The Dartmouth Memory Handbook
Section 3: Alzheimer’s Disease
WHAT IS ALZHEIMER’S DISEASE?
From NIH Senior Health
Last Reviewed: May 2015
Alzheimer’s disease is a brain disease that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks. It begins slowly and gets worse over time. Currently, it has no cure.
A Common Cause of Dementia
Alzheimer’s disease is the most common cause of dementia among older people.
Dementia is a loss of thinking, remembering, and reasoning skills that interferes with a person’s daily life and activities. Dementia ranges in severity from the mild stage, when it is just beginning to affect a person’s functioning, to the severe stage, when the person must depend completely on others for basic care.
Estimates vary, but experts suggest that more than 5 million Americans may have Alzheimer’s disease. Alzheimer’s is currently ranked as the sixth leading cause of death in the United States, but recent estimates indicate that the disorder may rank third, just behind heart disease and cancer, as a cause of death for older people Risk Increases With Age
In most people with Alzheimer’s, symptoms first appear in their mid-60s, and the risk of developing the disease increases with age. While younger people — in their 30s, 40s, and 50s — may get Alzheimer’s disease, it is much less common. It is important to note that Alzheimer’s disease is not a normal part of aging.
The course of Alzheimer’s disease—which symptoms appear and how quickly changes occur—varies from person to person. The time from diagnosis to death varies, too. It can be as little as 3 or 4 years if the person is over 80 years old when diagnosed or as long as 10 years or more if the person is younger.
Memory Problems: One of the First Signs
Memory problems are typically one of the first signs of Alzheimer’s disease, though initial symptoms may vary from person to person. A decline in other aspects of thinking, such as finding the right words, vision/spatial issues, and impaired reasoning or judgment, may also signal the very early stages of Alzheimer’s disease.
People with Alzheimer’s have trouble doing everyday things like driving a car, cooking a meal, or paying bills. They may ask the same questions over and over, get lost easily, lose things or put them in odd places, and find even simple things confusing. Some people become worried, angry, or violent.
Other Reasons for Memory Issues
Not all people with memory problems have Alzheimer’s disease. Mild forgetfulness can be a normal part of aging. Some people may notice that it takes longer to learn new things, remember certain words, or find their glasses. That’s different from a serious memory problem, which makes it hard to do everyday things.
Sometimes memory problems are related to health issues that are treatable. For example, medication side effects, vitamin B12 deficiency, head injuries, or liver or kidney disorders can lead to memory loss or possibly dementia. Emotional problems, such as stress, anxiety, or depression, can also make a person more forgetful and may be mistaken for dementia.
Mild Cognitive Impairment (see also p. 9)
Some older people with memory or other thinking problems have a condition called mild cognitive impairment, or MCI. MCI can be an early sign of Alzheimer’s, but not everyone with MCI will develop Alzheimer’s disease. People with MCI have more memory problems than other people their age, but they can still take care of themselves and do their normal activities.
Signs of MCI may include Losing things often; forgetting to go to events and appointments; having more trouble coming up with words than other people the same age, and similar behaviors. If you or someone in your family thinks your forgetfulness is getting in the way of your normal routine, it’s time to see your doctor. Seeing the doctor when you first start having memory problems can help you find out what’s causing your forgetfulness.
What Happens to the Brain in Alzheimer’s?
Alzheimer’s disease is named after Dr. Alois Alzheimer, a German doctor. In 1906, Dr.
Alzheimer noticed changes in the brain tissue of a woman who had died of an unusual mental illness. After she died, he examined her brain and found many abnormal clumps (now called amyloid plaques) and tangled bundles of fibers (now called neurofibrillary, or tau, tangles). Plaques and tangles in the brain are two of the main features of Alzheimer’s disease. Another is the loss of connections between nerve cells (neurons) in the brain. Neurons send messages between different parts of the brain, and from the brain to muscles and organs in the body.
It seems likely that damage to the brain starts 10 years or more before memory or other thinking problems become obvious. During the earliest stage of Alzheimer’s, people are free of symptoms, but harmful changes are taking place in the brain. The damage at first appears to take place in cells of the hippocampus, the part of the brain essential in forming memories. Abnormal protein deposits form plaques and tangles in the brain.
Once-healthy nerve cells stop functioning, lose connections with each other, and die. As more nerve cells die, other parts of the brain begin to shrink. By the final stage of Alzheimer’s, damage is widespread, and brain tissue has shrunk significantly.
ALZHEIMER’S DISEASE FACT SHEET FROM THE NATIONAL INSTITUTE ON AGING
ALZHEIMER’S DISEASE EDUCATION AND REFERRAL CENTER
https://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-fact-sheet Updated: June 27, 2016
Alzheimer’s disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks. In most people with Alzheimer’s, symptoms first appear in their mid-60s. Estimates vary, but experts suggest that more than 5 million Americans may have Alzheimer’s.
Alzheimer’s disease is currently ranked as the sixth leading cause of death in the United States, but recent estimates indicate that the disorder may rank third, just behind heart disease and cancer, as a cause of death for older people. Alzheimer’s is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning—thinking, remembering, and reasoning—and behavioral abilities to such an extent that it interferes with a person’s daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person’s functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. The causes of dementia can vary, depending on the types of brain changes that may be taking place. Other dementias include Lewy body dementia, frontotemporal disorders, and vascular dementia. It is common for people to have mixed dementia—a combination of two or more disorders, at least one of which is dementia.
For example, some people have both Alzheimer’s disease and vascular dementia.
Alzheimer’s 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, or tau, tangles). These plaques and tangles in the brain are still considered some of the main features of Alzheimer’s disease. Another feature is the loss of connections between nerve cells (neurons) in the brain. Neurons transmit messages between different parts of the brain, and from the brain to muscles and organs in the body.
Changes in the Brain
Scientists continue to unravel the complex brain changes involved in the onset and progression of Alzheimer’s disease. It seems likely that damage to the brain starts a decade or more before memory and other cognitive problems appear. During this preclinical stage of Alzheimer’s disease, people seem to be symptom-free, but toxic changes are taking place in the brain. Abnormal deposits of proteins form amyloid plaques and tau tangles throughout the brain, and once-healthy neurons stop functioning, lose connections with other neurons, and die. The damage initially appears to take place in the hippocampus, the part of the brain essential in forming memories. As more neurons die, additional parts of the brain are affected, and they begin to shrink. By the final stage of Alzheimer’s, damage is widespread, and brain volume has shrunk significantly.
Signs and Symptoms
Memory problems are typically one of the first signs of cognitive impairment related to Alzheimer’s disease. Some people with memory problems have a condition called mild cognitive impairment (MCI). In MCI, people have more memory problems than normal for their age, but their symptoms do not interfere with their everyday lives. Movement difficulties and problems with the sense of smell have also been linked to MCI. Older people with MCI are at greater risk for developing Alzheimer’s, but not all of them do.
Some may even go back to normal cognition. The first symptoms of Alzheimer’s vary from person to person. For many, decline in non-memory aspects of cognition, such as word-finding, vision/spatial issues, and impaired reasoning or judgment, may signal the very early stages of Alzheimer’s disease. Researchers are studying biomarkers to see if they can detect early changes in the brains of people with MCI and in cognitively normal people who may be at greater risk for Alzheimer’s disease. Studies indicate that such early detection may be possible, but more research is needed before these techniques can be relied upon to diagnose Alzheimer’s disease in everyday medical practice.
Mild Alzheimer’s Disease
As Alzheimer’s disease progresses, people experience greater memory loss and other cognitive difficulties. Problems can include wandering and getting lost, trouble handling money and paying bills, repeating questions, taking longer to complete normal daily tasks, and personality and behavior changes. People are often diagnosed at this stage.
Moderate Alzheimer’s Disease
In this stage, damage occurs in areas of the brain that control language, reasoning, sensory processing, and conscious thought. Memory loss and confusion grow worse, and people begin to have problems recognizing family and friends. They may be unable to learn new things, carry out multistep tasks such as getting dressed, or cope with new situations. In addition, people at this stage may have hallucinations, delusions, and paranoia and may behave impulsively.
Severe Alzheimer’s Disease
Ultimately, plaques and tangles spread throughout the brain, and brain tissue shrinks significantly. People with severe Alzheimer’s 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 Alzheimer’s
Scientists don’t yet fully understand what causes Alzheimer’s disease in most people. In people with early-onset Alzheimer’s, a genetic mutation is usually the cause. Late-onset Alzheimer’s arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors.
The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer’s may differ from person to person.
The Basics of Alzheimer’s
Scientists are conducting studies to learn more about plaques, tangles, and other biological features of Alzheimer’s disease. Advances in brain imaging techniques allow researchers to see the development and spread of abnormal amyloid and tau proteins in the living brain, as well as changes in brain structure and function. Scientists are also exploring the very earliest steps in the disease process by studying changes in the brain and body fluids that can be detected years before Alzheimer’s symptoms appear.
Findings from these studies will help in understanding the causes of Alzheimer’s and make diagnosis easier. One of the great mysteries of Alzheimer’s disease is why it largely strikes older adults. Research on normal brain aging is shedding light on this question. For example, scientists are learning how age-related changes in the brain may harm neurons and contribute to Alzheimer’s damage. These age-related changes include atrophy (shrinking) of certain parts of the brain, inflammation, production of unstable molecules called free radicals, and mitochondrial dysfunction (a breakdown of energy production within a cell).
Most people with Alzheimer’s have the late-onset form of the disease, in which symptoms become apparent in their mid-60s. The apolipoprotein E (APOE) gene is involved in late-onset Alzheimer’s. This gene has several forms. One of them, APOE ε4, increases a person’s risk of developing the disease and is also associated with an earlier age of disease onset. However, carrying the APOE ε4 form of the gene does not mean that a person will definitely develop Alzheimer’s disease, and some people with no APOE ε4 may also develop the disease. Also, scientists have identified a number of regions of interest in the genome (an organism’s complete set of DNA) that may increase a person’s risk for late onset Alzheimer’s to varying degrees.
Early-onset Alzheimer’s disease occurs in people age 30 to 60 and represents less than 5 percent of all people with Alzheimer’s. Most cases are caused by an inherited change in one of three genes, resulting in a type known as early-onset familial Alzheimer’s disease, or FAD. For others, the disease appears to develop without any specific, known cause, much as it does for people with late-onset disease.
Most people with Down syndrome develop Alzheimer’s. This may be because people with Down syndrome have an extra copy of chromosome 21, which contains the gene that generates harmful amyloid.
Health, Environmental, and Lifestyle Factors
Research suggests that a host of factors beyond genetics may play a role in the development and course of Alzheimer’s disease. There is a great deal of interest, for example, in the relationship between cognitive decline and vascular conditions such as heart disease, stroke, and high blood pressure, as well as metabolic conditions such as diabetes and obesity. Ongoing research will help us understand whether and how reducing risk factors for these conditions may also reduce the risk of Alzheimer’s. A nutritious diet, physical activity, social engagement, and mentally stimulating pursuits have all been associated with helping people stay healthy as they age. These factors might also help reduce the risk of cognitive decline and Alzheimer’s disease. Clinical trials are testing some of these possibilities.
Diagnosis of Alzheimer’s Disease
Doctors use several methods and tools to help determine whether a person who is having memory problems has “possible Alzheimer’s dementia” (dementia may be due to another cause) or “probable Alzheimer’s dementia” (no other cause for dementia can be found). To diagnose Alzheimer’s, doctors may:
• Ask the person and a family member or friend questions about 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 standard medical tests, such as blood and urine tests, to identify other possible causes of the problem
• Perform brain scans, such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET), to rule out other possible causes for symptoms. These tests may be repeated to give doctors information about how the person’s memory and other cognitive functions are changing over time.
Alzheimer’s disease can be definitively diagnosed only after death, by linking clinical measures with an examination of brain tissue in an autopsy. People with memory and thinking concerns should talk to their doctor to find out whether their symptoms are due to Alzheimer’s or another cause, such as stroke, tumor, Parkinson’s disease, sleep disturbances, side effects of medication, an infection, or a non-Alzheimer’s dementia.
Some of these conditions may be treatable and possibly reversible. If the diagnosis is Alzheimer’s, beginning treatment early in the disease process may help preserve daily functioning for some time, even though the underlying disease process cannot be stopped or reversed. An early diagnosis also helps families plan for the future. They can take care of financial and legal matters, address potential safety issues, learn about living arrangements, and develop support networks. In addition, an early diagnosis gives people greater opportunities to participate in clinical trials that are testing possible new treatments for Alzheimer’s disease or other research studies.
Treatment of Alzheimer’s Disease
Alzheimer’s disease is complex, and it is unlikely that any one drug or other intervention will successfully treat it. Current approaches focus on helping people maintain mental function, manage behavioral symptoms, and slow or delay the symptoms of disease.
Researchers hope to develop therapies targeting specific genetic, molecular, and cellular mechanisms so that the actual underlying cause of the disease can be stopped or prevented.
Maintaining Mental Function
The U.S. Food and Drug Administration has approved to treat symptoms of Alzheimer’s.
Donepezil (Aricept¨), rivastigmine (Exelon¨), and galantamine (Razadyne¨) are used to treat mild to moderate Alzheimer’s (donepezil can be used for severe Alzheimer’s as well). Memantine (Namenda¨) is used to treat moderate to severe Alzheimer’s. These drugs work by regulating neurotransmitters, the brain chemicals that transmit messages between neurons. They may help maintain thinking, memory, and communication skills, and help with certain behavioral problems. However, these drugs don’t change the underlying disease process. They are effective for some but not all people and may help only for a limited time.
Common behavioral symptoms of Alzheimer’s include sleeplessness, wandering, agitation, anxiety, and aggression. Scientists are learning why these symptoms occur and are studying new treatments—drug and nondrug— to manage them. Research has shown that treating behavioral symptoms can make people with Alzheimer’s more comfortable and makes things easier for caregivers. Looking for New Treatments Alzheimer’s disease research has developed to a point where scientists can look beyond treating symptoms to think about addressing underlying disease processes. In ongoing clinical trials, scientists are developing and testing several possible interventions, including immunization therapy, drug therapies, cognitive training, physical activity, and treatments used for cardiovascular disease and diabetes.
Support for Families and Caregivers
Caring for a person with Alzheimer’s disease can have high physical, emotional, and financial costs. The demands of day-to-day care, changes in family roles, and decisions about placement in a care facility can be difficult. There are several evidence-based approaches and programs that can help, and researchers are continuing to look for new and better ways to support caregivers. Becoming well informed about the disease is one important strategy. Programs that teach families about the various stages of Alzheimer’s and about ways to deal with difficult behaviors and other caregiving challenges can help.
Good coping skills, a strong support network, and respite care are other ways that help caregivers handle the stress of caring for a loved one with Alzheimer’s disease. For example, staying physically active provides physical and emotional benefits. Some caregivers have found that joining 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. Many organizations sponsor in-person and online support groups, including groups for people with early-stage Alzheimer’s and their families.
Participating in Clinical Trials
Everybody—those with Alzheimer’s disease or mild cognitive impairment as well as healthy volunteers with or without a family history of Alzheimer’s—may be able to take part in clinical trials and studies. Participants in Alzheimer’s clinical research help scientists learn how the brain changes in healthy aging and in Alzheimer’s. Currently, at least 70,000 volunteers are needed to participate in more than 150 active clinical trials and studies that are testing ways to understand, diagnose, treat, and prevent Alzheimer’s disease. Volunteering for a clinical trial is one way to help in the fight against Alzheimer’s disease. Studies need participants of different ages, sexes, races, and ethnicities to ensure that results are meaningful for many people. The National Institute on Aging (NIA) at the National Institutes of Health (NIH) leads the Federal Government’s research efforts on Alzheimer’s. NIA-supported Alzheimer’s Disease Centers throughout the United States conduct a wide range of research, including studies of the causes, diagnosis, and management of Alzheimer’s. NIA also sponsors the Alzheimer’s Disease Cooperative Study (ADCS), a consortium of leading researchers throughout the United States and Canada who conduct clinical trials.
To find out more about Alzheimer’s clinical trials and studies:
• Talk to your health care provider about local studies that may be right for you.
• Visit the ADEAR Center website at www.nia.nih.gov/alzheimers/volunteer.
• Contact Alzheimer’s disease centers or memory or neurology clinics in your community.
• Search the ADEAR Center clinical trials finder for a trial near you or to sign up for email alerts about new trials: www.nia.nih.gov/alzheimers/clinical-trials.
FREQUENTLY ASKED QUESTIONS ABOUT ALZHEIMER’S DISEASE
From NIH Senior Health
Updated May, 2015
1. What is Alzheimer’s disease?
Alzheimer’s disease is a brain disease that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks. It begins slowly and gets worse over time. Currently, it has no cure. Alzheimer’s disease is the most common cause of dementia in older people.
2. What is dementia?
Dementia is a loss of thinking, remembering, and reasoning skills that interferes with a person’s daily life and activities. Alzheimer’s disease is the most common cause of dementia among older people. Dementia ranges in severity from the mild stage, when it is just beginning to affect a person’s functioning, to the severe stage, when the person must depend completely on others for care.
3. How many people in the United States have Alzheimer’s disease? Estimates vary, but experts suggest that more than 5 million Americans may have Alzheimer’s disease. Alzheimer’s is currently ranked as the sixth leading cause of death in the United States, but recent estimates indicate that the disorder may rank third, just behind heart disease and cancer, as a cause of death for older people.
4. What is mild cognitive impairment?
Mild cognitive impairment, or MCI, is a condition that can be an early sign of Alzheimer’s disease—but not everyone with MCI will develop Alzheimer’s. People with MCI can still take care of themselves and do their normal activities. Signs of MCI may include: losing things often; forgetting to go to events and appointments; having more trouble coming up with words than other people the same age, and similar behaviors.
5. What is typically the first sign of Alzheimer’s disease? Memory problems are typically one of the first signs of Alzheimer’s disease, though different people may have different initial symptoms. A decline in other aspects of thinking, such as finding the right words, vision/spatial issues, and impaired reasoning or judgment, may also signal the very early stages of Alzheimer’s disease.
6. What are the stages in the development of Alzheimer’s disease? Alzheimer’s disease has three stages: early (also called mild), middle (moderate), and late (severe).
A person in the early stage of Alzheimer’s may:
• Find it hard to remember things
• Ask the same questions over and over
• Get lost in familiar places
• Lose things or put them in odd places
• Have trouble handling money and paying bills
• Take longer than normal to finish daily tasks.
As Alzheimer’s disease progresses to the middle stage, memory loss and confusion grow worse, and people may have problems recognizing family and friends. Other symptoms are this stage include:
-Difficulty learning new things and coping with new situations
-Trouble carrying out tasks that involve multiple steps, like getting dressed -Impulsive behavior
-Forgetting the names of common things
-Hallucinations, delusions, or paranoia
-Wandering away from home.
As Alzheimer’s disease becomes more severe, people lose the ability to communicate.
They may sleep more, lose weight, and have trouble swallowing. Often they are incontinent—they cannot control their bladder and/or bowels. Eventually, they need total care.
7. What changes in the brain happen to people with Alzheimer’s disease? Although we still don’t know how Alzheimer’s disease begins, it seems likely that damage to the brain starts 10 years or more before problems become obvious. During the earliest stage of Alzheimer’s, people are free of symptoms, but harmful changes are taking place in the brain. Abnormal protein deposits form amyloid plaques and neurofibrillary tangles in the brain. Once-healthy nerve cells lose their ability to function and communicate with each other, and eventually they die. As nerve cells in the brain die, parts of the brain begin to shrink. By the final stage of Alzheimer’s, damage is widespread, and brain tissue has shrunk significantly.
8. What causes Alzheimer’s disease?
Scientists do not yet fully understand what causes Alzheimer’s disease in most people.
In early-onset Alzheimer’s, which occurs in people between the ages of 30 and 60, a genetic mutation is usually the cause. Late-onset Alzheimer’s, which usually develops after age 60, arises from a complex series of brain changes that occur over decades.
The causes probably include a mix of genetic, environmental, and lifestyle factors.
These factors affect each person differently. Increasing age is the most important known risk factor for Alzheimer’s disease. Lifestyle factors, such as diet and physical exercise, and long-term health conditions, like high blood pressure and diabetes, might also play a role in the risk of developing Alzheimer’s disease.
9. If a family member has Alzheimer’s disease, will I get it, too? Just because a family member has Alzheimer’s disease does not mean that you will get it, too. A rare form of Alzheimer’s disease, called early-onset familial Alzheimer’s, is inherited. It occurs in people between the ages of 30 and 60 and is caused by mutations, or changes, in certain genes. Most cases of Alzheimer’s are late-onset. They occur after age 60 and usually have no obvious family pattern. However, genetic factors appear to increase a person’s risk of developing late-onset Alzheimer’s.
10. If you become forgetful as you get older, does that mean you will get Alzheimer’s disease?
Not all memory problems are caused by Alzheimer’s disease. Mild forgetfulness can be a normal part of aging. Sometimes memory problems are related to health issues that are treatable. For example, these conditions may cause memory loss or possibly dementia:
Medication side effects
Vitamin B12 deficiency
Tumors or infections in the brain.
Thyroid, liver or kidney disorders also can lead to memory loss. Emotional problems, such as stress, anxiety, or depression, can also make a person more forgetful and may be mistaken for dementia. The confusion and forgetfulness caused by emotions usually are temporary and go away when the feelings fade.
If you or someone in your family thinks your forgetfulness is getting in the way of your normal routine, it’s time to see your doctor. He or she can find out what’s causing these problems.
11. How is Alzheimer’s disease diagnosed?
The only definitive way to diagnose Alzheimer’s disease is to find out whether plaques and tangles exist in brain tissue. To look at brain tissue, doctors perform a brain autopsy, an examination of the brain done after a person dies.
Doctors can only make a diagnosis of “possible” or “probable” Alzheimer’s disease while a person is alive. Doctors with special training can diagnose Alzheimer’s disease correctly up to 90 percent of the time. Doctors who can diagnose Alzheimer’s include geriatricians, geriatric psychiatrists, and neurologists. A geriatrician specializes in the treatment of older adults. A geriatric psychiatrist specializes in mental problems in older adults. A neurologist specializes in brain and nervous system disorders.
To diagnose Alzheimer’s disease, doctors may ask questions about overall health, past medical problems, ability to carry out daily activities, and changes in behavior and personality; conduct tests to measure memory, problem solving, attention, counting, and language skills; carry out standard medical tests, such as blood and urine tests; and perform brain scans to look for anything in the brain that does not look normal.
12. Why is early diagnosis of Alzheimer’s important? An early, accurate diagnosis of Alzheimer’s disease helps people and their families plan for the future. It gives them time to discuss care options, find support, and make legal and financial arrangements while the person with Alzheimer’s can still take part in making decisions. Also, even though no medicine or other treatment can stop or slow the disease, early diagnosis offers the best chance to treat the symptoms.
13. How long do people live after getting diagnosed with Alzheimer’s? The time from diagnosis of Alzheimer’s disease to death varies. It can be as little as 3 or 4 years if the person is over 80 years old when diagnosed or as long as 10 years or more if the person is younger.
14. Are there any medicines to treat Alzheimer’s disease? Currently, no treatment can stop Alzheimer’s disease. However, four medications are used to treat its symptoms. These medicines may help maintain thinking, memory, and speaking skills for a limited time. They work by regulating certain brain chemicals. Most of these medicines work best for people in the early or middle stages of the disease.
For people with mild or moderate Alzheimer’s, donepezil (Aricept¨), rivastigmine (Exelon¨), or galantamine (Razadyne¨) may help. Donepezil is also approved to treat symptoms of moderate to severe Alzheimer’s. Another drug, memantine (Namenda¨), is used to treat symptoms of moderate to severe Alzheimer’s, although it also has limited effects. All of these medicines have possible side effects.
Certain medicines and other approaches can help control the behavioral symptoms of Alzheimer’s disease. These symptoms include sleeplessness, agitation, wandering, anxiety, anger, and depression.
15. Is there anything I can do to prevent Alzheimer’s disease? Currently, no medicines or treatments are known to prevent Alzheimer’s disease, but scientists are studying many possibilities. These possibilities include lifestyle factors such as exercise and physical activity, a healthy diet, and mentally stimulating activities.
In addition to lifestyle factors, scientists have found clues that some long-term health conditions, like heart disease, high blood pressure, and diabetes, are related to Alzheimer’s disease. It’s possible that controlling these conditions will reduce the risk of developing Alzheimer’s.
16. Can exercising prevent Alzheimer’s disease? Research suggests that exercise may play a role in reducing risk for Alzheimer’s disease. Animal studies show that exercise increases both the number of small blood vessels that supply blood to the brain and the number of connections between nerve cells in older rats and mice. In addition, researchers have found that exercise raises the level of a nerve growth factor (a protein key to brain health) in an area of the brain that is important to memory and learning.
17. Can controlling certain diseases protect against Alzheimer’s? Age-related diseases and conditions—such as vascular disease, high blood pressure, heart disease, and diabetes—may increase the risk of Alzheimer’s. Many studies are looking at whether this risk can be reduced by preventing or controlling these diseases and conditions.
For example, one clinical trial is looking at how lowering blood pressure to or below current recommended levels may affect cognitive decline and the development of MCI (mild cognitive impairment) and Alzheimer’s disease. Participants are older adults with high systolic (upper number) blood pressure who have a history of heart disease or stroke, or are at risk for those conditions.
Diabetes is another disease that has been linked to Alzheimer’s. Past research suggests that abnormal insulin production contributes to Alzheimer’s-related brain changes.
(Insulin is the hormone involved in diabetes.) Diabetes treatments have been tested in people with Alzheimer’s, but the results have not been conclusive.
18. Can eating certain foods prevent Alzheimer’s disease? A number of studies suggest that eating certain foods may help keep the brain healthy— and that others can be harmful. Researchers are looking at whether a healthy diet—one that includes lots of fruits, vegetables, and whole grains and is low in fat and added sugar—can help prevent Alzheimer’s.
19. Can you prevent Alzheimer’s by keeping your brain active? Keeping the mind sharp—through social engagement or intellectual stimulation—is associated with a lower risk of Alzheimer’s disease. Activities like working, volunteering, reading, going to lectures, and playing computer and other games are being studied to see if they might help prevent Alzheimer’s. But we do not know with certainty whether these activities can actually prevent Alzheimer’s.
20. What is basic research and why is it an important part of Alzheimer’s disease research?
Basic research helps scientists gain new knowledge about a disease process, including how and why it starts and progresses. In Alzheimer’s disease, basic research seeks to identify the cellular, molecular, and genetic processes that lead to the disease. For example, scientists are studying the ways in which plaques and tangles damage nerve cells in the brain; the very earliest brain changes in the disease process; the role of Alzheimer’s risk-factor genes in the development of the disease; how risk-factor genes interact with other genes and lifestyle or environmental factors to affect Alzheimer’s risk.
21. What is translational research and why is it an important part of Alzheimer’s disease research?
Translational research grows out of basic research. It creates new medicines, devices, or behavioral interventions aimed at preventing, diagnosing, or treating a disease. An important goal of Alzheimer’s translational research is to increase the number and variety of potential new medicines and other interventions that are approved for testing in humans. Scientists also examine medicines approved to treat other diseases to see they might be effective in people with Alzheimer’s.
The most promising interventions are tested in test-tube and animal studies to make sure they are safe and effective. Currently, a number of different substances are under development that may one day be used to treat the symptoms of Alzheimer’s disease or mild cognitive impairment.
22. What is clinical research and why is it an important part of Alzheimer’s disease research?
Clinical research is medical research involving people. It includes clinical studies, which observe and gather information about large groups of people. It also includes clinical trials, which test a medicine, therapy, medical device, or intervention in people to see if it is safe and effective.
Clinical trials are the best way to find out whether a particular intervention actually slows, delays, or prevents Alzheimer’s disease. Trials may compare a potential new treatment with a standard treatment or placebo (mock treatment). Or, they may study whether a certain behavior or condition affects the progress of Alzheimer’s or the chances of developing it.
23. How can people help test possible new treatments for Alzheimer’s People with Alzheimer’s disease, those with mild cognitive impairment, those with a family history of Alzheimer’s, and healthy people with no memory problems who want to help scientists test new treatments may be able to take part in clinical trials. Participants in clinical trials help scientists learn about the brain in healthy aging as well as what happens in Alzheimer’s. Results of these trials are used to improve prevention and treatment methods.
To find out more about Alzheimer’s clinical trials, talk to your health care provider or contact the Alzheimer’s Disease Education and Referral (ADEAR) Center at 1-800438-4380
STAGES OF ALZHEIMER’S DISEASE
Adapted from Santulli RB:
The Alzheimer’s Family: Helping Caregivers Cope
New York: WW Norton, 2011
Alzheimer’s disease is a progressive illness. From diagnosis (often several years after symptoms have begun) until death, anywhere from 2 to 20 years can elapse. The typical person with Alzheimer’s has symptoms for about 10 years, although the actual duration can depend on numerous factors such as the person’s age at the time of disease onset, general health, the quality and intensity of medical care throughout the disease, and other factors.
It is useful to talk about stages of Alzheimer’s disease, just as doctors will stage other long-term illnesses such as cancer or heart disease. It is important to remember, however, that there is great variability from one individual to the next. While certain characteristics may be typical of a person at, for example, the moderate stage of the disease, features of more advanced illness as well as more mild symptoms may be present in the same individual at the same time. Staging is useful for clinicians and others, as a shorthand way to communicate some information about a given person without having to describe every symptom or disability. But staging is only a rough approximation.
The most common and useful staging system has just three stages. In this system, people with Alzheimer’s are classified as being in the mild, moderate, or severe stage of the disease. In practice, specialists also speak frequently of persons with mild-tomoderate or moderate-to-severe disease, when features of both stages are present; the term end-stage disease refers to the final sub-stage of severe dementia.
Typical features of mild or early-stage Alzheimer’s disease include the following:
- Disorientation to time and place.
- Loss of initiative (apathy).
- Mood and personality changes may occur.
- Impairment of judgment in decision making.
- Difficulty managing money, paying bills, and other instrumental activities of daily living
Impact on Day-to-Day Life
To meet criteria for a diagnosis of Alzheimer’s disease or other form of dementia, there needs to be evidence that the impairments have an impact on daily life. This is a gray area. For example, just how much difficulty remembering names is beyond the boundaries of normal aging or MCI and therefore qualifies instead for a diagnosis of Alzheimer’s? For example, impairment in functioning may be present if someone refuses to go to social events or lunches at the senior center because they can no longer reliably remember anyone’s name there.
Another example of memory impairment impacting daily life is someone who develops adverse medication effects from taking his or her daily medications more frequently than prescribed, because of forgetfulness, or not taking the medications at all for several days in a row.
When difficulties of this kind are present, persons with mild Alzheimer’s disease generally need some supervision or assistance from others on a daily basis. Usually, however, they are able to live in the community with family, or even alone with sufficient, regular caregiver support and assistance.
The mild stage of Alzheimer’s disease usually lasts two to four years, although there is great variability, and will depend on how early the diagnosis as made.
Persons with moderate-stage disease typically display the following characteristics:
- Increasing memory loss and confusion
- Difficulty recognizing friends and family (usually not the spouse or primary care partner, although this varies)
- Significant difficulty with reading, writing, and finding words
- Loss of impulse control
- Reluctance or refusal to bathe
- Difficulty with dressing and other ADLs, but not yet in need of total assistance with these
- Significant mood or behavioral problems (see p. 117)
Moderate-stage Alzheimer’s disease covers a wide range of functions and impairments.
Someone in the early-moderate stages of disease may need some help with cueing to get dressed, whereas someone in the late-moderate stages may need near total assistance with ADLs. Similarly, speech may be only mildly disturbed, or it may be almost completely incoherent. Persons with moderate Alzheimer’s disease may live at home, with considerable help from others. Usually, they do not live alone unless someone is assisting them for at least some period of time every day, and that is not an ideal situation in most cases. Other individuals with moderate dementia may reside in a memory care unit of an assisted living facility, or possibly even a nursing home, depending on their degree of dependency or concurrent medical problems. The moderate stage of the disease can last anywhere from two to ten years.
By the time an individual reaches the severe stages of Alzheimer’s, he or she has usually have been ill for many years. Typical symptoms at this stage include:
- Little or no short-term memory;
- in need of complete assistance with all basic activities of daily living (eating, bathing, dressing, toileting, ambulating, and continence);
- language, both expressive (speaking) and receptive(understanding what someone else is saying) is extremely impaired, if still present at all;
- usually incontinent of both urine and bowel.
Individuals in the severe stage of dementia are frequently in a nursing home, due to their impairment in all ADLs and incontinence. If the person still lives at home, they need nearly continuous care for survival as they are literally unable to do anything for themselves.
The final phase of severe dementia is referred to as the end stage. Persons in end stage dementia often show the following characteristics: Weight loss; increasing difficulty with eating or reluctance to eat; inability to recognize even close family members; minimal or no language; minimal to no interaction with the environment; automatic reactions, only, to stimulation
The severe and end stages of Alzheimer’s disease, together, can last for many years, depending on a number of factors including the person’s overall state of physical health.
Persons in the end stage of Alzheimer’s are eligible for hospice care through Medicare.
EARLY-ONSET ALZHEIMER’S DISEASE
Robert B. Santulli, M.D.
(added September, 2016)
While Alzheimer’s disease most commonly occurs in individuals over the age of 65, about 5% of all cases begin earlier. When the disease begins before age 65, it is referred to as “Early-Onset Alzheimer’s Disease” (EOAD). The more typical form of the disease is referred to as “Late-Onset Alzheimer’s Disease” (LOAD).
Familial Early-Onset Alzheimer’s Disease (FAD)
About half of individuals with EOAD have a genetic mutation that has caused the disease. A genetic mutation is a permanent alteration in the DNA sequence that characterizes the gene. These occur for reasons that are unknown. In people with familial early-onset Alzheimer’s disease (FAD), there is usually a parent who has earlyonset Alzheimer’s disease, and that person’s siblings and children have a 50% chance of inheriting the disease.
The genetic mutation responsible for FAD occurs in one of three genes: APP, on chromosome 21; presenilin-1 on chromosome 14; or presenilin-2 on chromosome 1.
Of the three, presenilin-1 is by far the most common cause of FAD. Each of these genes influences the production of beta-amyloid protein that is thought by many to be important in the causation of Alzheimer’s disease. In addition, there may be several other genes that cause FAD, but these have not yet been identified.
Research on Familial Early-Onset Alzheimer’s Disease The Dominantly Inherited Alzheimer Network (DIAN) is a research partnership involving a number of institutions in the United States and abroad. Individuals who come from families with inherited forms of Alzheimer’s disease (whether or not they, themselves, have the disease or the gene) are studied intensively by this group, in the hopes that this will lead to a better understanding of the disease, and will help develop new treatments.
Eligible individuals may find out more about the DIAN at https://www.dian-info.org/. Other research studies of early-onset Alzheimer’s disease are also ongoing. This is particularly important since many studies of LOAD exclude individuals younger than 65.
Sporadic (Non-Familial) Early-Onset Alzheimer’s Disease About half of those with EOAD have no identified genetic causes. These persons may or may not have direct relatives with the disease, just as is the case in those who develop late-onset Alzheimer’s. It is not known why the disease begins early in these individuals, although this is an active area of research.
Age of Onset
In the non-familial form of early-onset Alzheimer’s, the disease typically begins in the 50’s or early 60’s, whereas the genetic form of the disease often has an earlier age of onset. It has been reported to occur in the 30’s although that is exceedingly uncommon.
Clinical Similarity to Late-Onset Alzheimer’s Disease Other than the age at which the illness begins, there appear to be no notable differences in the disease pathology (the actual appearance of the brain tissue, when viewed at autopsy both grossly and under a microscope) between EOAD and LOAD. Symptoms and overall course of the illnesses are likewise very similar, although there are some reports that persons with early-onset Alzheimer’s disease may have more non-memory symptoms, such as apraxias or visuospatial dysfunction. Likewise, anti-dementia medication treatment has about the same overall degree of effectiveness in each group.
Because EOAD is similar in so many respects to the LOAD, most of what is written in this Handbook applies to these individuals, as well.
Making the Diagnosis
Particularly for those with early-onset Alzheimer’s who have no family history of the disease, making the diagnosis can be very difficult; often, symptoms have been present for many years before an accurate diagnosis is ultimately made. This is due to two factors: (1) the rarity of Alzheimer’s in the years before 65; and (2) the presentation of the disease in both young and old is often very insidious, with initial symptoms that could easily be mistaken for other conditions.
Typically, individuals may present in their fifties or very early sixties with vague complaints, such as new difficulties at work; trouble concentrating; low mood; social withdrawal; personality changes, and the like. With hindsight, it might be obvious that this array of symptoms fits the pattern for EOAD, but it is certainly not the first diagnosis that individuals themselves or their physicians are likely to consider when the person presents with these difficulties at a relatively early age. Often, patients are seen as merely being under “stress”; having a “midlife crisis” or marital difficulties, or possibly using excessive amounts of alcohol or other drugs. Another common misdiagnosis is depression; of course, depression can be a presenting feature of Alzheimer’s disease at any age, but a careful exploration may reveal that other symptoms are also present, when the depression is a component of dementia rather than a condition existing by itself. Similarly, apathy commonly occurs in early Alzheimer’s and can easily be mistaken for depression.
Other Dementias Can Appear Before Age 65:
Early-onset Alzheimer’s disease is the most common form of dementia that occurs before the age of 65. However, other dementias can also occur at an early age. The most common of these is fronto-temporal dementia (see p. 97). FTD typically begins in the 50’s, although it can have an onset that is earlier or later. Most other types of dementia presenting before age 65 are exceedingly rare.
The Impact on Working Life
Of the many challenges associated with early-onset dementia, the impact on work is one of the most significant. Since the disease begins so insidiously, and since diagnosis can be delayed for so many years, symptoms can significantly interfere with the person’s ability to perform adequately at his or her job before the cause of this change in work performance is identified. While it is illegal to simply fire someone because they have early-onset dementia, if this diagnosis is not known, employers may simply feel that the individual is not performing well on the job for other reasons, and it is not rare that persons lose their employment because of performance issues before it is clear that they are suffering from early –onset dementia. This humiliation only adds to the enormous psychological and, especially, financial burden of the disease.
The Social Security Administration considers early-onset Alzheimer’s and frontotemporal dementia to be conditions that are eligible for the “Compassionate Allowance” program. This permits expedited review for eligibility for Social Security Disability Insurance (SSDI) or Supplemental Security Income (SSI). While these are certainly valuable benefits for chronically ill individuals, the remuneration rarely equals that which someone earned prior to developing Alzheimer’s disease. More information about the Compassionate Allowance program is available at the following website: https://www.ssa.gov/compassionateallowances/.
For these reasons, it is especially important to attempt to obtain a definitive diagnosis as soon as possible, particularly if developing symptoms are causing difficulties on the job and threatening continued employment.
The Impact on the Family
One of the particular burdens of EOAD is that the individual often has young children at home. Not only is the afflicted individual progressively less able to provide appropriate care for his or her offspring, but also, living with a demented parent can be extremely traumatic for children. It is important to talk openly with children (in an age-appropriate fashion) about the disease, sooner rather than later. See p. 267 for a list of books and other resources to help children understand and cope with the illness. Most of these resources, not surprisingly, are oriented toward dealing with the illness in a grandparent, rather than a parent, but they can be quite helpful nevertheless. It may be very useful for children to speak with a counselor or a therapist about the situation.
Spouses who previously stayed at home to raise their young children may be compelled back into the workforce for financial reasons. Additionally, spouses who work outside of the home need to consider how to provide proper supervision and care for the individual with EOAD who is now at home full-time. Some members of this “sandwich generation” had also been caring for elderly parents, in addition to young children, and now have a spouse with dementia who needs care as well; these are burdens that no one person can manage alone, and outside help from other family and/or community resources is essential.
Aside from these practical realities, there are, of course, the enormous emotional burdens of losing a loved one, gradually, to dementia. Spouses of any age must cope with this, but it can be particularly devastating for those who are younger (see Santulli RB and Blandin K, The Emotional Journey of the Alzheimer’s Family, for a more thorough discussion of the emotional losses experienced by the spouse and other family members when someone has dementia).
The Eventual Need for Care in a Facility
Because of their younger age, many people who develop EOAD will live for an exceptionally long time with the disease, often spending years in the later stages of the illness. Many people with early-onset Alzheimer’s resist going to adult day programs for dementia care, since they may be decades younger than the majority of other clients in the program.
Unlike those with the more common LOAD, where both the patient and spouse are likely to be retired, the spouse of the younger-onset individual may well be working full-time.
Children are still in school and often too young to provide significant amounts of care for the ill parent. For all of these reasons, care in a facility (assisted living or nursing home) is a frequent necessity, eventually. This is, of course, a wrenching move for everyone.
Some nursing facilities have units for younger residents, but these are mostly found in urban areas. Persons with early-onset Alzheimer’s may have greater physical strength and vitality than most facilities are accustomed to in their residents, and if there is aggressive behavior or wandering, continued stay in the facility can be threatened. This may also be the case for individuals with fronto-temporal dementia.
ALZHEIMER’S DISEASE GENETICS FACT SHEET FROM THE NATIONAL INSTITUTE ON AGING
ALZHEIMER’S DISEASE EDUCATION AND REFERRAL CENTER
Page Last Updated: April 8, 2016
Scientists believe that many factors influence when Alzheimer’s disease begins and how it progresses. The more they study this devastating disease, the more they realize that genes play an important role. Research conducted and funded by the National Institute on Aging (NIA) at the National Institutes of Health (NIH) and others is advancing our understanding of Alzheimer’s disease genetics.
The Genetics of Disease
Some diseases are caused by a genetic mutation, or permanent change in one or more specific genes. If a person inherits from a parent a genetic mutation that causes a certain disease, then he or she will usually get the disease. Sickle cell anemia, cystic fibrosis, and early-onset familial Alzheimer’s disease are examples of inherited genetic disorders.
In other diseases, a genetic variant may occur. A single gene can have many variants.
Sometimes, this difference in a gene can cause a disease directly. More often, a variant plays a role in increasing or decreasing a person’s risk of developing a disease or condition. When a genetic variant increases disease risk but does not directly cause a disease, it is called a genetic risk factor.
Identifying genetic variants may help researchers find the most effective ways to treat or prevent diseases such as Alzheimer’s in an individual. This approach, called precision medicine, takes into account individual variability in genes, environment, and lifestyle for each person.
Alzheimer’s Disease Genetics
Alzheimer’s disease is an irreversible, progressive brain disease. It is characterized by the development of amyloid plaques and neurofibrillary, or tau, tangles; the loss of connections between nerve cells (neurons) in the brain; and the death of these nerve cells. There are two types of Alzheimer’s—early-onset and late-onset. Both types have a genetic component.
What Are DNA, Chromosomes, and Genes?
Genetic mutations in a cell can lead to abnormal proteins and, in turn, diseases such as early-onset Alzheimer’s.
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 (deoxyribonucleic acid), 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 compact structures called chromosomes. Normally, each cell has 46 chromosomes in 23 pairs, which are inherited equally from a person’s biological parents.
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 Ychromosomes, which, among other functions, determine a person’s sex. The genes “instruct” the cell to make unique proteins that, in turn, dictate the types of cells made.
Genes also direct almost every aspect of the cell’s construction, operation, and repair.
Even slight changes in a gene can produce a protein that functions abnormally, which may lead to disease. Other changes in genes may increase or decrease a person’s risk of developing a particular disease.
Early-Onset Alzheimer’s Disease
(see also p. 63)
Early-onset Alzheimer’s disease occurs in people age 30 to 60 and represents less than 5 percent of all people with Alzheimer’s. Most cases are caused by an inherited change in one of three genes, resulting in a type known as early-onset familial Alzheimer’s disease, or FAD. For others, the disease appears to develop without any specific, known cause.
A child whose biological mother or father carries a genetic mutation for early-onset FAD has a 50/50 chance of inheriting that mutation. If the mutation is in fact inherited, the child has a very strong probability of developing early-onset FAD.
Early-onset FAD is caused by any one of a number of different single-gene mutations on chromosomes 21, 14, and 1. 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.
Each of these mutations plays a role in the breakdown of APP, a protein whose precise function is not yet fully understood. This breakdown is part of a process that generates harmful forms of amyloid plaques, a hallmark of the disease.
Critical research findings about early-onset Alzheimer’s have helped identify key steps in the formation of brain abnormalities typical of the more common late-onset form of Alzheimer’s. Genetics studies have helped explain why the disease develops in people at various ages.
NIA-supported scientists are continuing research into early-onset disease through the Dominantly Inherited Alzheimer Network (DIAN), an international partnership to study families with early-onset FAD. By observing the Alzheimer’s-related brain changes that occur in these families long before symptoms of memory loss or cognitive issues appear, scientists hope to gain insight into how and why the disease develops in both its early- and late-onset forms.
In addition, a clinical trial in Colombia, South America, supported by the NIA, is testing the effectiveness of an amyloid-clearing drug in symptom-free volunteers at high risk of developing early-onset FAD.
Late-Onset Alzheimer’s Disease
Most people with Alzheimer’s have the late-onset form of the disease, in which symptoms become apparent in the mid-60s and later. The causes of late-onset Alzheimer’s are not yet completely understood, but they likely include a combination of genetic, environmental, and lifestyle factors that affect a person’s risk for developing the disease.
Researchers have not found a specific gene that directly causes the late-onset form of the disease. However, one genetic risk factor—having one form of the apolipoprotein E (APOE) gene on chromosome 19—does increase a person’s risk. APOE comes in several different forms, or alleles:
• APOE ε2 is relatively rare and may provide some protection against the disease.
If Alzheimer’s disease occurs in a person with this allele, it usually develops later in life than it would in someone with the APOE ε4 gene.
• APOE ε3, the most common allele, is believed to play a neutral role in the disease—neither decreasing nor increasing risk.
• APOE ε4 increases risk for Alzheimer’s disease and is also associated with an earlier age of disease onset. A person has zero, one, or two APOE ε4 alleles.
Having more APOE ε4 alleles increases the risk of developing Alzheimer’s.
APOE ε4 is called a risk-factor gene because it increases a person’s risk of developing the disease. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer’s. Some people with an APOE ε4 allele never get the disease, and others who develop Alzheimer’s do not have any APOE ε4 alleles.
Using a relatively new approach called genome-wide association study (GWAS), researchers have identified a number of regions of interest in the genome (an organism’s complete set of DNA, including all of its genes) that may increase a person’s risk for late-onset Alzheimer’s to varying degrees. By 2015, they had confirmed 33 regions of interest in the Alzheimer’s genome.
A method called whole genome sequencing determines the complete DNA sequence of a person’s genome at a single time. Another method called whole exome sequencing looks at the parts of the genome that directly code for the proteins. Using these two approaches, researchers can identify new genes that contribute to or protect against disease risk. Recent discoveries have led to new insights about biological pathways involved in Alzheimer’s and may one day lead to effective interventions.
A blood test can identify which APOE alleles a person has, but results cannot predict who will or will not develop Alzheimer’s disease. It is unlikely that genetic testing will ever be able to predict the disease with 100 percent accuracy, researchers believe, because too many other factors may influence its development and progression.
Currently, APOE testing is used in research settings to identify study participants who may have an increased risk of developing Alzheimer’s. 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 APOE testing is useful for studying Alzheimer’s disease risk in large groups of people but not for determining any one person’s risk.
Genetic testing is used by researchers conducting clinical trials and by physicians to help diagnose early-onset Alzheimer’s disease. However, genetic testing is not otherwise recommended.
Epigenetics: Nature Meets Nurture
Scientists have long thought that genetic and environmental factors interact to influence a person’s biological makeup, including the predisposition to different diseases. More recently, they have discovered the biological mechanisms for those interactions. The expression of genes (when particular genes are “switched” on or off) can be affected— positively and negatively—by environmental factors at any time in life. These factors include exercise, diet, chemicals, or smoking, to which an individual may be exposed, even in the womb.
Epigenetics is an emerging science focused on how and when particular genes are turned on or off. Diet and exposure to chemicals in the environment, among other factors, can alter a cell’s DNA in ways that affect the activity of genes. That can make people more or less susceptible to developing a disease.
There is emerging evidence that epigenetic mechanisms contribute to Alzheimer’s disease. Epigenetic changes, whether protective, benign, or harmful, may help explain, for example, why one family member develops the disease and another does not.
Scientists are learning more about Alzheimer’s-related epigenetics, with the hope of developing individualized treatments based on epigenetic markers and their function.
Discovering all that we can about the role of Alzheimer’s disease genetic risk and protective factors is an important area of research. Understanding more about the genetic basis of the disease will help researchers to answer a number of basic questions: (1) Determine what makes the disease process begin? (2) Understand why do some people with memory and other thinking problems develop Alzheimer’s while others do not? (3) Determine how genetic risk and protective factors may interact with other genes and lifestyle or environmental factors to affect Alzheimer’s risk in any one person; (4) Identify people who are at high risk for developing Alzheimer’s so they can benefit from new interventions and treatments as soon as possible; and (5) Focus on new prevention and treatment approaches.
Major Alzheimer’s Genetics Research Efforts Underway The National Institute on Aging supports several major genetics research programs: (1) The Alzheimer’s Disease Sequencing Project (ADSP) is an innovative collaboration between NIA and the National Human Genome Research Institute, both part of NIH. The first phase of the project determined the order of all 3 billion letters in the individual genomes of 580 participants. It also generated whole exome sequencing data for an additional 11,000 volunteers.
(2) The Alzheimer’s Disease Genetics Consortium is a collaborative effort to collect and analyze genetic data from thousands of families around the world to identify genes associated with an increased risk of developing late-onset Alzheimer’s.
(3) The Late-Onset Alzheimer’s Disease Genetics Study is gathering and analyzing genetic and other information from 1,500 or more families in the United States with two or more members who have late-onset Alzheimer’s.
(4) The International Genomic Alzheimer’s Project (IGAP) is comprised of four consortia in the United States and Europe that have been working together since 2011 on genome-wide association studies (GWAS) involving thousands of DNA samples and shared data sets. In a study of more than 74,000 individuals, IGAP recently reported the identification of 19 novel regions of interest that are associated with the disease.
(5) The Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) is a national genetics data repository that gives investigators access to data to study the genetics of late-onset Alzheimer’s disease.
(6) The National Cell Repository for Alzheimer’s Disease (NCRAD) is a national resource that helps researchers find genes that increase the risk of Alzheimer’s by providing biological samples and data.
Volunteers are critical to Alzheimer’s disease genetics research. The more genetic information that researchers can gather and analyze from individuals and families—both healthy volunteers and those who may be at risk—the more clues they will have for finding additional risk-factor genes.
• Allele—A form of a gene. Each person receives two alleles of a gene, one from each biological parent. This combination is one factor among many that influence a variety of processes in the body. On chromosome 19, the apolipoprotein E (APOE) gene has three common alleles: ε2, ε3, and ε4.
• Apolipoprotein E (APOE) gene—A gene on chromosome 19 involved in making a protein that helps carry cholesterol and other types of fat in the bloodstream.
The APOE ε4 allele is the major known risk-factor gene for late-onset Alzheimer’s disease.
• Chromosome — A compact structure containing DNA and proteins present in nearly all cells of the body. Chromosomes carry genes, which direct the cell to make proteins and direct a cell’s construction, operation, and repair. Normally, each cell has 46 chromosomes in 23 pairs. Each biological parent contributes one of each pair of chromosomes.
• DNA (deoxyribonucleic acid)—The hereditary material in humans and almost all other organisms. Almost all cells in a person’s body have the same DNA. Most DNA is located in the cell nucleus.
• Gene—A basic unit of heredity. Genes direct a cell to make proteins and guide almost every aspect of a cell’s construction, operation, and repair.
• Genetic mutation—A permanent change in a gene that can be passed on to children. The rare, early-onset familial form of Alzheimer’s disease is associated with mutations in genes on chromosomes 21, 14, and 1.
• Genetic risk factor—A change in a gene that increases a person’s risk of developing a disease.
• Genetic variant—A change in a gene that may increase or decrease a person’s risk of developing a disease or condition.
• Genome—An organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism.
• Protein—A substance that determines the physical and chemical characteristics of a cell and therefore of an organism. Proteins are essential to all cell functions and are created using genetic information.