag- together with more beta-amyloid peptides. As the ment called sAPPα, which has beneficial properties, process continues, oligomers grow larger, becoming such as promoting neuronal growth and survival. The entities called protofibrils and fibrils. Eventually, other 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 the end of the beta-amyloid segment. The smaller of well-known plaques that are characteristic of AD. 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 222 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 23
  • P A R T 2 What Happens to the Brain in AD Healthy and Diseased Neurons Inside a Healthy Neuron NEUROFIBRILLARY TANGLES The second hallmark of AD, also described by Dr. Alzheimer, is neurofibrillary tangles. Tangles are abnormal collections of twisted protein threads found inside nerve cells. The chief component of tangles is a protein called tau. Healthy neurons are internally supported in part by structures called microtubules, which help transport nutrients and other cellular components, such as 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 Tau Tangles24 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 25
  • P A R T 2 What Happens to the Brain in AD The LOSS OF CONNECTION BETWEEN CELLS AND CELL DEATH The AD process not only inhibits communi- cation between neurons but can also damage Changing Brain AD The third major feature of AD is the gradual neurons to the point that they cannot function loss of connections between neurons. Neurons live to communicate with each other, and this vital function takes place at the synapse. Since properly and eventually die. As neurons die throughout the brain, affected regions begin to shrink in a process called brain atrophy. By the in 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. N 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 aging 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 This illustration shows brain once AD takes hold and about the physical AD begins deep in the brain, in the entorhinal 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 neurons. 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 to26 ALZH EIMER’S D ISE ASE Unraveling the Mystery A LZ HEI M ER’ S D I S EA S E Unraveling the Mystery 27
  • P A R T 2 What Happens to the Brain in AD PiB and PET Charting the Course from Healthy Aging to AD 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 T his chart shows cur- rent thinking about the evolution from healthy aging AD brain Amnestic MCI: memory problems; Cognitive decline 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 profound impact on improving early diagnosis, monitoring a series of events that occur symptoms brain compensates diagnosis 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 brain and it can be imaged using PET scans. Initial studies mental, and lifestyle factors, memory loss 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 independent tists have found high levels of PiB in some cognitively healthy possibly AD. Other people, function 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 cognitively healthy people who have high PiB levels to see of the person with AD than in the cognitively who experience a different Birth 40 60 80 Death whether they do, in fact, develop AD over time. healthy person. combination of factors over a Life Course 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. Mild Cognitive Impairment begins to show itself in very early clinical signs and 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 in28 ALZ HE I ME R’ S D I S EA SE Unraveling the Mystery A LZH EI M ER’S D I SEA SE Unraveling the Mystery 29
  • P A R T 2 What Happens to the Brain in AD explored whether changes in older adults’ ability to Mild to Moderate AD 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- MILD AD 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- risk of progressing to AD. and more and more of the cerebral cortex is 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 cognitive problems. For example, in one study they clinical diagnosis of AD is usually made during ■ 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 swallowing30 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 31
  • P A R T 2 What Happens to the Brain in AD ■ Groaning, moaning, or grunting AD Spreads Through the Brain The Buddy Program at Northwestern University ■ 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 T he medical school curriculum The Buddy Program at Northwestern University demands that students spend 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 A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 33
  • AD RESEARCH : PART 3 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 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 Better 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 ADQuestions, ■ 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 New 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 Answers diagnostic tests, new ways to manage behavioral aspects of AD, and a growing number of possible A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 35
  • P A R T 3 AD Research: Better Questions, New Answers Looking DNA, Chromosomes, and Genes: The Body’s Amazing Control Centerfor the Causes AD T he nucleus of almost of every human cell contains an encrypted “blueprint,” along with the means to decipher it. This blueprint, accumulated over eonsO 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, What makes the disease process begin main types of AD. intertwined, thread-like strandsin the first place? What makes it worse over time? One type is the rare, early-onset Alzheimer’s called chromosomes. Each cellWhy 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 madeAD 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 sequencehave clear-cut causes. They can be prevented with more common form and occurs in those 60 and patterns. The DNA in nearly allvaccines 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 containsand 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 twofactors 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 theWe do not yet fully understand what causes AD, X and Y chromosomes, which are construction, operation, and repair. DNA that causes a disease isbut we believe it develops because of a complex chromosomes that, among other Even though all genes are present called a mutation. Mutationsseries 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 activationlong period of time. Many studies are exploring Each person normally has one pair they are activated varies from cell of a particular gene. Other morethe factors involved in the cause and develop- of sex chromosomes (females are to cell, and gives each cell type common (or frequent) changes inment 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, butGENETIC FACTORS AT WORK IN AD the cell how to make specific an abnormal protein, which, in turn, they can increase the chances thatGenetic studies of complex neurodegenera- proteins. Proteins in large part deter- may lead to cell malfunction and, a person will develop a particulartive 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 aa 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 mightinfluence some particular aspect of a A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 37
  • P A R T 3 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 realized that some cases, particularly of the rare early-onset AD, ran in families. This led them to chromosomes 21, 14, and 1 in early-onset AD, others were looking elsewhere to see if they could F or some time, scientists have suspected that, in addition to APOE ε4, as many as half a In 2003, NIA launched the Alzheimer’s Disease Genetics 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 A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 39
  • P A R T 3 AD Research: Better Questions, New Answers OTHER FACTORS AT WORK IN AD 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 Beta-Amyloid 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 into plaques (see page 22 in The Hallmarks of have on neurons and in cellular communication. Researchers Explore Neurodegenerative “Cousins” AD for more on this process). Armed with this Understanding more about these processes may knowledge, investigators are intensely interested in the toxic effects that beta-amyloid, oligomers, allow scientists to develop specific therapies to block the toxic effects. N eurodegenerative diseases like AD, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and dementia with Lewy bodies share more than the a combination of genetic, lifestyle, and environmental causes and they develop over many years. 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 Tau to develop transgenic animal models of AD. share clinical characteristics. For example, people makes them unique. By investigating the unique Tau, the chief component of neurofibrillary tangles Transgenics are animals that have been specially with AD have trouble moving, a characteristic of characteristics of these diseases as well as the (see page 25 in The Hallmarks of AD for more bred to develop AD-like features, such as Parkinson’s disease. Sleep-wake disorders, delusions, characteristics they share, scientists hope to learn on tau), is generating new excitement as an area beta-amyloid plaques. psychiatric disturbances, and memory loss occur in even more than they would if they focused on each of study. The recent focus on tau has been spurred Beta-amyloid studies have moved forward to all of these diseases. These diseases also result from disease by itself. 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 formation, or breaking down early forms before form is known as frontotemporal dementia with Influences Symptoms Appear Early Symptoms Diseases* 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 Tremor ceutical company started with the observation that because it suggested that abnormalities in the tau Memory loss Amyloid plaques AD/PD injecting beta-amyloid into AD transgenic mice protein itself can cause dementia. Executive function AD Tau tangles problems DLB PD caused them to form antibodies to the beta- New transgenic mouse models of AD have Genes Other abnormal Movement problems PDD amyloid and reduced the number of amyloid helped tau research make rapid progress. For Environment protein deposits VaD plaques in the brain. This exciting finding led to Systemic Gait and balance problems example, a recent model, the “triple transgenic” Reduced oxygen factors flow to tissues Sleep-wake disorders FTLD other studies and ultimately to clinical trials in mouse, forms plaques and tangles over time in Toxic processes Hallucinations ALS which human participants were immunized with brain regions similar to those in human AD. Delusions beta-amyloid. These studies had to be stopped Another recent transgenic mouse model, which Rigidity 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 not give up hope. Rather, they went back to the fashion similar to AD in humans. *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, 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 A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 41
  • P A R T 3 AD Research: Better Questions, New Answers perform its specific function. This crucial process Scientists do not know exactly why or how The Brain’s Vascular System 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 indicate the movement of free out the possible effects of the aging process on the radicals, which can spread easily development of AD. from damaged mitochondria to other parts of the cell.42 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 43
  • P A R T 3 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 are interested in discovering the causes of AD are associated with reduced risk of cognitive decline 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 diseases, such as heart disease, stroke, and type 2 levels of blood sugar, or it may be due to other of exercise on cognitive function. Here are a few 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— older animals. logic studies, which compare the lifestyles, be- epidemiologic studies, test tube and animal Diet haviors, and characteristics of groups of people studies, and clinical trials. The objective of these Researchers have explored whether diet may help (see Describing Scientific Findings: The Type of studies is to learn more about the relationship preserve cognitive function or reduce AD risk, If you want to know more about the Study Makes an Important Difference on page between diabetes and cognitive problems and to with some intriguing findings. For example, benefits of exercise and physical activity 47 for more information about epidemiologic find out in clinical trials whether treating the disease studies have examined specific foods that are rich and learn ways to be active every day, rigorously can positively affect cognitive health and in antioxidants and anti-inflammatory properties NIA has free information just for you! possibly slow or prevent the development of AD. to find out whether those foods affect age-related Call 1-800-222-2225 or visit www.nia.nih.gov/Exercise.44 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 45
  • P A R T 3 AD Research: Better Questions, New Answers changes in brain tissue. One laboratory study In one of these studies, researchers worked the risk of developing AD was 47 percent lower in The reasons for these findings are not entirely found that curcumin, the main ingredient of with older adults living in New York who ate the the people who did them the most frequently clear, but a number of explanations are possible. turmeric (a bright yellow spice used in curry), “Mediterranean diet”—a diet with lots of fruits, compared with the people who did the activities Among them: can bind to beta-amyloid and prevent vegetables, and bread; low to moderate least frequently. Another study supported the value ■ Intellectually stimulating activities and social oligomer formation. Another study in amounts of dairy foods, fish, and of lifelong learning and mentally stimulating engagement may protect the brain in some way, mice found that diets high in DHA poultry; small amounts of red meat; activity by finding that, compared with older study perhaps by establishing a cognitive reserve. (docosahexaenoic acid), a type of low to moderate amounts of wine; participants who may have had AD or who had ■ These activities may help the brain become healthy omega-3 fatty acid found and frequent use of olive oil. The AD, healthy older participants had engaged in more more adaptable and flexible in some areas of in fish, reduced beta-amyloid researchers found that sticking mentally stimulating activities and spent more time mental function so that it can compensate for and plaques in brain tissue. to this type of diet was associated at them during their early and middle adulthood. declines in other areas. Other studies have shown with a reduced risk of AD and Studies of animals, nursing home residents, and ■ Less engagement with other people or in that old dogs perform better on that the association seemed to people living in the community also have suggested intellectually stimulating activities could be learning tasks when they eat diets be driven by the whole approach, a link between social engagement and cognitive the result of very early effects of the disease rich in antioxidants, such as vitamin rather than by its individual dietary performance. Older adults who have a full social rather than its cause. E and other healthful compounds, while components. A follow-up study found network and participate in many social activities tend ■ People who engage in stimulating activities may living in an “enriched” environment (one in that this pattern also was associated with to have less cognitive decline and a decreased risk of have other lifestyle qualities that may protect which the dogs have many opportunities to play and longer survival in people with AD. dementia than those who are not socially engaged. them against developing AD. interact with people and other dogs). All of these results are exciting and suggestive, Scientists also have examined the effects of but they are not definitive. To confirm the results, diet on cognitive function in people. A very large scientists are conducting clinical trials to examine the Describing Scientific Findings: epidemiologic study of nurses found an association relationship of various specific dietary components The Type of Study Makes an Important Difference between participants who ate the most vegetables and their effect on cognitive decline and AD. (especially green leafy and cruciferous vegetables) and a slower rate of cognitive decline compared with nurses who ate the least amount of these Intellectually Stimulating Activities and Social Engagement T hese days, the media are full of stories about scientific studies. It can be hard to know followed by the participants. That is why, in epidemiologic studies of AD, scientists only say that a find- of control allows scientists to be more certain about why they get the results they do. It also allows foods. An epidemiologic study of older adults Many older people love to read, do puzzles, play what to conclude about their find- ing is “associated with” AD, or not. them to be more definitive in the living in Chicago found the same association. The games, and spend time with family and friends. All ings. Knowing how the study was The epidemiologic evidence linking words they use to describe their researchers do not know the exact reason behind these activities are fun and help people feel alert conducted can help put the results a behavior and AD is, at best, sug- results. Of course, showing a this association, but speculate that the beneficial and engaged in life. Researchers are beginning to into the right perspective. gestive, but we do not know that cause-and-effect relationship in effects may result from the high antioxidant and find other possible benefits as well, for some studies One main type of research is the behavior by itself actually helps tissue samples or even in animal folate content of the vegetables. have shown that keeping the brain active is associ- the epidemiologic study. These to cause or prevent AD. studies still does not mean that the Dietary studies, such as the curcumin study in ated with reduced AD risk. For example, over a studies are observational—they Other types of research—test relationship will be the same in mice or the vegetables study in nurses, generally 4-year period, one group of researchers tracked how gather information about people tube studies and studies in ani- humans. Clinical trials in humans examine individual dietary components so that often a large group of older people did activities who are going about their daily mals—add to the findings from are the gold standard for decid- scientists can pinpoint their specific effects on an that involved significant information processing, lives. Study participants follow epidemiologic studies. Scientists ing whether a behavior or a issue of interest. This approach has obvious such as listening to the radio, reading newspapers, many behaviors and practices. It use them to examine the same specific therapeutic agent limitations because people do not eat just single playing puzzle games, and going to museums. The is difficult, therefore, to determine issue but in ways in which the actually prevents or delays AD foods or nutrients. Several recent epidemiologic researchers then looked at how many of the partici- the exact benefits or risks of one various factors that might influ- (see Participating in a Clinical studies have taken a different approach and looked pants developed AD. The researchers found that particular behavior from among all ence a result are controlled to Trial on page 59 for more on at an entire dietary pattern. the healthy or harmful behaviors a greater degree. This element this kind of research).46 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 47
  • P A R T 3 AD Research: Better Questions, New Answers Current Tools for Diagnosing AD New Techniques W ith the tools now available, how behavior and personality They may do a computed Help in Diagnosing AD experienced physicians have changed; many times, tomography (CT) scan or a can be reasonably confident about family and friends know some- magnetic resonance imaging making an accurate diagnosis of thing is wrong even before (MRI) test: AD in a living person. Here is changes are evident on tests. ■ CT and MRI scans can detect how they do it. strokes or tumors or can reveal They conduct physical and changes in the brain’s structure A man in his mid-60s begins to notice that his mimic those of AD. Finding out early that the They take a detailed neurological examinations that indicate early AD. memory isn’t as good as it used to be. More and more observed changes in cognitive abilities are not AD patient history, including: and laboratory tests: often, a word will be on the tip of his tongue but but something else is almost always a relief and ■ A description of how and when ■ Blood and other medical tests Exams and tests may be repeated he just can’t remember it. He forgets appointments, may be just the prod needed to seek appropriate symptoms developed. help determine neurological every so often to give physicians makes mistakes when paying his bills, and finds that medical treatment (see Causes of Dementia on ■ A description of the person’s functioning and identify possible information about how the person’s he’s often confused or anxious about the normal hustle page 50 for more information). For the small and his or her family’s overall non-AD causes of dementia. memory and other symptoms are and bustle of life around him. One evening, he sud- percentage of dementias that are treatable or medical condition and history. changing over time. denly finds himself walking in a neighborhood he even reversible, early diagnosis increases the ■ An assessment of the person’s They conduct neuro- Based on findings from these doesn’t recognize. He has no idea how he got there or chances of successful treatment. Increasing early emotional state and living psychological testing: exams and tests, experienced how to get home. diagnosis and improving treatment are among environment. ■ Question-and-answer tests physicians can diagnose or rule NIA’s most important goals. N or other tasks that measure out other causes of dementia, or ot so long ago, this man’s condition Even when the cause of a loved one’s dementia They get information memory, language skills, ability determine whether the person has would have been swept into a broad turns out to be AD, it is best to find out sooner from family members or to do arithmetic, and other MCI, “possible AD” (the symptoms catch-all category called “senile rather than later. One benefit of knowing is medi- close friends: abilities related to brain func- may be due to another cause), or dementia” or “senility.” Although we cal. The drugs now available to treat AD can help ■ People close to the person can tioning help show what kind of “probable AD” (no other cause for now know that AD and other causes of dementia are some people maintain their mental abilities for provide valuable insights into cognitive changes are occurring. the symptoms can be found). distinct diseases, in the early stages it is difficult to months to years, although they do not change differentiate between the onset of AD and other types the underlying course of the disease (see Helping of age-related cognitive decline. We have improved People with AD Maintain their Mental Function- our ability to diagnose AD correctly, and doctors ing on page 55 for more about these drugs). experienced in AD can diagnose the disease with up Other benefits are practical. The sooner the per- network, and even consider joining a clinical trial with them for as long as possible. Finally, early to 90 percent accuracy. A definitive diagnosis of AD, son with AD and the family have a firm diagnosis, or other research study. Being able to participate diagnosis gives family caregivers the opportunity to however, is still only possible after death, during an the more time they have to make future living for as long as possible in making personal decisions learn how to recognize and cope with changes over autopsy, and we are still far from the ultimate goal— arrangements, handle financial matters, establish is important to many people with AD. time in their loved one as well as to develop strate- a reliable, valid, inexpensive, and early diagnostic a durable power of attorney and advance direc- Early diagnosis also gives families time to recog- gies that support their own physical, emotional, marker that can be used in any doctor’s office. tives, deal with other legal issues, create a support nize that life does not stop with a diagnosis of AD. and financial health. Early diagnosis has several advantages. For The person is still able to participate in many of example, many conditions cause symptoms that the daily activities he or she has always enjoyed, and families can encourage the person to continue48 ALZH EIMER’S D ISE ASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 49
  • P A R T 3 AD Research: Better Questions, New Answers highly sophisticated imaging systems that have Causes of Dementia been used in many areas of medicine, including AD. PET scans, single photon emission D ementia is the loss of cognitive functioning—thinking, remembering, and reasoning—to such an extent that it interferes with a person’s daily life and activities. It is not a disease itself, but a group of symptoms that often accompanies a disease or condition. Some dementias are caused by computed tomography (SPECT), and MRI are all examples. These “windows” on the living brain may help scientists measure the earliest changes neurodegenerative diseases. Dementia also has other causes, some of which are treatable. in brain function or structure in order to identify Neurodegenerative Diseases that Cause Dementia Other Causes of Dementia people who are at the very first stages of the ■ Alzheimer’s disease ■ Medication side effects disease—well before they develop clinically ■ Vascular dementia ■ Depression apparent signs and symptoms. ■ Parkinson’s disease with dementia ■ Vitamin B12 deficiency To help advance this area of research, NIA ■ Frontotemporal lobar degeneration, including: ■ Chronic alcoholism launched the multi-year AD Neuroimaging ■ frontotemporal dementia ■ Certain tumors or infections of Initiative (ADNI) in 2004. This project is fol- ■ frontotemporal dementia with parkinsonism the brain lowing about 200 cognitively healthy individuals linked to chromosome 17 (FTDP-17) ■ Blood clots pressing on the brain and 400 people with MCI for 3 years and 200 ■ Pick’s disease ■ Metabolic imbalances, including people with early AD for 2 years. Over the course ■ supranuclear palsy thyroid, kidney, or liver disorders of this study, participants undergo multiple MRI ■ corticobasal degeneration and PET scans so that study staff can assess how the brain changes in the course of normal aging Biological samples also are available for approved and MCI, and with the progression of AD. By biomarker projects. NIA hopes that this initiative using MRI and PET scans at regularly scheduled will help create rigorous imaging and biomarker intervals, study investigators hope to learn when standards that will provide measures for the Scientists also see advantages to early diagnosis. measured through memory and recall tests. Tests and where in the brain degeneration occurs as success of potential treatments. This would Developing tests that can reveal what is happen- that measure a person’s abilities in areas such as memory problems develop. substantially increase the pace and decrease the ing in the brain in the early stages of AD will help abstract thinking, planning, and language can Another innovative aspect of ADNI is that cost of developing new treatments. The ADNI them understand more about the cause and devel- help pinpoint changes in these areas of cognitive scientists are correlating the participants’ imaging study is being replicated in similar studies by opment of the disease. It also will help scientists function. Researchers are working to improve information with information from clinical, researchers in Europe, Japan, and Australia. learn when and how to prescribe the use of drugs standardized tests that might be used to point memory, and other cognitive function tests, and These types of neuroimaging scans are still and other treatments so they can be most effective. to early AD or predict which individuals are at with information from blood, cerebrospinal fluid, primarily research tools, but one day they may be higher risk of developing AD in the future. and urine samples. Results from these samples used more commonly to help physicians diagnose EXCITING NEW DEVELOPMENTS Other studies are examining the relationship may provide valuable biomarkers of disease AD at very early stages. It is conceivable that IN AD DIAGNOSIS between early damage to brain tissue and out- progress, such as changing levels of beta-amyloid these tools also may someday be used to monitor Scientists are now exploring ways to help physicians ward clinical signs. Still others are looking for and tau, indicators of inflammation, measures of the progress of the disease and to assess responses diagnose AD earlier and more accurately. For changes in biomarkers in the blood or cerebro- oxidative stress, and changing cognitive abilities. to drug treatment. example, some studies are focusing on changes spinal fluid that may indicate the progression of An important ADNI achievement is the in mental functioning. These changes can be AD (see Very Early Signs and Symptoms on creation of a publicly accessible database of page 28 for more on this work). images, biomarker data, and clinical information One of the most exciting areas of ongoing available to qualified researchers worldwide. research in this area is neuroimaging. Over the past decade, scientists have developed several50 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 51
  • P A R T 3 AD Research: Better Questions, New Answers New Technologies Help People Participate in AD Research at Home T raditionally, AD scientists have collected data by asking people to come to a clinic once or twice a year over a period of years. They give the participants Science University is exploring the use of unobtrusive, simple technology and intelligent systems to detect and monitor subtle changes in movement that may a physical exam and ask them to take a series of indicate age-related cognitive changes. This project is memory, language, and other cognitive function tests. building on research that has suggested that motor- These studies collect much useful information, but function changes may arise before memory changes they have their limitations. For one thing, participants become apparent (see Very Early Signs and are seen only once or twice during the year, so the Symptoms on page 28 for more on this research). data collected represent only a “snapshot” in time. All of the 300 study participants are 80 years or The studies cannot effectively capture day-to-day older or have a spouse of a similar age, and live fluctuations in behaviors and cognitive abilities. independently in Portland-area retirement communi- Another limitation is that participants are seen in ties. Wireless, infrared motion sensors, like those a research setting, not in their natural community used to automatically open grocery store doors, have environment. For many, coming to the clinic can be been placed strategically throughout the participants’ This photo shows ORCATECH inconvenient, difficult, or both. homes to gather data about changes in their walking study participants at home. The Advances in technology, as shown in the two or dressing speed over time. Special software also small device between the photo- research projects described here, offer some hope has been installed on each participant’s home graphs on the wall is an infrared for dealing with these challenges by bringing computer to measure motor skills and speed in typing motion sensor. research to people right in their own homes. or using a mouse. The sensors and computer software collect data about motion, not what the volunteer USING TECHNOLOGY mood. This study is looking at questions such as MOTION DETECTORS TELL is actually doing. Privacy is largely not a concern TO COLLECT DATA AT HOME how likely people are to complete the questions AN INTERESTING STORY therefore, because the volunteers are not directly Researchers at nearly 30 sites nationwide are using each method, which method is the most Scientists who are trying to develop methods for observed and no video or photographs are taken. comparing various ways of collecting data, including efficient, and how sensitive each method is. diagnosing AD as early as possible continually The 3-year study began in early 2007, so results the use of an in-home “kiosk” that combines a Having a data collection system that is easy to grapple with two challenges in conducting their are not yet available. However, a small pilot study touch-screen computer monitor with a telephone use and that collects data accurately and completely research. First, they need to find easy and accurate using the same type of sensors showed a clear handset, an interactive voice-response system, and may encourage wider participation in AD clinical ways to collect data from older people, who often difference in the walking speeds of people age 65 traditional mail and telephone. All three methods trials. It also may reduce the expense and burden of have physical, emotional, or cognitive problems. and older who had MCI, compared with cognitively gather the same data about several areas known to conducting AD research. Early results from this study Second, they need to find ways to assess accurately healthy people of the same age, over time periods be important in early detection of cognitive decline: show that the older participants were skeptical at first the very early changes in physical or cognitive of nearly a year. These data suggest that a remote memory; language skills; attention and concentration; about using the kiosk, but once they learned how to abilities that could indicate that AD is progressing. sensing system like this is a feasible technology and is activities of daily living; quality of life; health care use it, they became enthusiastic and excited about Under an NIA grant, the Oregon Center for Aging potentially sensitive enough to distinguish accurately and resource use; and changes in “global” well-being participating. and Technology (ORCATECH) at Oregon Health & between affected and unaffected people. as measured by self-rating of health, cognition, and52 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 53
  • P A R T 3 AD Research: Better Questions, New Answers HELPING PEOPLE WITH The AD MAINTAIN THEIR MENTAL Search FUNCTIONING In the mid-1970s, scientists discovered that levels of a neurotransmitter (a chemical that carries messages between neurons) called acetylcholine for New Treatments 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 M ore and more, scientists are able most immediate need is for treatments to control forming memories. It is used by neurons in the to think about ways to treat, slow, cognitive loss as well as problem behaviors, such as hippocampus and cerebral cortex, which are areas or perhaps even prevent AD at a aggression, agitation, wandering, depression, sleep of the brain important to memory function. This number of possible points during disturbances, hallucinations, and delusions. Safe discovery was an important initial breakthrough in the years-long continuum of disease progression. medications that remain effective over time are the search for drugs to treat AD. This continuum begins with the very earliest needed to ease a broad range of symptoms and to Four medications, tested in clinical trials, have disease stage, even before symptoms are evident, improve a person’s cognitive function and ability been approved by the FDA for use in treating AD moves to the first signs of memory and cognitive to carry out activities of daily living. Scientists also symptoms. Donepezil (Aricept®), rivastigmine problems, then continues through the mild and are investigating treatments that combine medica- (Exelon®), and galantamine (Razadyne®) are pre- moderate stages, and ends with the very late stages tions with lifestyle strategies to lessen the risk of scribed to treat mild to moderate AD symptoms. and the person’s death. developing cognitive decline or AD. Eventually, Donepezil was recently approved to treat severe As a result, researchers who focus on developing scientists hope to develop treatments that attack AD as well. These drugs, known as cholinesterase AD treatments think a lot about the importance the earliest manifestations and underlying causes inhibitors, act by stopping or slowing the action of of timing: When would it be best to intervene of AD, thereby slowing, delaying, or preventing acetylcholinesterase, an enzyme that breaks down and what interventions are most appropriate at the disease from progressing and damaging cog- acetylcholine. They help to maintain higher levels which time? These questions are similar to those nitive function and quality of life. Scientists use of acetylcholine in the brain. In some people, the asked with other conditions, such as heart disease. clinical trials to pursue all these goals. drugs maintain abilities to carry out activities of For example, a physician would prescribe different Today, NIA, other NIH institutes, and private daily living. They also may maintain some think- treatments for a patient who is seemingly healthy industry are conducting many clinical trials of ing, memory, or speaking skills, and can help with but who is at risk of having future heart disease AD interventions (see page 59 for more about certain behavioral symptoms. However, they will than for a patient who is actually having a heart clinical trials). These studies focus on several not stop or reverse the underlying progression of attack or whose heart disease is well established. The key areas: AD and appear to help people only for months to same decision process now can be applied to AD. a few years. The newest approved AD medication ■ Helping people with AD maintain their mental It has become clear that there probably is no is memantine (Namenda®), which is prescribed to functioning single “magic bullet” that will, by itself, prevent or treat moderate to severe AD symptoms. This drug ■ Managing symptoms cure AD. Therefore, investigators are working to appears to work by regulating levels of glutamate, ■ Slowing, delaying, or preventing AD develop an array of options from which physicians another neurotransmitter involved in memory can choose. For people who already have AD, the function. Like the cholinesterase inhibitors, memantine will not stop or reverse AD.54 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 55
  • P A R T 3 AD Research: Better Questions, New Answers MANAGING SYMPTOMS The damage of AD affects many different parts SLOWING, DELAYING, of the brain. This presents a problem because even OR PREVENTING AD “My father is often agitated. He paces up and down, small tasks require the brain to process signals that AD research has developed to the point where wringing his hands and crying. I know he’s sad or often involve more than one region of the brain. If scientists are looking beyond treating symptoms anxious about something but he can’t tell me what’s this processing is disrupted because of AD, the to addressing the underlying disease process. bothering him. Asking him about it just makes him person may not be able to do the task or may act Slowing the progress of AD could do much to more upset.” in a strange or inappropriate way. maintain the functioning of people with AD and “Last week, I visited Mom in the nursing home. We In light of our growing understanding about the reduce physical and emotional stress on caregivers. had a great time. Then yesterday, I went to see her effects of AD on the brain, behaviors like the ones Delaying AD’s effects also could help to postpone again. When I walked into her room, she didn’t know highlighted above suddenly make sense or even or prevent placement in an assisted living facility me. She thought I was her sister.” provide a loving opportunity for caregivers: or nursing home, and reduce the financial costs of the disease. Preventing AD altogether is, of course, “My husband used to be such an easy going, calm For a man who can no longer distinguish between past the ultimate long-term goal. person. Now, he suddenly lashes out at me and uses and present, the anguish caused by the death of a par- NIA and pharmaceutical companies support awful language. Last week, he got angry when our ent may be as real today as it was many years before. treatment clinical trials that are aimed at slow- daughter and her family came over and we sat down Sitting down to a family meal may produce ing, delaying, or preventing AD. The advances to eat. I never know when it’s going to happen. He’s intense anxiety when a person has no idea what to do in our knowledge about the mechanisms and risk changed so much—it scares me sometimes.” with the knife and fork in front of him and all the factors associated with AD have expanded the memory performance. The trial will provide “Gran hums all the time. She used to be a singer. Is conversation and activity feel overwhelming. types of interventions under study. These trials useful data on the safety, feasibility, and she trying to relive her past?” are examining a host of possible interventions, potential effectiveness of this innovative treatment Memories of favorite songs from long ago resurface and including cardiovascular treatments, hormones, approach. Investigators may be able to use the As AD begins to affect memory and mental provide a compelling link to a happy time in the past. type 2 diabetes treatments, antioxidants, omega-3 results to plan future full-scale clinical trials. abilities, it also begins to change a person’s emo- Behavioral symptoms, often emotional and fatty acids, immunization, cognitive training, and Beyond pilot studies, investigators also are tions and behaviors. Between 70 and 90 percent upsetting, are one of the hardest aspects of the exercise, among others. conducting full-scale AD clinical trials of various of people with AD eventually develop one or more disease for families and other caregivers to deal For example, NIA funds pilot trials to learn interventions. One of these trials, the Alzheimer’s behavioral symptoms. These symptoms include with. They are also a visible sign of the terrible whether treating one or another aspect of type 2 Disease Cooperative Study (ADCS), is testing sleeplessness, wandering and pacing, aggression, change that has taken place in the person with diabetes will affect cognitive health and AD pro- whether one omega-3 fatty acid (DHA), found in agitation, anger, depression, and hallucinations AD. Researchers are slowly learning more about gression. A pilot trial is a relatively small clinical the oil of certain fish, can slow the progression of and delusions. Some of these symptoms may why behavioral symptoms occur and are conduct- trial that collects initial data on the safety, cognitive and functional decline in people with become worse in the evening (a phenomenon ing clinical trials on new treatments—both drug effectiveness, and best dosage of a potential mild to moderate AD. During the 18-month called “sundowning”) or during daily routines, and non-drug—to deal with difficult behaviors. treatment. This information helps investigators clinical trial, investigators will measure the especially bathing. decide which treatments should be tested in progress of the disease using standard tests for larger, full-scale trials. One 4-month pilot trial functional and cognitive change. Researchers also has examined the effects on AD of administering will evaluate whether taking DHA supplements Coping with Behavioral Symptoms a nasal-spray form of insulin. This trial is has a positive effect on possible physical and For more information on how to deal with founded on evidence that AD is associated with biological markers of AD, such as brain atrophy behavioral issues and symptoms, visit the reduced levels of insulin in cerebrospinal fluid caregiving section of NIA’s Alzheimer’s and that treatment with insulin improves Disease Education and Referral (ADEAR) Center website at: www.nia.nih.gov/ Alzheimers/Caregiving/HomeAndFamily.56 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 57
  • P A R T 3 AD Research: Better Questions, New Answers Participating in a Clinical Trial R apid advances in our knowledge about AD have led to the development of many a trial. Here are some facts that potential participants might want to know about clinical trials. small number of participants and examines its action in the body and its safety. The main goals of promising new drugs and treatment Phase I trials are to establish the strategies. However, before these WHAT KIND OF highest dose of a new drug that new strategies can be used in clini- TRIALS ARE THERE? people can tolerate and to define cal practice, they must be shown Treatment trials with existing drugs the dose at which people may to work in people. This means or behavioral strategies assess begin to experience harmful side that clinical trials—and volunteer whether an intervention already effects. These trials generally last participants—are an essential approved for other purposes may only a few months. part of AD research. Advances be useful in treating age-related If results show that the treat- in prevention and treatment are cognitive decline or AD. For ment appears to be safe, it will possible thanks to volunteers who example, trials have tested whether go on to Phase II and Phase participate in clinical trials. drugs used to lower cholesterol III clinical trials. Phase II trials Clinical trials are the primary help slow progression of AD. involve larger numbers of people way that researchers find out if Treatment trials with experimental studied over longer periods of a promising treatment is safe. drugs or strategies show whether time than Phase I trials. In these Clinical trials tell researchers which a new drug or treatment approach trials, the study team wants to treatments are the most effective can help improve cognitive function know whether the treatment is and for which people they may or lessen symptoms in people with safe and effective at changing work best. Trials can take place AD, slow the progression to AD, the course of the disease. Phase in various settings, such as private or prevent it. Interventions tested II trials occasionally also involve research facilities, teaching hos- in these trials are developed from the use of a placebo (an inactive pitals, specialized AD research knowledge about the mechanisms substance that looks like the study centers, and doctors’ offices. FDA involved in the AD process. Experi- drug). Results from Phase II trials and proteins in blood and spinal fluid. The ADCS Cancer Prevention Trial (SELECT). SELECT approval is necessary before mental drugs, for example, are give study staff an indication of is a federally established consortium conducting is evaluating whether taking selenium and/or scientists can begin a clinical trial. first tested in tissue culture and in the effective dose to take into clinical trials on AD, with sites across the United vitamin E supplements can prevent prostate Participating in a clinical trial animals to determine their actions in Phase III trials. Phase III trials are States and Canada. cancer in healthy men older than 60 years. is a big step for anyone, including the body. Safety and effectiveness large studies that compare an Full-scale AD prevention trials are under- PREADVISE is evaluating whether these people with AD and their care- studies are also conducted in experimental treatment with a way as well. One such trial, Prevention of supplements can help prevent memory loss and givers. That is why physicians and animals before the compounds placebo or standard treatment Alzheimer’s Disease with Vitamin E and dementia by protecting brain cells from oxidative clinical trials staff spend time talking are tested in humans. to determine safety and efficacy Selenium (PREADVISE), is being conducted in damage (see The Aging Process on page 42 for with participants about what it is (whether the treatment has the conjunction with a National Cancer Institute- more on oxidative damage). About 6,000 of the like to be in a trial and the pros and WHAT ARE THE PHASES power to produce an effect). funded trial called the Selenium and Vitamin E more than 30,000 men enrolled in SELECT are cons of participating. It is also why OF CLINICAL TRIALS? After these phases are complete participating in PREADVISE. they get a signed informed consent During Phase I trials, a research form before a person enrolls in team gives the treatment to a C o n t i nu ed o n nex t p a ge58 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 59
  • P A R T 3 AD Research: Better Questions, New Answers Participating in a Clinical Trial (Continued) and investigators are satisfied that representative (usually a family groups may receive a different WHAT SHOULD choose which study group to be the treatment is safe and effective, member) to give permission for the drug, a placebo, or a different PEOPLE CONSIDER in, or not knowing for a long time the study team may submit its person to participate. Laws and intervention. Comparing results for BEFORE PARTICIPATING IN whether the study was successful. data to the FDA for approval. FDA regulations regarding informed different groups gives researchers A CLINICAL TRIAL? Ongoing and open communica- experts review the data and consent differ across States and confidence that changes in the People who have participated in tion with study staff can help to decide whether to approve the research institutions, but all are test group are the result of the AD clinical trials say that it’s a good reduce this frustration. drug or treatment for use in patients intended to ensure that participants experimental treatment and not idea to consider the following issues ■ Finding the right clinical with the disease under study. are protected and well cared for. some other factor, such as the before deciding to join a trial. trial. Some clinical trials involve Next, people go through a placebo effect (this is when people participants who are cognitively ■ Expectations and motiva- WHAT HAPPENS WHEN screening process to see if they feel an effect because they think healthy or have only mild symp- tions. The test drug or treatment A PERSON SIGNS UP FOR A qualify to participate in the trial. they are getting the test medica- toms because they are testing a give insights into what to expect may relieve a symptom, change CLINICAL TRIAL? If they qualify and can safely tion even though they are really drug that might delay a decline in the future. They also can share a clinical measurement, or reduce First, it is important to learn participate, then they are enrolled getting a placebo). In many trials, in cognitive function. Other trials information about support groups the risk of death, but clinical trials about the trial. Staff at the clinical in the trial. no one—not even the research involve participants who have and other helpful resources. generally do not have miraculous research center explain the trial team—knows who is getting the more advanced AD because they results and participants may not in detail to potential participants WHAT HAPPENS treatment and who is getting the are testing a treatment that might FOR MORE INFORMATION receive any direct benefit. With and describe possible risks DURING A TRIAL? placebo or other intervention. This lessen behavioral symptoms. Or, a To learn more about AD clinical a complex disease like AD, it is and benefits. Staff also talk If participants agree to join the means that the participant, family trial may be testing new strategies trials, visit the Alzheimer’s Disease unlikely that one treatment will about the participants’ rights as trial and an evaluation process member, and the staff are “blind” to help caregivers. Even if a par- Education and Referral (ADEAR) cure or prevent the disease. Some research volunteers, including shows they meet all the criteria for to the treatment being received. ticipant is not eligible for one trial, Center’s Clinical Trials Database people choose not to participate their right to leave the trial at participation, then a “baseline” This kind of trial is called a double- another trial may be just right. website (www.nia.nih.gov/ or decide to drop out of a study any time. Participants and their visit is scheduled with the trial blind, placebo-controlled trial. ■ The biggest benefit of all. Alzheimers/ResearchInformation/ because this reality does not meet family members are entitled to staff. This visit generally involves As the trial progresses, partici- Many families find that the biggest ClinicalTrials). This NIA website their expectations. Others choose have this information repeated cognitive and physical tests. This pants and family members usually benefit of participating in a clinical includes a list of AD and dementia to stay in a trial because they and explained until they feel they gives the team information against must follow strict medication or trial is the regular contact with the clinical trials currently in progress realize that even if they get no understand the nature of the trial which to measure future mental treatment instructions and keep study team. These visits provide an at research centers throughout or only a slight benefit, they are and any potential risks. and physical changes. detailed records of symptoms. Every opportunity to get state-of-the-art the United States. It also provides making a valuable contribution to After all questions have been In most clinical trials, partici- so often, participants visit the clinic AD care and to talk regularly with information about the phases knowledge that will help people answered, participants who are pants are randomly assigned to or research center to have physical AD experts who have lots of practi- of clinical trials and how to in the future. still interested in joining the trial different study groups so that and cognitive exams, give blood cal experience and a broad per- participate, explains the drug ■ Uncertainty. Some families are asked to sign an informed each study group has people and urine samples, and talk with spective on the disease. The study development process, and provides have a hard time with the un- consent form. In some cases, a in it of about the same average trial staff. These visits allow the inves- team understands and can provide links to other useful websites. certainties of participation—for participant may no longer be characteristics (such as age, sex, tigators to collect information on the advice about the emotional and Also, visit the clinical trials web- example, not knowing whether able to provide informed consent educational level, or cognitive effects of the test drug or treatment, physical aspects of the person with sites of the National Institutes the person is taking the test because of problems with memory ability). One group, the test see how the disease is progressing, AD and the caregivers’ experi- of Health (www.clinicaltrials.gov) treatment, a placebo, or a control and thinking. In such cases, it is group, receives the experimental and see how the participant and ence. Team members can suggest or the Alzheimer’s Association treatment, not being able to still possible for an authorized drug or intervention. Other the caregiver are doing. ways to cope with the present and (www.alz.org).60 ALZH EIMER’S D ISE ASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 61
  • O ne of the greatest costs of AD can One of the hardest decisions that many be the physical and emotional toll families face is whether and when to place on family members, caregivers, and a loved one with AD in a nursing home or friends of people with the disease. other type of care facility. Once this decision The changes in a loved one’s personality and is made, families must decide what type of mental abilities; the need to provide constant, care is best for the person and the family. loving attention for years on end; and the demands Many investigators are working to identify of bathing, dressing, and other caregiving duties in strategies that can lead to improved quality of the later stages of the disease can be hard to bear. care in various facilities, including adult day Many caregivers must assume new and unfamiliar care centers, assisted living facilities, continuing roles in the family, and these changes can be both care retirement communities, nursing homes, 4 difficult and sad. Not surprisingly, caregivers of and special care units (separate areas within people with dementia spend significantly more nursing homes or assisted living facilities PART time on caregiving tasks than do caregivers of people with other types of illnesses. designed especially for people with dementia). Who Are AD Family Caregivers?Improving Support Many primary caregivers are family raising children of their own. Brothers and sisters: Siblings members, and NIA-funded research Juggling two sets of responsibilities may assume primary responsibility has shown that the value of informal is often tough for these members for care if they live close by. Many Families family caregiving of people with of the “sandwich generation.” of these caregivers also are older cognitive impairment adds up to and may be coping with their ownfor billions of dollars every year. Who are these family caregivers? Daughters-in-law: Many women in this group help take care of an older person with AD. They are frailties or health problems. Grandchildren: Older children and Other Spouses: This is the largest groupCaregivers the third largest group of family may become major helpers in of caregivers. Most are older, too, caregivers. caring for a grandparent with AD. and many have their own health Grandchildren may need extra Sons: Although many are involved problems. support if their parents’ attention is in the daily care of a parent with heavily focused on the ill grand- Daughters: The second largest AD, sons often focus on the finan- parent or if the grandparent with group of primary caregivers is cial, legal, and business aspects of AD lives in the family’s home. daughters. Many are married and caregiving. ALZHEIMER’S DISEASE Unraveling the Mystery 63
  • P A R T 4 Improving Support for Families and Other Caregivers services and information geared to different Where Are People with stages of the disease. Alzheimer’s Disease Cared For? Research Findings Benefit ■ Traditions and attitudes about caregiving vary across cultural groups. For example, some Home Caregivers ■ researchers have found that African-American ■ Assisted living facilities (those in the early stages) caregivers use fewer formal in-home services than ■ Adult day care centers do white caretakers. Some populations may find ■ Nursing homes it difficult to publicly admit that a family member ■ Special care units has AD and may be reluctant to seek help with caregiving issues. Therefore, programs and services A lthough research on family caregiver for caregivers must be culturally appropriate and support is still in its early days, we have sensitive to factors that positively and negatively already learned much about the unique influence caregivers’ attitudes and ability to carry ones, made life easier for them, improved their aspects of caregivers’ personalities and out their responsibilities. caregiving ability, improved the care recipient’s situations. For example, it is well established that ■ Use of multiple types of support over an life, and helped them keep their loved one at AD caregivers often experience stress, anxiety, extended period of time helps caregivers. For home. depression, and other mental health problems as a example, the Resources for Enhancing Alzheimer’s ■ Developing ways to help caregivers become result of the continuing and demanding nature of Caregiver Health (REACH) clinical trial showed educated about AD, improve flexibility in AD care. This chronic stress can have detrimental that caregivers who received 6 months of inten- responding to caregiving demands, and learn a effects on the physical health of caregivers. The sive help with caregiving strategies had significant variety of practical strategies can help. Studies physical and emotional effects of AD caregiving improvements in overall quality of life. They also are teaching caregivers how to read the emotional can last a long time, even after the death of the had lower rates of clinical depression compared to and physical cues of the person with AD and to person with AD. caregivers who did not participate in the program. understand the sequence of events that often On the other hand, research also has shown The caregiving strategies included information leads to inappropriate behaviors. They are also that caregiving can have important positive effects, AD caregivers do not all have the same sharing, instruction, role plays, problem-solving, helping caregivers respond to the needs of the including: psychological and physical response to caregiving. skills training, stress-management techniques, and person with AD in a variety of creative ways, For example, caregivers who have strong support telephone support groups. Caregivers reported such as maintaining flexibility in the face of ■ A new sense of purpose or meaning in life systems and well-developed coping skills may be that taking part in REACH helped them feel many demands, becoming educated about the ■ Fulfillment of a lifelong commitment to a spouse able to weather the stresses of caring for a loved more confident in working with their loved disease, learning practical strategies, using available ■ An opportunity to give back to a parent some one with AD. Others who have few breaks from of what the parent has given to them caregiving responsibilities and/or have preexisting ■ Renewal of religious faith illnesses may be more vulnerable to the physical For Information About AD Support Groups ■ Closer ties with people through new relation- and emotional stresses associated with dementia To find out whether an AD support group is operating in your area, contact: ships or stronger existing relationships care. Caregiver research is beginning to discover ■ NIA’s Alzheimer’s Disease Education and Referral (ADEAR) Center at 800-438-4380 or effective ways to ease the burden of caregiving. visit www.nia.nih.gov/Alzheimers/ResearchInformation/ResearchCenters Researchers have learned that: ■ Alzheimer’s Association at 800-272-3900 or visit www.alz.org ■ 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 offering64 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 65
  • P A R T 4 Improving Support for Families and Other Caregivers resources, involving other family members and in the early stages often still have good coping separate groups; in others, people with AD and friends, and balancing the needs of the person skills and are intensely aware of themselves and their caregivers are together for part of the session with their own needs. their symptoms. They also may feel considerable and apart for the remainder. ■ Helping caregivers deal with the complicated distress, embarrassment, and isolation because of a Other types of early-stage support groups are issue of whether and when to place a loved one perceived stigma associated with the disease. As a less structured. Members discuss topics of their in a nursing home is an important aspect of result, a growing number of people with early-stage own choosing, and the groups meet regularly over caregiver support. People with dementia are AD and their family members are looking for cop- an extended time. Members with AD may stay in at much greater risk of nursing home placement ing strategies, meaningful activities, and mental the group as long as they are able to meaningfully than are other older people of the same age. stimulation. They are eager to educate themselves take part in the discussion and activities. Placing a loved one in a nursing home may relieve about AD, share common experiences, and break Early-stage support groups are not for everyone. some of the burden of caregiving, but it does not the potential barriers and isolation caused by their Some people with early AD and their families may necessarily reduce caregiver stress or emotional diagnosis. This has led to the formation of early- not benefit because of family conflict, denial, cogni- distress. Moreover, nursing home costs now ■ Helping caregivers stay physically active has stage support groups specifically designed to meet tive impairment, or discomfort with the intimacy average more than $70,000 per year. big benefits. Researchers have found that regular their needs. of a group experience. However, most participants One clinical trial tested the effects of an moderate exercise is an important stress reliever for Some early-stage support groups follow a report positive outcomes, such as a greater sense enhanced counseling and support program on caregivers. Exercise helps to reduce blood pressure structured model, with 1- to 2-hour sessions of control over their lives and feelings that they nursing home placement and caregiver health. increases due to stress, improves sleep quality, and scheduled over 6 to 8 weeks. The sessions are are not alone. Many participants find early-stage This program for caregivers consisted of six sessions reduces psychological distress and depression. led by a facilitator and discussion topics are support groups helpful because they instill a spirit of individual and family counseling, support determined in advance. Guest speakers provide of camaraderie, build coping skills, and forge group participation, and on-demand telephone EARLY-STAGE AD SUPPORT GROUPS: information and help on specific topics such as relationships and emotional support that continue counseling. Participants in the program were able A VITAL SOURCE OF HELP legal and financial planning. In some programs, to help the person with AD and the caregiver even to delay placement of their loved ones in nursing For families and friends who care for a person with the person with AD and the caregiver meet in after the sessions end. homes by about 18 months. Researchers attributed AD, talking with others who are going through the the effects of the program to greater tolerance for same experience can be a vital lifeline. AD support memory and behavior problems in the person with groups provide a place where caregivers can seek AD, improved satisfaction with the support respite, express concerns, share experiences, get What Happens Next? provided by family and friends, and fewer tips, and receive emotional comfort. NIA-funded It is a question many people and their families ask when AD is first diagnosed. symptoms of depression. Moreover, it appears Alzheimer’s Disease Centers, the Alzheimer’s Members of an early-stage support group at the Northwestern University Alzheimer’s that the extra time at home did not come at the Association, and many other organizations sponsor Disease Center in Chicago wrote What Happens Next? to help people with early- expense of the caregivers’ sense of well-being. in-person and online AD support groups all stage dementia cope with their feelings and the practical aspects of everyday life. around the country. For a free copy, call the Alzheimer’s Disease Education and Referral (ADEAR) Improved diagnostic tests and increasing aware- Center at 800-438-4380 or visit www.nia.nih.gov/Alzheimers/Publications/ ness of AD mean that more and more people are WhatHappensNext.htm. now being diagnosed at early stages of AD. People66 ALZHEIMER’S DISEASE Unraveling the Mystery A LZ HE IME R’ S D ISE A SE Unraveling the Mystery 67
  • P A R T 4 Improving Support for Families and Other Caregivers Conclusion Taking Care of Mom or Dad at a Distance T aking care of a parent with AD who lives hundreds of miles away is a real worry facing brothers decided to see whether videoconferencing could be a way to keep in touch with her. They in- T many adults. “How can we make sure Mom gets the stalled a computer with a video camera in her home so he future builds upon the events and best care possible if we’re not there all the time?” they could check on her daily, helping fulfill her wish to experiences of the past. That’s certainly true “What can I do to help Dad live at home for as long continue living independently on the family farm while of AD research. Our knowledge of AD is as possible?” assuring themselves that she was faring well. advancing rapidly, and we have much to That was the dilemma facing Ken Nixon and his “We had a need, and we patched the system celebrate in our scientific successes. two brothers in 2001. Their mother lived in an Arkan- together at first,” says Ken. “It exceeded our At the same time, we cannot forget that AD remains sas farming community and wanted to stay there. Ken expectations in being able to keep our mother an urgent problem for our Nation. The challenge is and his brothers lived 3 to 5 hours away—close, but independent and connected to the family. We could to continue building on these discoveries so that we not close enough. call and have coffee with her every morning, and it can create a brighter future in which the potential of With funding from NIA, Ken and his brothers got her day started off right. She had something to successfully managing AD or even preventing this created a multi-purpose, Internet-based system called look forward to every day—one or two of her boys terrible disease can become a reality. AttentiveCare that is currently available to others faced was going to visit.” with the same long-distance caregiving challenges. After 6 months of using the home-grown system, Back in 2001, broadband Internet service had just Nixon decided to develop it to help other caregivers. become available in their mother’s community, so the 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 recipi- ents connected with family. The system’s journal and data logging capability also allows family caregivers to maintain and share information about the care Ken Nixon and his grandson use AttentiveCare to recipient’s health and well-being, whether they are check in with Ken’s mother. across the street or thousands of miles away.68 ALZH EIMER’S D ISE ASE Unraveling the Mystery
  • Glossary Acetylcholine—a neurotransmitter that plays Axon—the long extension from a neuron that Cerebrospinal fluid—the fluid found in DNA (deoxyribonucleic acid)—a long, an important role in many neurological functions, transmits outgoing signals to other cells. and around the brain and spinal cord. It protects double-stranded molecule within the nucleus of including learning and memory. these organs by acting like a liquid cushion and the cell that forms chromosomes and genes. Beta-amyloid—a part of the amyloid precursor by providing nutrients. Amygdala—an almond-shaped structure protein found in plaques, the insoluble deposits Early-onset Alzheimer’s disease—a rare involved in processing and remembering strong outside neurons. Chromosome—a threadlike structure in form of AD that usually affects people between emotions such as fear. It is part of the limbic the nucleus of a cell that contains DNA. DNA ages 30 and 60. It is called familial AD (FAD) if it Brain-derived neurotrophic factor system and located deep inside the brain. sequences make up genes. Most human cells runs in the family. (BDNF)—a growth factor that stimulates survival, have 23 pairs of chromosomes containing Amyloid plaque—a largely insoluble growth, and adaptability of some neurons. Entorhinal cortex—an area deep within the approximately 30,000 genes. deposit found in the space between nerve cells brain where damage from AD often begins. Brain stem—the portion of the brain that in the brain. Plaques are made of beta-amyloid, Clinical trial—a research study involving connects to the spinal cord and controls automatic Enzyme—a protein that causes or speeds up a other molecules, and different kinds of nerve humans that rigorously tests safety, side effects, body functions, such as breathing, heart rate, and biochemical reaction. and non-nerve cells. and how well a medication or behavioral blood pressure. treatment works. Free radical—a highly reactive molecule Amyloid precursor protein (APP)—the Capillary—a tiny blood vessel. The brain has (typically oxygen or nitrogen) that combines larger protein from which beta-amyloid is formed. Cognitive functions—all aspects of conscious billions of capillaries that carry oxygen, glucose easily with other molecules because it contains an thought and mental activity, including learning, Apolipoprotein E—a protein that carries (the brain’s principal source of energy), nutrients, unpaired electron. The combination with other perceiving, making decisions, and remembering. cholesterol in blood and that appears to play some and hormones to brain cells so they can do their molecules sometimes damages cells. role in brain function. The gene that produces this work. Capillaries also carry away carbon dioxide Computed tomography (CT) scan— Gene—the biologic unit of heredity passed from protein comes in several forms, or alleles: ε2, ε3, and cell waste products. a diagnostic procedure that uses special x-ray parent to child. Genes are segments of DNA and and ε4. The APOE ε2 allele is relatively rare and equipment and computers to create cross-sectional Cerebellum—the part of the brain contain instructions that tell a cell how to make may provide some protection against AD (but it pictures of the body. responsible for maintaining the body’s balance specific proteins. may increase risk of early heart disease). APOE and coordination. Corpus callosum—thick bundles of nerve cell ε3 is the most common allele and appears to play Genetic risk factor—a variant in a cell’s fibers that connect the two cerebral hemispheres. a neutral role in AD. APOE ε4 occurs in about Cerebral cortex—the outer layer of nerve cells DNA that does not cause a disease by itself but 40 percent of all people with AD who develop surrounding the cerebral hemispheres. Dementia—a broad term referring to a decline may increase the chance that a person will the disease in later life; it increases the risk of in cognitive function to the extent that it interferes develop a disease. Cerebral hemispheres—the largest developing AD. with daily life and activities. portion of the brain, composed of billions of nerve cells in two structures connected by the Dendrite—a branch-like extension of a neuron corpus callosum. The cerebral hemispheres control that receives messages from other neurons. conscious thought, language, decision making, emotions, movement, and sensory functions.70 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 71
  • Glossary Glial cell—a specialized cell that supports, release energy. In others, the cells use energy to Neurofibrillary tangle—a filamentous Synapse—the tiny gap between nerve cells protects, or nourishes nerve cells. make complex compounds out of simpler ones collection of twisted and hyperphosphorylated tau across which neurotransmitters pass. (like making proteins from amino acids). found in the cell body of a neuron in AD. Hippocampus—a structure in the brain that Tau—a protein that helps to maintain the plays a major role in learning and memory and is Microtubule—an internal support structure for Neuron—a nerve cell. structure of microtubules in normal nerve cells. involved in converting short-term to long-term a neuron that guides nutrients and molecules from Abnormal tau is a principal component of the Neurotransmitter—a chemical messenger memory. the body of the cell to the end of the axon. paired helical filaments in neurofibrillary tangles. between neurons. These substances are released by Hypothalamus—a structure in the brain Mild cognitive impairment (MCI)— the axon on one neuron and excite or inhibit Thalamus—a small structure in the front of the under the thalamus that monitors activities such a condition in which a person has memory activity in a neighboring neuron. cerebral hemispheres that serves as a way station as body temperature and food intake. problems greater than those expected for his or that receives sensory information of all kinds and Nucleus—the structure within a cell that her age, but not the personality or cognitive relays it to the cortex; it also receives information Late-onset Alzheimer’s disease—the contains the chromosomes and controls many problems that characterize AD. from the cortex. most common form of AD. It occurs in people of its activities. aged 60 and older. Mutation—a permanent change in a cell’s DNA Transgenic—an animal that has had a gene Oxidative damage—damage that can occur that can cause a disease. (like human APP) inserted into its chromosomes. Limbic system—a brain region that links to cells when they are exposed to too many free Mice carrying the mutated human APP gene often the brain stem with the higher reasoning elements Myelin—a whitish, fatty layer surrounding radicals. develop plaques in their brains as they age. of the cerebral cortex. It controls emotions, an axon that helps the axon rapidly transmit Positron emission tomography (PET)— instinctive behavior, and the sense of smell. electrical messages from the cell body to the Ventricle—a cavity within the brain that is an imaging technique using radioisotopes that synapse. filled with cerebrospinal fluid. Magnetic resonance imaging (MRI)— allows researchers to observe and measure activity a diagnostic and research technique that uses Nerve growth factor (NGF)—a substance in different parts of the brain by monitoring blood Vesicle—a small container for transporting magnetic fields to generate a computer image of that maintains the health of nerve cells. NGF also flow and concentrations of substances such as neurotransmitters and other molecules from one internal structures in the body. MRIs are very clear promotes the growth of axons and dendrites, the oxygen and glucose, as well as other specific part of the neuron to another. and are particularly good for imaging the brain parts of the nerve cell that are essential to its ability constituents of brain tissues. and soft tissues. to communicate with other nerve cells. Single photon emission computed Metabolism—all of the chemical processes Neurodegenerative disease—a disease tomography (SPECT)—an imaging technique that take place inside the body. In some metabolic characterized by a progressive decline in the that allows researchers to monitor blood flow to reactions, complex molecules are broken down to structure, activity, and function of brain tissue. different parts of the brain. These diseases include AD, Parkinson’s disease, frontotemporal lobar degeneration, and dementia with Lewy bodies. They are usually more common in older people.72 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 73
  • For More Information INFORMATION AND referrals to local resources and services and spon- CAREGIVING SUPPORT AND SERVICES National Family SUPPORT RESOURCES sor support groups and educational programs. Caregivers Association Children of Aging Parents Online and print publications are also available. 10400 Connecticut Avenue, Suite 500 Alzheimer’s Disease Education P.O. Box 167 and Referral (ADEAR) Center The Association also funds AD research. Kensington, MD 20895-3944 Richboro, PA 18954-0167 P.O. Box 8250 800-896-3650 (toll-free) 800-227-7294 (toll-free) Alzheimer’s Foundation of America 301-942-6430 Silver Spring, MD 20907-8250 www.caps4caregivers.org 322 Eighth Avenue, 7th Floor www.thefamilycaregiver.org 800-438-4380 (toll-free) New York, NY 10001 This nonprofit organization provides information www.nia.nih.gov/Alzheimers The National Family Caregivers Association helps 866-232-8484 (toll-free) and referrals for nursing homes, retirement This service of the National Institute on Aging educate and support people who care for loved www.alzfdn.org communities, elder-law attorneys, adult day-care (NIA) offers information and publications on ones with chronic illness, disability, or the frailties centers, insurance providers, respite care, assisted The Alzheimer’s Foundation of America provides of old age. The Association offers an online library diagnosis, treatment, patient care, caregiver living centers, support groups, and State and care and services to individuals confronting of information and educational materials, work- needs, long-term care, education and training, county agencies. It also offers fact sheets, a news- dementia and to their caregivers and families, shops, and other resources. and research related to Alzheimer’s disease. Staff letter, and conferences and workshops. through member organizations dedicated to members answer telephone, email, and written improving quality of life. Services include a National Hospice and requests and make referrals to local and national Eldercare Locator toll-free hotline, consumer publications and Palliative Care Organization resources. The ADEAR website offers free, online 800-677-1116 (toll-free) other educational materials, and conferences and 1700 Diagonal Road, Suite 625 publications in English and Spanish; email alerts www.eldercare.gov workshops. Alexandria, VA 22314 and online Connections newsletter registration; Eldercare Locator is a nationwide, directory- 800-658-8898 (toll-free) an AD clinical trials database; the AD Library Dana Alliance for Brain Initiatives assistance service helping older people and their www.nhpco.org database; and more. 745 Fifth Avenue, Suite 900 caregivers locate local support and resources. It is This nonprofit organization works to enhance the New York, NY 10151 funded by the U.S. Administration on Aging, whose Alzheimer’s Association quality of life for people who are terminally ill. It 212-223-4040 website at www.aoa.gov also features AD information 225 North Michigan Avenue, Suite 1700 provides information, resources, and referrals to www.dana.org/danaalliances for families, caregivers, and health professionals. Chicago, IL 60601-7633 local hospice services, and offers publications and 800-272-3900 (toll-free) The Dana Alliance for Brain Initiatives, a non- online resources. Family Caregiver Alliance www.alz.org profit organization of more than 265 leading 180 Montgomery Street, Suite 1100 neuroscientists, helps advance public awareness Well Spouse Association The Alzheimer’s Association is a national, San Francisco, CA 94104 about the progress and promise of brain research 63 West Main Street, Suite H non-profit organization with a network of 800-445-8106 (toll-free) and disseminates information about the brain. Freehold, NJ 07728 local chapters that provide education and www.caregiver.org 800-838-0879 (toll-free) support for people diagnosed with AD, their The Family Caregiver Alliance is a nonprofit www.wellspouse.org families, and caregivers. Chapters offer organization that offers support services and The nonprofit Well Spouse Association gives information for people caring for adults with support to spouses and partners of people who are AD, stroke, traumatic brain injuries, and chronically ill and/or disabled. It offers support other cognitive disorders. groups and a newsletter.74 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 75
  • More ForInformation RESEARCH AND CLINICAL TRIALS RECOMMENDED READING of AD and the available options for coping Mace, N.L., & Rabins, P.V. The 36-Hour Day: with and managing this illness. Sixteen chapters A Family Guide to Caring for People With Alzheimer’s Disease Cooperative Study The ADEAR Center offers fact sheets; easy-to- answer questions about topics such as the Alzheimer’s Disease, Other Dementias, and University of California, San Diego read materials; booklets about topics such as being definition of AD and dementia, AD versus other Memory Loss in Later Life, 4th ed. Baltimore: 9500 Gilman Drive diagnosed with early-stage AD, caregiving, home causes of dementia, treatments for behavioral Johns Hopkins University Press, 2006. La Jolla, CA 92093-0949 safety, and comfort and care at the end of life; symptoms and other complications of AD, 858-622-5880 and more. See the ADEAR Center listing under This book offers guidance and comfort for families and practical issues for the patient and family. www.adcs.org “Information and Support Resources” above for caring for loved ones with AD, other dementias, Illustrations, a glossary, and a list of resources contact information. and memory loss in later life. The fourth edition The Alzheimer’s Disease Cooperative Study are also included. includes chapters on topics such as getting (ADCS) is a cooperative agreement between NIA Consumers and professionals interested in AD also medical help for the person with dementia, and the University of California, San Diego, to may wish to refer to the following materials: Doraiswamy, P.M., & Gwyther, L., with Adler, behavioral symptoms of dementia, nursing homes advance research in the development of drugs to T. The Alzheimer’s Action Plan: The Experts’ and other living arrangements, and research in treat AD. The ADCS is a consortium of medical Ballard, E.L., & Poer, C.M. Lessons Learned: Guide to the Best Diagnosis and Treatment for dementia. New information discusses diagnostic research centers and clinics working to develop Shared Experiences in Coping. Durham, NC: Memory Problems. New York: St. Martin’s Press, evaluation, caregiver resources, legal and clinical trials of medicines to treat behavioral The Duke Family Support Program, 1999. 2008. financial information, nursing homes and other symptoms of AD, improve cognition, slow the rate Available for $7 from the ADEAR Center, communal living arrangements, and the latest of decline caused by AD, delay the onset of AD, This book, by a physician and social worker at P.O. Box 8250, Silver Spring, MD 20907-8250; updates on research, medications, and the or prevent the disease altogether. The ADCS also Duke University, offers information about how to 800-438-4380; www.nia.nih.gov/Alzheimers. biological causes and effects of dementia. develops new and more reliable ways to evaluate get an early and accurate AD diagnosis and why This book documents the experiences of people Available in a large-print version. patients enrolled in clinical trials. it matters, life after the diagnosis, state-of-the-art caring for loved ones with AD. Filled with short treatments, coping with behavioral and emotional stories and advice, it is intended for caregivers Alzheimer Research Forum changes through the early and middle stages of Messer, M. Pressure Points: Alzheimer’s and who wish to take comfort and learn from the www.alzforum.org AD, accessing the latest clinical trials, and Anger. Durham, NC: Duke Family Support experiences of others. Caregivers discuss the The Alzheimer Research Forum, an online com- understanding the future of AD. Program, 2000. Available for $12.50 from the caregiving process, such as getting a diagnosis, munity and resource center, offers professionals and finding support services, making decisions about ADEAR Center, P.O. Box 8250, Silver Spring, the general public access to an annotated index of MD 20907-8250; 800-438-4380; www.nia.nih. treatment and living arrangements, and coping Kuhn, D., & Bennett, D.A. Alzheimer’s Early scientific papers, research news, moderated discus- gov/Alzheimers. with stress and caregiver burden. Stages: First Steps for Family, Friends and sions on scientific topics, libraries of animal models Caregivers, 2nd ed. Alameda, CA: Hunter House In simple, easy-to-read language, this book and antibodies, and directories of clinical trials, Publishers, 2003. addresses issues such as setting boundaries, Dash, P., & Villemarette-Pittman, N. Alzheimer’s conferences, jobs, and research-funding sources. managing anger positively, and risk factors for Disease. New York: American Academy of With increased awareness of the symptoms of AD anger in AD care. It offers tangible action steps for ClinicalTrials.gov Neurology, 2005. and improved diagnostic techniques, more people responding appropriately, rather than abusively, www.ClinicalTrials.gov are learning that they or a family member have a This concise volume provides an overview of memory disorder. This book, written by experts ClinicalTrials.gov is a registry of federally and recent findings regarding the causes, diagnosis, and at Rush University Alzheimer’s Disease Center in privately supported clinical trials conducted in the treatment of AD. It is designed to help caregivers Chicago, helps readers understand and find ways United States and around the world. Users can and family members gain a better understanding to cope with the early stages of the disease. It also search for clinical trials and find information includes an extensive resource list of websites, about each trial’s purpose, who may participate, organizations, and references to consumer and locations, and phone numbers for more details. professional literature.76 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 77
  • More ForInformation when feeling angry. Participants in Alzheimer’s Petersen, R., ed. Mayo Clinic Guide to Restak, R. The Secret Life of the Brain. Tanzi, R.E., & Sisodia, S.S. Alzheimer’s Disease: support groups share helpful techniques and Alzheimer’s Disease: The Essential Resource for Washington, DC: Joseph Henry Press, 2001. Advances in Genetics, Molecular and Cellular coping mechanisms, as well as enlightening Treatment, Coping and Caregiving. Rochester, Biology. New York: Springer Publishing Company, This companion to the PBS documentary takes anecdotes about caring for a loved one with AD. MN: Mayo Clinic Health Solutions, 2006. 2006. the reader on a fascinating journey through the Caregivers, family members of AD patients, This guide is designed to help nonprofessionals developing brain, from infancy and childhood This book examines every major aspect of AD— clergy, and health professionals all may benefit understand dementia and its effects on the mind, through adulthood and old age. The author ex- clinical, epidemiologic, structural, chemical, from this publication. Two companion the differences between dementia and changes amines brain disorders and mechanisms of brain genetic, molecular, and therapeutic. This edition booklets are also available from the ADEAR associated with normal aging, and how to improve repair and healing. includes expanded coverage of related dementing Center: “Hit Pause”: Helping Dementia Families memory and maintain good mental function. It disorders, including prion diseases, Pick’s disease, Deal with Anger (for health professionals; $3.00) includes information about changes that occur in frontotemporal disorders, an in-depth discussion and Wait a Minute! When Anger Gets Too Much Shenk, D. The Forgetting. Alzheimer’s: Portrait normal aging; the process of diagnosing dementia; of transgenic models, and the biochemistry (for families and caregivers; $2.00). of an Epidemic. New York: Random House, Inc., non-AD forms of dementia; how AD develops, of presenilins. It also discusses treatment of 2003. and AD stages, diagnosis, and treatment. New symptoms with therapeutic drugs and AD clini- Perry, G., ed., Alzheimer’s Disease: A Century information about mild cognitive impairment, An eloquent and moving description of AD, The cal trials. The broad coverage of AD in this book of Scientific and Clinical Research. Journal of ways to stay mentally sharp, and research trends, Forgetting is an exploration of, and meditation on, will be of special interest to clinicians, educators, Alzheimer’s Disease, book edition, Fairfax, VA: IOS along with an action guide for caregivers, are the nature of memory and perceptions of self. It investigators, and health administrators. Press, Inc., 2006. also included. is a readable, accessible description of the history of AD, research, and the human impact of the This volume brings together the important Uetz, D., & Lindsay, A. Into the Mist: disease. Calling AD a “death by a thousand discoveries in the AD field since the disease’s When Someone You Love Has Alzheimer’s. subtractions,” the author describes the science original description by Dr. Alois Alzheimer a Philadelphia: Xlibris Corporation, 2005. of AD in clear and easy-to-understand terms. century ago. It traces how the importance of AD This book combines information from as the major cause of late-life dementia came to researchers, experts, and families in a light and narrates the evolution of the concepts Snowdon, D. Aging With Grace: What the comprehensive guide for AD caregivers. It related to AD throughout the years. Fifty papers Nun Study Teaches Us About Leading Longer, offers personal accounts of three families caring are organized into sections on historical Healthier, and More Meaningful Lives. New for a loved one from the earliest stages to the perspective, neuropathology, synaptic changes, York: Random House, Inc., 2002. last stages, illustrating the commonalities and amyloid, tau, disease mechanisms, genetics, and This book describes the participants and findings differences among AD patients and the ways their diagnosis and treatment. from the Nun Study, a long-term project examin- families handle the most difficult challenges. It ing aging and AD in a unique population of 678 also provides information to help families cope Catholic sisters. The nuns gave Dr. Snowdon with the psychological aspects of AD, behavior access to their medical and personal records and problems, and communication difficulties. The agreed to donate their brains upon death. The book covers such topics as the stages of AD, book discusses the relationship of early linguistic Medicare, Medicaid, long-term care insurance, ability to risk of AD, the association of stroke and geriatric care management, the diagnosis of AD, depression with AD, and the role of heredity and causes and prevention, and drug treatments. lifestyle in healthy aging.78 ALZHEIMER’S DISEASE Unraveling the Mystery A L Z H E I M E R’ S D I S E A SE Unraveling the Mystery 79
  • Credits Writer Photography Anne Brown Rodgers Front Cover – Doug Sanford, Photogroup Inside front cover, page 8, 55 – Blend Images Medical Illustrator Page 1 – Blend Stock Stacy Jannis Jannis Productions Pages 9, 19, 39, 61 – Photodisc Page 13 – Dynamic Graphics; scans on computer 3D Modeling screen courtesy of William Jagust, M.D., University of Bill Dempsey California, Berkeley Rebekah Fredenburg Page 16 – Fancy Photography Page 20 – Comstock Graphic Design Fatima Ameen and Jeffrey Dever Page 28 – University of Pittsburgh Dever Designs Page 33 – Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Project Coordinator Page 34, back cover – Thinkstock Susan R. Farrer JBS International, Inc. Pages 36, 62 – Corbis Page 43 – Berislav Zlokovic, M.D., Ph.D., University of Special Thanks Rochester, and Stacy Jannis, Jannis Productions For additional copies of this NIA appreciates the extraordinary contributions Page 45 – Pixland Stock report or further information about of the following people to the vision and creation of this book: Page 46, inside back cover – Brand X Pictures Alzheimer’s disease, please contact: Page 51 – Jeff Miller, University of Wisconsin-Madison Marcelle Morrison-Bogorad, Ph.D., and the staff Alzheimer’s Disease Education of the NIA Division of Neuroscience Page 53 – Oregon Center for Aging and Technology, Oregon Health & Science University and Referral (ADEAR) Center Patricia D. Lynch, former senior public affairs Page 57 – Plainpicture Photography P.O. Box 8250 specialist, NIA Office of Communications and Public Liaison Silver Spring, MD 20907-8250 Page 58 – Digital Vision David M. Burton, JBS International, Inc. Page 64 – Alloy Photography Phone: Page 66 – Marty Katz 800-438-4380 Page 68 – Caregiver Technologies, Inc. Email: Page 69 – Flirt Photography adear@nia.nih.gov Page 78 – Stockbyte Website: www.nia.nih.gov/Alzheimers80 ALZHEIMER’S DISEASE Unraveling the Mystery
  • U.S. Department ofHealth and Human ServicesNIH Publication Number: 08-3782September 2008