Alzheimer's Disease Fact Sheet

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http://www.nia.nih.gov/Alzheimers/Publications/adfact.htm Alzheimers disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills, and eventually even the ability to carry out the simplest tasks. In most people with Alzheimers, symptoms first appear after age 60. Alzheimers disease is the most common cause of dementia among older people. Dementia is the loss of cognitive functioningthinking, remembering, and reasoningto such an extent that it interferes with a persons daily life and activities. Estimates vary, but experts suggest that as many as 5.1 million Americans may have Alzheimers. Alzheimers disease is named after Dr. Alois Alzheimer. In 1906, Dr. Alzheimer noticed changes in the brain tissue of a woman who had died of an unusual mental illness. Her symptoms included memory loss, language problems, and unpredictable behavior. After she died, he examined her brain and found many abnormal clumps (now called amyloid plaques) and tangled bundles of fibers (now called neurofibrillary tangles). Plaques and tangles in the brain are two of the main features of Alzheimers disease. The third is the loss of connections between nerve cells (neurons) in the brain.

Changes in the Brain in Alzheimers Disease

Although we still dont know what starts the Alzheimers disease process, we do know that damage to the brain begins as many as 10 to 20 years before any problems are evident. Tangles begin to develop deep in the brain, in an area called the entorhinal cortex, and plaques form in other areas. As more and more plaques and tangles form in particular brain areas, healthy neurons begin to work less efficiently. Then, they lose their ability to function and communicate with each other, and eventually they die. This damaging process spreads to a nearby structure, called the hippocampus, which is essential in forming memories. As the death of neurons increases, affected brain regions begin to shrink. By the final stage of Alzheimers, damage is widespread and brain tissue has shrunk significantly. Very Early Signs and Symptoms Memory problems are one of the first signs of Alzheimers disease. Some people with memory problems have a condition called amnestic mild cognitive impairment (MCI). People with this condition have more memory problems than normal for people their age, but their symptoms are not as severe as those with Alzheimers. More people with MCI, compared with those without MCI, go on to develop Alzheimers. Other changes may also signal the very early stages of Alzheimers disease. For example, brain imaging and biomarker studies of people with MCI and those with a family history of Alzheimers are beginning to detect early changes in the brain like those seen in Alzheimers. These findings will need to be confirmed by other studies but appear promising. Other recent research has found links between some movement difficulties and MCI. Researchers also have seen links between some problems with the sense of smell and cognitive problems. Such findings offer hope that some day we may have tools that could help detect Alzheimers early, track the course of the disease, and monitor response to treatments. Mild Alzheimers Disease As Alzheimers disease progresses, memory loss continues and changes in

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other cognitive abilities appear. Problems can include getting lost, trouble handling money and paying bills, repeating questions, taking longer to complete normal daily tasks, poor judgment, and small mood and personality changes. People often are diagnosed in this stage. Moderate Alzheimers Disease In this stage, damage occurs in areas of the brain that control language, reasoning, sensory processing, and conscious thought. Memory loss and confusion increase, and people begin to have problems recognizing family and friends. They may be unable to learn new things, carry out tasks that involve multiple steps (such as getting dressed), or cope with new situations. They may have hallucinations, delusions, and paranoia, and may behave impulsively. Severe Alzheimers Disease By the final stage, plaques and tangles have spread throughout the brain and brain tissue has shrunk significantly. People with severe Alzheimers cannot communicate and are completely dependent on others for their care. Near the end, the person may be in bed most or all of the time as the body shuts down.

What Causes Alzheimers

Scientists dont yet fully understand what causes Alzheimers disease, but it is clear that it develops because of a complex series of events that take place in the brain over a long period of time. It is likely that the causes include genetic, environmental, and lifestyle factors. Because people differ in their genetic make-up and lifestyle, the importance of these factors for preventing or delaying Alzheimers differs from person to person. The Basics of Alzheimers Scientists are conducting studies to learn more about plaques, tangles, and other features of Alzheimers disease. They can now visualize plaques by imaging the brains of living individuals. They are also exploring the very earliest steps in the disease process. Findings from these studies will help them understand the causes of Alzheimers.

One of the great mysteries of Alzheimers disease is why it largely strikes older adults. Research on how the brain changes normally with age is shedding light on this question. For example, scientists are learning how age-related changes in the brain may harm neurons and contribute to Alzheimers damage. These age-related changes include atrophy (shrinking) of certain parts of the brain, inflammation, and the production of unstable molecules called free radicals. Genetics In a very few families, people develop Alzheimers disease in their 30s, 40s, and 50s. Many of these people have a mutation, or permanent change, in one of three genes that they inherited from a parent. We know that these gene mutations cause Alzheimers in these earlyonset familial cases. Not all early-onset cases are caused by such mutations. Most people with Alzheimers disease have late-onset Alzheimers, which usually develops after age 60. Many studies have linked a gene called APOE to late-onset Alzheimers. This gene has several forms. One of them, APOE 4, increases a persons risk of getting the disease. About 40 percent of all people who develop late-onset Alzheimers carry this gene. However, carrying the APOE 4 form of the gene does not necessarily mean that a person will develop Alzheimers disease, and people carrying no APOE 4 forms can also develop the disease. Most experts believe that additional genes may influence the development of late-onset Alzheimers in some way. Scientists around the world are searching for these genes. Researchers have identified variants of the SORL1, CLU, PICALM, and CR1 genes that may play a role in risk of late-onset Alzheimers. For more about this area of research, see the Alzheimers Disease Genetics Fact Sheet, available at www.nia.nih.gov/Alzheimers/Publications/geneticsfs.htm. Lifestyle Factors A nutritious diet, physical activity, social engagement, and mentally stimulating pursuits can all help people stay healthy. New research suggests the possibility that these factors also might help to reduce the risk of cognitive decline and Alzheimers disease. Scientists are investigating associations between cognitive decline and vascular and metabolic conditions such as heart disease, stroke, high blood pressure,

diabetes, and obesity. Understanding these relationships and testing them in clinical trials will help us understand whether reducing risk factors for these diseases may help with Alzheimers as well. How Alzheimers Disease Is Diagnosed Alzheimers disease can be definitively diagnosed only after death by linking clinical course with an examination of brain tissue and pathology in an autopsy. But doctors now have several methods and tools to help them determine fairly accurately whether a person who is having memory problems has possible Alzheimers disease (dementia may be due to another cause) or probable Alzheimers disease (no other cause for dementia can be found). To diagnose Alzheimers, doctors:

ask questions about the persons overall health, past medical problems, ability to carry out daily activities, and changes in behavior and personality conduct tests of memory, problem solving, attention, counting, and language carry out medical tests, such as tests of blood, urine, or spinal fluid perform brain scans, such as computerized tomography (CT) or magnetic resonance imaging (MRI)

These tests may be repeated to give doctors information about how the persons memory is changing over time. Early diagnosis is beneficial for several reasons. Having an early diagnosis and starting treatment in the early stages of the disease can help preserve function for months to years, even though the underlying disease process cannot be changed. Having an early diagnosis also helps families plan for the future, make living arrangements, take care of financial and legal matters, and develop support networks. In addition, an early diagnosis can provide greater opportunities for people to get involved in clinical trials. In a clinical trial, scientists test drugs or treatments to see which are most effective and for whom they work best. (See the box, below, for more information.) Participating in Clinical Trials

People with Alzheimers disease, those with MCI, those with a family history of Alzheimers, and healthy people with no memory problems and no family history of the disease may be able to take part in clinical trials. Study volunteers help scientists learn about the brain in healthy aging as well as what happens in Alzheimers. Results of clinical trials are used to improve prevention and treatment approaches. Participating in clinical trials is an effective way to help in the fight against Alzheimers disease. NIA, which is part of the National Institutes of Health (NIH), leads the Federal Governments research efforts on Alzheimers. NIAsupported Alzheimers Disease Centers located throughout the United States conduct many clinical trials and carry out a wide range of research, including studies of the causes, diagnosis, and management of Alzheimers. NIA also sponsors the Alzheimers Disease Cooperative Study (ADCS), a consortium of leading researchers throughout the U.S. and Canada who conduct clinical trials on promising Alzheimers treatments. To find out more about Alzheimers clinical trials, talk to your health care provider or contact NIAs ADEAR Center at 1-800438-4380. Or, visit the ADEAR Center clinical trials database at www.nia.nih.gov/Alzheimers/ResearchInformation/ClinicalTrials. You also can sign up for email alerts that let you know when new clinical trials are added to the database. More information about clinical trials is available at www.ClinicalTrials.gov. Also see Participating in Alzheimers Disease Clinical Trials and Studies at www.nia.nih.gov/Alzheimers/Publications/trialsstudies.htm.

How Alzheimers Is Treated

Alzheimers disease is a complex disease, and no single magic bullet is likely to prevent or cure it. Thats why current treatments focus on several different aspects, including helping people maintain mental function; managing behavioral symptoms; and slowing, delaying, or preventing the disease. Helping People with Alzheimers Maintain Mental Function

Four medications are approved by the U.S. Food and Drug Administration to treat Alzheimers. Donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne) are used to treat mild to moderate Alzheimers (donepezil can be used for severe Alzheimers as well). Memantine (Namenda) is used to treat moderate to severe Alzheimers. These drugs work by regulating neurotransmitters (the chemicals that transmit messages between neurons). They may help maintain thinking, memory, and speaking skills, and help with certain behavioral problems. However, these drugs dont change the underlying disease process and may help only for a few months to a few years. Managing Behavioral Symptoms Common behavioral symptoms of Alzheimers include sleeplessness, agitation, wandering, anxiety, anger, and depression. Scientists are learning why these symptoms occur and are studying new treatments drug and non-drugto manage them. Treating behavioral symptoms often makes people with Alzheimers more comfortable and makes their care easier for caregivers. Slowing, Delaying, or Preventing Alzheimers Disease Alzheimers disease research has developed to a point where scientists can look beyond treating symptoms to think about addressing the underlying disease process. In ongoing clinical trials, scientists are looking at many possible interventions, such as cardiovascular and diabetes treatments, antioxidants, immunization therapy, cognitive training, and physical activity.

Supporting Families and Caregivers

Caring for a person with Alzheimers disease can have high physical, emotional, and financial costs. The demands of day-to-day care, changing family roles, and difficult decisions about placement in a care facility can be hard to handle. Researchers are learning a lot about Alzheimers caregiving, and studies are helping experts develop new ways to support caregivers. Becoming well-informed about the disease is one important long-term strategy. Programs that teach families about the various stages of Alzheimers and about flexible and practical strategies for dealing with

difficult caregiving situations provide vital help to those who care for people with Alzheimers. Developing good coping skills and a strong support network of family and friends also are important ways that caregivers can help themselves handle the stresses of caring for a loved one with Alzheimers disease. For example, staying physically active provides physical and emotional benefits. Some Alzheimers caregivers have found that participating in a support group is a critical lifeline. These support groups allow caregivers to find respite, express concerns, share experiences, get tips, and receive emotional comfort. The Alzheimers Association, Alzheimers Disease Centers, and many other organizations sponsor in-person and online support groups across the country. There are a growing number of groups for people in the early stage of Alzheimers and their families. Support networks can be especially valuable when caregivers face the difficult decision of whether and when to place a loved one in a nursing home or assisted living facility. For more information about at-home caregiving, see Caring for a Person with Alzheimers Disease: Your Easy-to-Use Guide from the National Institute on Aging at www.nia.nih.gov/Alzheimers/Publications/CaringAD.

Advancing Our Understanding

Thirty years ago, we knew very little about Alzheimers disease. Since then, scientists have made many important advances. Research supported by NIA and other organizations has expanded knowledge of brain function in healthy older people, identified ways we might lessen normal age-related declines in mental function, and deepened our understanding of the disease. Many scientists and physicians are now working together to untangle the genetic, biological, and environmental factors that, over many years, ultimately result in Alzheimers. This effort is bringing us closer to the day when we will be able to manage successfully or even prevent this devastating disease.
http://www.benthamscience.com/cdt/contabs/cdt7-11.htm Multiple Roles for Glycogen Synthase Kinase-3 as a Drug Target in Alzheimers Disease H.-C. Huang and P.S. Klein

Alzheimers disease (AD) is a common neurodegenerative disorder that presents clinically as inexorable cognitive impairment and decline in performance of activities of daily living. AD is characterized pathologically by neuronal depopulation, extracellular amyloid plaques, and intraneuronal accumulation of neurofibrillary tangles (NFTs). Accumulation of these polypeptide aggregates is generally believed to be integral to the pathogenesis of AD. Recent evidence implicates the protein kinase glycogen synthase kinase 3 (GSK-3) in the regulation of both of these processes. GSK-3 has long been studied as one of several tau protein kinases, and has more recently been shown to be involved in the generation of A peptides. GSK-3 activity may also promote cell death and conversely, inhibition of GSK-3 has been associated with increased cell survival under a variety of cytotoxic conditions. Thus drugs that target GSK-3 could attack AD pathogenesis on multiple fronts simultaneously. Here we will briefly review the molecular understanding of AD pathogenesis as it stands at this point, and then discuss the emerging role of GSK-3 in regulating these processes.

Alzheimer's Disease Genetics Fact Sheet

http://www.nia.nih.gov/Alzheimers/Publications/geneticsfs.htm

Scientists dont yet fully understand what causes Alzheimers disease (AD). However, the more they learn about AD, the more they realize that genes* play an important role in the development of this devastating disease. Research conducted and funded by the National Institute on Aging (NIA) and others is advancing the field of AD genetics. *Terms in bold are defined at the end of this fact sheet.

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The Genetics of Disease

Some diseases are caused by a genetic mutation, or permanent change, in one specific gene. If a person inherits a genetic mutation that is linked to a certain disease from a parent, then he or she will usually get the disease. Cystic fibrosis, muscular dystrophy, and Huntingtons disease are examples of single-gene disorders. In other diseases, a genetic variant, or a change in a gene, may occur, but it doesnt necessarily cause the person to develop the disease. More than one gene variant may be necessary to cause the disease, or the variant may increase a persons risk of developing the disease. When this happens, the changed gene is called a genetic risk factor.

The Genetics of Alzheimers Disease

AD is an irreversible, progressive brain disease characterized by the development of amyloid plaques and neurofibrillary tangles, the loss of connections between nerve cells in the brain, and the death of these nerve cells. AD has two types: early-onset and late-onset. Both types have genetic links. Early-Onset AD Early-onset AD is a rare form of AD, affecting only about 5 percent of all people who have AD. It develops in people ages 30 to 60. Some cases of early-onset AD, called familial AD (FAD), are inherited. FAD is caused by a number of different gene mutations on

chromosomes 21, 14, and 1, and each of these mutations causes abnormal proteins to be formed. Mutations on chromosome 21 cause the formation of abnormal amyloid precursor protein (APP). A mutation on chromosome 14 causes abnormal presenilin 1 to be made, and a mutation on chromosome 1 leads to abnormal presenilin 2. Even if only one of these mutated genes is inherited from a parent, the person will almost always develop early-onset AD. This inheritance pattern is referred to as autosomal dominant inheritance. In other words, offspring in the same generation have a 50/50 chance of developing FAD if one of their parents had it. Scientists know that each of these mutations causes an increased amount of the beta-amyloid protein to be formed. Beta-amyloid, a major component of AD plaques, is formed from APP. These early-onset findings were critical because they showed that genetics were involved in AD, and they helped identify key players in the AD process. The studies also helped explain some of the variation in the age at which AD develops. Late-Onset AD Most cases of Alzheimers are of the late-onset form, developing after age 60. Scientists studying the genetics of AD have found that the mutations seen in early-onset AD are not involved in this form of the disease. Although a specific gene has not been identified as the cause of lateonset AD, one predisposing genetic risk factor does appear to increase a persons risk of developing the disease. This increased risk is related to the apolipoprotein E (APOE) gene found on chromosome 19. APOE contains the instructions needed to make a protein that helps carry cholesterol in the bloodstream. APOE comes in several different forms, or alleles. Three formsAPOE 2, APOE 3, and APOE 4 occur most frequently.

APOE 2 is relatively rare and may provide some protection against the disease. If AD does occur in a person with this allele, it develops later in life than it would in someone with the APOE 4 gene.

APOE 3 is the most common allele. Researchers think it plays a neutral role in ADneither decreasing nor increasing risk. APOE 4 occurs in about 40 percent of all people who develop late-onset AD and is present in about 25 to 30 percent of the population. People with AD are more likely to have an APOE 4 allele than people who do not develop AD. However, many people with AD do not have an APOE 4 allele. Dozens of studies have confirmed that the APOE 4 allele increases the risk of developing AD, but how that happens is not yet understood. These studies also have helped explain some of the variation in the age at which AD develops, as people who inherit one or two APOE 4 alleles tend to develop AD at an earlier age than those who do not have any. APOE 4 is called a risk-factor gene because it increases a persons risk of developing AD. However, inheriting an APOE 4 allele does not mean that a person will definitely develop AD. Some people with one or two APOE 4 alleles never get the disease, and others who develop AD do not have any APOE 4 alleles.

Scientists believe that four to seven other AD risk-factor genes exist and are using a new approach called a genome-wide association study (GWAS) to help speed the discovery process. Another possible riskfactor gene, SORL1, was discovered in 2007. This gene is involved in transporting APP within cells, and its association with AD has been identified and confirmed in three separate studies. Researchers found that when SORL1 is present at low levels or in a variant form, betaamyloid levels increase and may harm neurons. DNA, Chromosomes, and Genes

The nucleus of almost every human cell contains a blueprint that carries the instructions a cell needs to do its job. The blueprint is made up of DNA, which is present in long strands that would stretch to nearly 6 feet in length if attached end to end. The DNA is packed tightly together with proteins into Click here for a larger version compact structures called chromosomes in the nucleus of each cell. Each cell has 46 chromosomes in 23 pairs. The DNA in nearly all cells of an individual is identical. Each chromosome contains many thousands of segments, called genes. People inherit two copies of each gene from their parents, except for genes on the X and Y chromosomes, which, among other functions, determine a persons sex. The gene tells the cell how to make specific proteins, which determine the different kinds of cells that make up an organism and direct almost every aspect of the cells construction, operation, and repair. Even slight alterations in a gene can produce an abnormal protein, which may lead to cell malfunction and, eventually, to disease. Other changes in genes may not cause disease but can increase a persons risk of developing a particular disease.

APOE Testing
A blood test is available that can identify which APOE alleles a person has, but it is not yet possible to predict who will or will not develop AD. Because APOE 4 is only a risk factor for AD, this blood test cannot say for sure whether a person will develop AD or not. Some researchers believe that screening measures may never be able to predict AD with 100 percent accuracy. However, a small battery of tests for other riskfactor genes might eventually be useful. At present, APOE testing is used in a research setting to identify study participants who may have an increased risk of developing AD. This knowledge helps scientists look for early brain changes in participants

and compare the effectiveness of treatments for people with different APOE profiles. Most researchers believe that the APOE test is useful for studying AD risk in large groups of people but not for determining any one persons specific risk. Someday, perhaps, screening in otherwise healthy people may be useful if an accurate and reliable test is developed and effective ways to treat or prevent AD become available.

Research Questions
Learning more about the role of APOE 4 and other risk-factor genes in the development of AD is a vitally important area of AD research. Understanding more about the genetic underpinnings of the disease will help researchers:

Answer remaining basic questions about mechanismsWhat makes the disease process begin, and why do some people who have memory problems go on to develop AD while others do not? Determine how AD risk-factor genes may interact with other genes and lifestyle or environmental factors to affect AD risk in any one person. Identify people who are at high risk so they can possibly receive early treatment. Focus on new prevention or treatment approaches. Major AD Genetics Research Efforts Underway

As AD genetics research has intensified, it has become clear that scientists need many genetic samples to make further progress. The National Institute on Aging (NIA) has launched two large programs, the Alzheimers Disease Genetics Study and the Alzheimers Disease Genetics Consortium, to collect and analyze blood samples and other biological information from thousands of families around the world with members who do and do not have late-onset AD. NIA also funds the National Cell Repository for Alzheimers Disease (NCRAD), a national resource where clinical information and DNA can be stored and accessed by qualified researchers. Through these programs, AD researchers are working together to develop new technologies and methods and to share data. The AD Genetics Study is gathering genetic and other information

from 1,000 or more families in the United States that include a pair of living siblings (brothers or sisters) who have late-onset AD. Families who meet this criteria are urged to participate and can contact NCRAD (www.ncrad.org) for more information. The AD Genetics Consortium is a collaborative effort of AD geneticists to collect more than 10,000 samples to do GWAS, the DNA analysis studies needed to identify risk-factor genes. The participation of volunteer families is a critical part of AD genetics research. The more genetic information that researchers can gather and analyze from a wide range of families, the more clues they will have for finding additional risk-factor genes.

Small Clumps of Tau Protein Disrupt Memory; Animal Study Suggests Possible Target for Alzheimers Disease Therapies
http://www.sciencedaily.com/releases/2010/11/101116204837.htm

ScienceDaily (Nov. 17, 2010) Too many small aggregates of a protein called tau in the brain can directly interfere with memory, according to new animal research presented at Neuroscience 2010, the annual meeting of the Society for Neuroscience, held in San Diego. "Our findings are important because they suggest that tau may be a good target for developing therapies against Alzheimer's and related diseases," said senior author Ottavio Arancio, PhD, of Columbia University. Many neurodegenerative diseases are marked by an accumulation of protein aggregates in the brain, and Alzheimer's disease is no exception. The two most common aggregating proteins associated with Alzheimer's disease are amyloid- beta and tau, which form the neural plaques and tangles that are hallmarks of the disease. Recently,

scientists have begun to focus on some of the smaller, still-soluble forms of these protein aggregates, called oligomers, which may be especially toxic to neurons. Arancio and his colleagues found that tau oligomers impaired fearful memories in mice. Tau oligomers also disrupted synaptic plasticity -cellular events important for memory formation. "Our findings suggest that tau is critically involved in the development of Alzheimer's disease -- and that reducing the abnormal aggregation of the protein may prove to be an effective treatment approach," Arancio said. Research was supported by the Alzheimer's Drug Discovery Foundation, the National Institutes of Health, and Oligomerix, Inc.