Alzheimer's Disease: Unraveling the Mystery - 5 AD Rese...

Alzheimer's Disease: Unraveling the Mystery - 5 AD Research on Cause, Diagnosis, Treatment, Clinical Trials

Scientists have studied AD from many angles. They have looked at populations to see how many cases of AD occur every year and whether there might be links between the disease and lifestyles or genetic backgrounds. They also have conducted clinical studies with healthy older people and those at various stages of AD. They have done many studies with laboratory animals. They have begun to look at neuronal circuits and networks of cells to learn how AD pathology develops and spreads. They even have examined individual nerve cells to see how beta-amyloid, tau, and other molecules affect the ability of cells to function normally.

These studies have led to a fuller understanding of many aspects of the disease, improved diagnostic tests, new ways to manage behavioral aspects of AD, and a growing number of possible drug treatments. Findings from current research are pointing scientists in promising directions for the future. They are also helping researchers to ask better questions about the issues that are still unclear.

Part 3 of Unraveling the Mystery describes what scientists are learning from their search for:

* The causes of AD
* New techniques to help in diagnosis
* New treatments

Results from this research will bring us closer to the day when we will be able to delay the onset of, prevent, or cure the devastating disease that robs our older relatives and friends of their most precious possession—their minds.


LOOKING FOR THE CAUSES OF AD

One of the most important parts of unraveling the AD mystery is finding out what causes the disease. What makes the disease process begin in the first place? What makes it worse over time? Why does the number of people with the disease increase with age? Why does one person develop AD while another remains healthy?

Some diseases, such as measles or pneumonia, have clear-cut causes. They can be prevented with vaccines or cured with antibiotics. Others, such as diabetes or arthritis, develop when genetic, lifestyle, and environmental factors work together to start a disease process. The role that any or all of these factors play may be different for each individual.

AD fits into the second group of diseases. We do not yet fully understand what causes AD, but we believe it develops because of a complex series of events that take place in the brain over a long period of time. Many studies are exploring the factors involved in the cause and development of AD.


Genetic factors at work in AD

Genetic studies of complex neurodegenerative diseases such as AD focus on two main issues—whether a gene might influence a person’s overall risk of developing a disease and whether a gene might influence some particular aspect of a person’s risk, such as the age at which the disease begins. Slow and careful detective work by scientists has paid off in discoveries of genetic links to the two main types of AD.

One type is the rare, early-onset Alzheimer’s disease. It usually affects people aged 30 to 60. Some cases of early-onset disease are inherited and are called familial AD (FAD). The other is late-onset Alzheimer’s disease. It is by far the more common form and occurs in those 60 and older. Gaining insight into the genetic factors associated with both forms of AD is important because identifying genes that either cause the disease or influence a person’s risk of developing it improves our ability to understand how and why the disease starts and progresses.

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

The nucleus of almost every human cell contains an encrypted “blueprint,” along with the means to decipher it. This blueprint, accumulated over eons of genetic trial and error, carries all the instructions a cell needs to do its job. The blueprint is made up of DNA, which exists as two long, intertwined, thread-like strands called chromosomes. Each cell has 46 chromosomes in 23 pairs. The DNA in chromosomes is made up of four chemicals, or bases, strung together in various sequence patterns. The DNA in nearly all cells of an individual is identical.

Each chromosome contains many thousands of segments, called genes. People inherit two copies of each gene from their parents, except for genes on the X and Y chromosomes, which are chromosomes that, among other functions, determine a person’s sex. Each person normally has one pair of sex chromosomes (females are XX and males are XY). The sequence of bases in a gene tells the cell how to make specific proteins. Proteins in large part determine the different kinds of cells that make up an organism and direct almost every aspect of the cell’s construction, operation, and repair. Even though all genes are present in most cells, the pattern in which they are activated varies from cell to cell, and gives each cell type its distinctive character. Even slight alterations in a gene can produce an abnormal protein, which, in turn, may lead to cell malfunction and, eventually, to disease.

Any permanent change in the sequence of bases in a gene’s DNA that causes a disease is called a mutation. Mutations also can change the activation of a particular gene. Other more common (or frequent) changes in a gene’s sequence of bases do not automatically cause disease, but they can increase the chances that a person will develop a particular disease. When this happens, the changed gene is called a genetic risk factor.

Genes and Early-Onset Alzheimer’s Disease
In the early days of AD genetics research, scientists realized that some cases, particularly of the rare early-onset AD, ran in families. This led them to examine DNA samples from these families to see whether they had some genetic trait in common. Chromosomes 21, 14, and 1 became the focus of attention. The scientists found that some families have a mutation in selected genes on these chromosomes. On chromosome 21, the mutation causes an abnormal amyloid precursor protein to be produced (see "From APP to Beta-Amyloid Plaques" for more on APP). On chromosome 14, the mutation causes an abnormal protein called presenilin 1 to be produced. On chromosome 1, the mutation causes another abnormal protein to be produced. This protein, called presenilin 2, is very similar to presenilin 1. Even if only one of these genes that are inherited from a parent contains a mutation, the person will almost inevitably develop early-onset AD. This means that in these families, children have about a 50-50 chance of developing the disease if one of their parents has it.

Early-onset AD is very rare, and mutations in these three genes do not play a role in the more common late-onset AD. However, these findings were crucial because they showed that genetics was indeed a factor in AD, and they helped to identify some key cell pathways involved in the AD disease process. They showed that mutations in APP can cause AD, highlighting the presumed key role of beta-amyloid in the disease. Mutations in pre-senilin 1 and 2 also cause an increased amount of the damaging beta-amyloid to be made in the brain.

A Different Genetic Story in Late-Onset Alzheimer’s Disease
While some scientists were studying the role of chromosomes 21, 14, and 1 in early-onset AD, others were looking elsewhere to see if they could find genetic clues for the late-onset form. By 1992, investigators had narrowed their search to a region of chromosome 19. They found a gene on chromosome 19 that they were able to link to late-onset AD.

This gene, called APOE, produces a protein called apolipoprotein E. APOE comes in several forms, or alleles—ε2, ε3, and ε4:

* The APOE ε2 allele is relatively rare and may provide some protection against the disease. If AD does occur in a person with this allele, it develops later in life than in those with an APOE ε4 allele.
* APOE ε3 is the most common allele. Researchers think it plays a neutral role in AD.
* APOE ε4 occurs in about 40 percent of all people who develop late-onset AD and is present in about 25 to 30 percent of the population. People with AD are more likely to have an APOE ε4 allele than people who do not have AD. However, at least one-third of people with AD do not have an APOE ε4 allele. Dozens of studies have confirmed that the APOE ε4 allele increases the risk of developing AD, but how that happens is not yet understood. These studies also have helped to explain some of the variation in the age at which AD develops, as people who inherit one or two APOE ε4 alleles tend to develop AD at an earlier age than those who do not. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop AD. Some people with one or two APOE ε4 alleles never get the disease, and others who do develop AD do not have any APOE ε4 alleles.

The Hunt for New AD Genes

For some time, scientists have suspected that, in addition to APOE ε4, as many as half a dozen other risk-factor genes exist for late-onset AD, but they have been unable to find them. In 2007, scientists unveiled their discovery of one new AD risk-factor gene.

This AD risk-factor gene is called SORL1. It is involved in recycling APP from the surface of cells, and its association with AD was identified and confirmed in three separate studies. Researchers found that when SORL1 is expressed at low levels or in a variant form, harmful beta-amyloid levels increase, perhaps by deflecting APP away from its normal pathways and forcing it into cellular compartments that generate beta-amyloid.

As AD genetics research has intensified, it has become increasingly clear that scientists need many different samples of genetic material if they are to continue making progress in identifying new risk-factor genes. Genetic material is also essential for identifying associated environmental factors and understanding the interactions of genes and the environment. These advances ultimately will allow investigators to identify people at high risk of developing AD and help them focus on new pathways for prevention or treatment.

In 2003, NIA launched the Alzheimer’s Disease Genetics Study to identify at least 1,000 families with members who have late-onset AD as well as members who do not have the disease. All of these family members provide blood samples and other clinical data for the initiative. The material collected allows investigators to create and maintain “immortalized” cell lines—cells that are continuously regenerated in the laboratory. These cell lines are crucial for the exhaustive DNA analysis studies needed to identify risk-factor genes, each of which may have relatively small effects on AD development. More than 4,000 new cell lines are now available for researchers to study risk-factor genes for late-onset AD.

A new initiative, the Alzheimer’s Disease Genetics Consortium, was launched in 2007 to accelerate the application of genetics technologies to late-onset AD through collaborations among most of the leading researchers in AD genetics. The ultimate goal of this effort is to obtain genetic material from 10,000 people with AD and 10,000 cognitively healthy people to comprehensively scan the whole genome for the remaining AD risk-factor genes, as well as those for age-related cognitive decline. Some of the genetic material will be drawn from existing samples of blood and tissue; other genetic material will be collected from new participants.

New AD genetics discoveries are possible largely because of close collaboration among scientists, participation of volunteer families, new genetics technologies, statistical and analytic advances, and rapid data sharing. For example, the SORL1 studies involved 14 scientific institutions in North America, Europe, and Asia and the participation of more than 6,000 people who donated blood and tissue for genetic typing. An important part of NIA’s efforts to promote and accelerate AD genetics research is to make biological samples and data publicly available to approved researchers.


Other factors at work in AD

Genetics explains some of what might cause AD, but it does not explain everything. So, researchers continue to investigate other possibilities that may explain how the AD process starts and develops.

Beta-Amyloid
We now know a great deal about how beta-amyloid is formed and the steps by which beta-amyloid fragments stick together in small aggregates (oligomers), and then gradually form into plaques (see "From APP to Beta-Amyloid Plaques" for more on this process). Armed with this knowledge, investigators are intensely interested in the toxic effects that beta-amyloid, oligomers, and plaques have on neurons. This research is possible in part because scientists have been able to develop transgenic animal models of AD. Transgenics are animals that have been specially bred to develop AD-like features, such as beta-amyloid plaques.

Beta-amyloid studies have moved forward to the point that scientists are now carrying out preliminary tests in humans of potential therapies aimed at removing beta-amyloid, halting its formation, or breaking down early forms before they can become harmful.

For example, one line of research by a pharmaceutical company started with the observation that injecting beta-amyloid into AD transgenic mice caused them to form antibodies to the beta-amyloid and reduced the number of amyloid plaques in the brain. This exciting finding led to other studies and ultimately to clinical trials in which human participants were immunized with beta-amyloid. These studies had to be stopped because some of the participants developed harmful side effects, but the investigators did not give up hope. Rather, they went back to the drawing board to rethink their strategy. More refined antibody approaches are now being tested in clinical trials, and additional research on new ways of harnessing the antibody response continues in the lab.

Another important area of research is how beta-amyloid may disrupt cellular communication well before plaques form. One recent study described how beta-amyloid oligomers target specific synaptic connections between neurons, causing them to deteriorate. Other scientists are studying other potentially toxic effects that plaques have on neurons and in cellular communication. Understanding more about these processes may allow scientists to develop specific therapies to block the toxic effects.

Tau
Tau, the chief component of neurofibrillary tangles (see "Neurofibrillary Tangles" for more on tau), is generating new excitement as an area of study. The recent focus on tau has been spurred by the finding that a mutant form of the protein is responsible for one form of frontotemporal dementia, the third most common cause of late-life dementia, after AD and vascular dementia. This form is known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Finding this mutant protein was important because it suggested that abnormalities in the tau protein itself can cause dementia.

New transgenic mouse models of AD have helped tau research make rapid progress. For example, a recent model, the “triple transgenic” mouse, forms plaques and tangles over time in brain regions similar to those in human AD. Another recent transgenic mouse model, which contains only human tau, forms clumps of damaging tau filaments also in a region-specific fashion similar to AD in humans.

These studies of tau also have suggested a mechanism for tau damage that is different from that previously suspected. With these new insights, scientists now speculate that one reason tau may damage and kill neurons is because it upsets the normal activity of the cell, in addition to forming neurofibrillary tangles.

Other studies of mutant tau in mice suggest that the accumulation of tau in tangles may not even be the culprit in memory loss. Rather, as with beta-amyloid, it may be that an earlier and more soluble abnormal form of the protein causes the damage to neurons.

Protein Misfolding
Researchers have found that a number of devastating neurodegenerative diseases (for example, AD, Parkinson’s disease, dementia with Lewy bodies, frontotemporal lobar degeneration, Huntington’s disease, and prion diseases) share a key characteristic—protein misfolding.

When a protein is formed, it “folds” into a unique three-dimensional shape that helps it perform its specific function. This crucial process can go wrong for various reasons, and more commonly does go wrong in aging cells. As a result, the protein folds into an abnormal shape—it is misfolded. In AD, the misfolded proteins are beta-amyloid (the cleaved product of APP; see "From APP to Beta-Amyloid Plaques" for more on the formation of beta-amyloid) and a cleaved product of tau.

Normally, cells repair or degrade misfolded proteins, but if many of them are formed as part of age-related changes, the body’s repair and clearance process can be overwhelmed. Misfolded proteins can begin to stick together with other misfolded proteins to form insoluble aggregates. As a result, these aggregates can build up, leading to disruption of cellular communication, and metabolism, and even to cell death. These effects may predispose a person to AD or other neurodegenerative diseases.

Scientists do not know exactly why or how these processes occur, but research into the unique characteristics and actions of various misfolded proteins is helping investigators learn more about the similarities and differences across age-related neurodegenerative diseases. This knowledge may someday lead to therapies.


Researchers Explore Neurodegenerative “Cousins”

Neurodegenerative diseases like AD, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and dementia with Lewy bodies share more than the basic characteristic of misfolded proteins. They also share clinical characteristics. For example, people with AD have trouble moving, a characteristic of Parkinson’s disease. Sleep-wake disorders, delusions, psychiatric disturbances, and memory loss occur in all of these diseases. These diseases also result from a combination of genetic, lifestyle, and environmental causes and they develop over many years.

This graphic shows one way of thinking about how these diseases may be linked as well as what makes them unique. By investigating the unique characteristics of these diseases as well as the characteristics they share, scientists hope to learn even more than they would if they focused on each disease by itself.

________
This graphic illustrates the commonalities and unique characteristics of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration (FTLD), and dementia with Lewy bodies. The first column lists lifetime influences/causes for neurodegenerative diseases: genes, environment, and systemic factors. The second column lists damaging processes that occur before symptoms appear: amyloid plaques, tau tangles, other abnormal protein deposits, reduced oxygen flow to tissues, and toxic processes. The third column lists early symptoms of the diseases: tremor, memory loss, executive function problems, movement problems, gait and balance problems, sleep-wake disorders, hallucinations, delusions, and rigidity. The fourth column is a Venn diagram showing the overlap of AD and other neurodegenerative diseases. The largest circle represents AD. Smaller circles overlap the AD circle and one another. The circle representing vascular dementia overlaps with those for AD and amyotrophic lateral sclerosis. The circle representing amyotrophic lateral sclerosis overlaps with those for AD and vascular dementia. The circle representing FTLD overlaps with those for AD and Parkinson’s disease. The circle for Parkinson’s disease, which includes AD with parkinsonism, dementia with Lewy bodies, and Parkinson’s disease with dementia, overlaps with those for AD and FTLD. A key to abbreviations used in the fourth column is provided below the graphic. The graphic was adapted from an Emory University illustration.
________


The Aging Process
Another set of insights about the cause of AD comes from the most basic of all risk factors—aging itself. Age-related changes, such as inflammation, may make AD damage in the brain worse. Because cells and compounds that are known to be involved in inflammation are found in AD plaques, some researchers think that components of the inflammatory process may play a role in AD.


________
Figure: Mitochondria and Free Radicals: Any given cell has hundreds of mitochondria. This illustration shows two—a healthy mitochondrion and an oxidatively stressed and damaged one. The arrows indicate the movement of free radicals, which can spread easily from damaged mitochondria to other parts of the cell.
________


Other players in the aging process that may be important in AD are free radicals, which are oxygen or nitrogen molecules that combine easily with other molecules (scientists call them “highly reactive”). Free radicals are generated in mitochondria, which are structures found in all cells, including neurons.

Mitochondria are the cell’s power plant, providing the energy a cell needs to maintain its structure, divide, and carry out its functions. Energy for the cell is produced in an efficient metabolic process. In this process, free radicals are produced. Free radicals can help cells in certain ways, such as fighting infection. However, because they are very active and combine easily with other molecules, free radicals also can damage the neuron’s cell membrane or its DNA. The production of free radicals can set off a chain reaction, releasing even more free radicals that can further damage neurons (see illustration "Mitochondria and Free Radicals"). This kind of damage is called oxidative damage. The brain’s unique characteristics, including its high rate of metabolism and its long-lived cells, may make it especially vulnerable to oxidative damage over the lifespan. The discovery that beta-amyloid generates free radicals in some AD plaques is a potentially significant finding in the quest for better understanding of AD as well as for other neurodegenerative disorders and unhealthy brain aging.

Researchers also are studying age-related changes in the working ability of synapses in certain areas of the brain. These changes may reduce the ability of neurons to communicate with each other, leading to increased neuronal vulnerability in regions of the brain important in AD. Age-related reductions in levels of particular growth factors, such as nerve growth factor and brain-derived neurotrophic factor, also may cause important cell populations to be compromised. Many studies are underway to tease out the possible effects of the aging process on the development of AD.

________
Figure: The Brain’s Vascular System: This image shows the complexity of the human brain’s vascular system, particularly large and small arteries that carry oxygen from the lungs to the brain. Although many blood vessels are visible here, this image shows fewer than half of the total number in the brain.
________


Vascular Disease
For some time now, hints have been emerging that the body’s vast network of small and large blood vessels—the vascular system—may make an important contribution in the development of dementia and the clinical symptoms of AD. Some scientists are focusing on what happens with the brain’s blood vessels in aging and AD. Others are looking at the relationship between AD and vascular problems in other parts of the body.

AD and Vascular Problems in the Brain
The brain requires a constant and dependable flow of oxygen and glucose to survive and flourish. The brain’s blood vessels provide the highways to deliver these vital elements to neurons and glial cells.

Aging brings changes in the brain’s blood vessels—arteries can narrow and growth of new capillaries slows down. In AD, whole areas of nervous tissue, including the capillaries that supply and drain it, also are lost. Blood flow to and from various parts of the brain can be affected, and the brain may be less able to compensate for damage that accumulates as the disease progresses.

For some time now, study of the brain’s blood vessel system in AD has been a productive line of inquiry. One important finding has been that the brain’s ability to rid itself of toxic beta-amyloid by sending it out into the body’s blood circulation is lessened. Some scientists now think that poor clearance of beta-amyloid from the brain, combined with a diminished ability to develop new capillaries and abnormal aging of the brain’s blood vessel system, can lead to chemical imbalances in the brain and damage neurons’ ability to function and communicate with each other. These findings are exciting because they may help to explain part of what happens in the brain during the development of AD. These findings also suggest several new targets for potential AD therapies.

AD and Vascular Problems in Other Parts of the Body
Research also has begun to tease out some relationships between AD and other vascular diseases, such as heart disease, stroke, and type 2 diabetes. It is important to sort out the various effects on the brain of these diseases because they are major causes of illness and death in the United States today.

Much of this evidence comes from epidemiologic studies, which compare the lifestyles, behaviors, and characteristics of groups of people (see "Describing Scientific Findings: The Type of Study Makes an Important Difference" for more information about epidemiologic studies). These studies have found, for example, that heart disease and stroke may contribute to the development of AD, the severity of AD, or the development of other types of dementia. Studies also show that high blood pressure that develops during middle age is correlated with cognitive decline and dementia in later life.

Another focus of AD vascular research is the metabolic syndrome, a constellation of factors that increases the risk of heart disease, stroke, and type 2 diabetes. Metabolic syndrome includes obesity (especially around the waist), high triglyceride levels, low HDL (“good cholesterol”) levels, high blood pressure, and insulin resistance (a condition in which insulin does not regulate blood sugar levels very well). Evidence from epidemiologic studies now suggests that people with the metabolic syndrome have increased risk of cognitive impairment and accelerated cognitive decline.

Nearly one in five Americans older than age 60 has type 2 diabetes, and epidemiologic studies suggest that people with this disease may be at increased risk of cognitive problems, including MCI and AD, as they age. The higher risk associated with diabetes may be the result of high levels of blood sugar, or it may be due to other conditions associated with diabetes (obesity, high blood pressure, abnormal blood cholesterol levels, progressive atherosclerosis, or too much insulin in the blood). These findings about diabetes have spurred research on a number of fronts—epidemiologic studies, test tube and animal studies, and clinical trials. The objective of these studies is to learn more about the relationship between diabetes and cognitive problems and to find out in clinical trials whether treating the disease rigorously can positively affect cognitive health and possibly slow or prevent the development of AD.

Lifestyle Factors
We know that physical activity and a nutritious diet can help people stay healthy as they grow older. A healthy diet and exercise can reduce obesity, lower blood cholesterol and high blood pressure, and improve insulin action. In addition, association studies suggest that pursuing intellectually stimulating activities and maintaining active contacts with friends and family may contribute to healthy aging. A growing body of evidence now suggests that these lifestyle factors may be related to cognitive decline and AD. Researchers who are interested in discovering the causes of AD are intensively studying these issues, too.

Physical Activity and Exercise
Exercise has many benefits. It strengthens muscles, improves heart and lung function, helps prevent osteoporosis, and improves mood and overall well-being. So it is not surprising that AD investigators began to think that if exercise helps every part of the body from the neck down, then it might help the brain as well.

Epidemiologic studies, animal studies, and human clinical trials are assessing the influence of exercise on cognitive function. Here are a few things these studies have found:

* Animal studies have shown that exercise increases the number of capillaries that supply blood to the brain and improves learning and memory in older animals.
* Epidemiologic studies show that higher levels
of physical activity or exercise in older people are associated with reduced risk of cognitive decline and reduced risk of dementia. Even moderate exercise, such as brisk walking, is associated with reduced risk.
* Clinical trials show some evidence of short-term positive effects of exercise on cognitive function, especially executive function (cognitive abilities involved in planning, organizing, and decision making). One trial showed that older adults who participated in a 6-month program of brisk walking showed increased activity of neurons in key parts of the brain.

More clinical trials are underway to expand our knowledge about the relationship of exercise to healthy brain aging, reduced risk of cognitive decline, and development of AD. (See "Participating in a Clinical Trial" for more information).

________
If you want to know more about the benefits of exercise and physical activity and learn ways to be active every day, NIA has free information just for you! Call 1-800-222-2225 or visit www.nia.nih.gov/Exercise.
________

Diet
Researchers have explored whether diet may help preserve cognitive function or reduce AD risk, with some intriguing findings. For example, studies have examined specific foods that are rich in antioxidants and anti-inflammatory properties to find out whether those foods affect age-related changes in brain tissue. One laboratory study found that curcumin, the main ingredient of turmeric (a bright yellow spice used in curry), can bind to beta-amyloid and prevent oligomer formation. Another study in mice found that diets high in DHA (docosahexaenoic acid), a type of healthy omega-3 fatty acid found in fish, reduced beta-amyloid and plaques in brain tissue.

Other studies have shown that old dogs perform better on learning tasks when they eat diets rich in antioxidants, such as vitamin E and other healthful compounds, while living in an “enriched” environment (one in which the dogs have many opportunities to play and interact with people and other dogs).

Scientists also have examined the effects of diet on cognitive function in people. A very large epidemiologic study of nurses found an association between participants who ate the most vegetables (especially green leafy and cruciferous vegetables) and a slower rate of cognitive decline compared with nurses who ate the least amount of these foods. An epidemiologic study of older adults living in Chicago found the same association. The researchers do not know the exact reason behind this association, but speculate that the beneficial effects may result from the high antioxidant and folate content of the vegetables.

Dietary studies, such as the curcumin study in mice or the vegetables study in nurses, generally examine individual dietary components so that scientists can pinpoint their specific effects on an issue of interest. This approach has obvious limitations because people do not eat just single foods or nutrients. Several recent epidemiologic studies have taken a different approach and looked at an entire dietary pattern.

In one of these studies, researchers worked with older adults living in New York who ate the “Mediterranean diet”—a diet with lots of fruits, vegetables, and bread; low to moderate amounts of dairy foods, fish, and poultry; small amounts of red meat; low to moderate amounts of wine; and frequent use of olive oil. The researchers found that sticking to this type of diet was associated with a reduced risk of AD and that the association seemed to be driven by the whole approach, rather than by its individual dietary components. A follow-up study found that this pattern also was associated with longer survival in people with AD.

All of these results are exciting and suggestive, but they are not definitive. To confirm the results, scientists are conducting clinical trials to examine the relationship of various specific dietary components and their effect on cognitive decline and AD.

Intellectually Stimulating Activities and Social Engagement
Many older people love to read, do puzzles, play games, and spend time with family and friends. All these activities are fun and help people feel alert and engaged in life. Researchers are beginning to find other possible benefits as well, for some studies have shown that keeping the brain active is associated with reduced AD risk. For example, over a 4-year period, one group of researchers tracked how often a large group of older people did activities that involved significant information processing, such as listening to the radio, reading newspapers, playing puzzle games, and going to museums. The researchers then looked at how many of the participants developed AD. The researchers found that the risk of developing AD was 47 percent lower in the people who did them the most frequently compared with the people who did the activities least frequently. Another study supported the value of lifelong learning and mentally stimulating activity by finding that, compared with older study participants who may have had AD or who had AD, healthy older participants had engaged in more mentally stimulating activities and spent more time at them during their early and middle adulthood.

Studies of animals, nursing home residents, and people living in the community also have suggested a link between social engagement and cognitive performance. Older adults who have a full social network and participate in many social activities tend to have less cognitive decline and a decreased risk of dementia than those who are not socially engaged.

The reasons for these findings are not entirely clear, but a number of explanations are possible. Among them:

* Intellectually stimulating activities and social engagement may protect the brain in some way, perhaps by establishing a cognitive reserve.
* These activities may help the brain become more adaptable and flexible in some areas of mental function so that it can compensate for declines in other areas.
* Less engagement with other people or in intellectually stimulating activities could be
the result of very early effects of the disease rather than its cause.
* People who engage in stimulating activities may have other lifestyle qualities that may protect them against developing AD.


Describing Scientific Findings: The Type of Study Makes an Important Difference

These days, the media are full of stories about scientific studies. It can be hard to know what to conclude about their findings. Knowing how the study was conducted can help put the results into the right perspective.

One main type of research is the epidemiologic study. These studies are observational—they gather information about people who are going about their daily lives. Study participants follow many behaviors and practices. It is difficult, therefore, to determine the exact benefits or risks of one particular behavior from among all the healthy or harmful behaviors followed by the participants. That is why, in epidemiologic studies of AD, scientists only say that a finding is “associated with” AD, or not. The epidemiologic evidence linking a behavior and AD is, at best, suggestive, but we do not know that the behavior by itself actually helps to cause or prevent AD.

Other types of research—test tube studies and studies in animals—add to the findings from epidemiologic studies. Scientists use them to examine the same issue but in ways in which the various factors that might influence a result are controlled to a greater degree. This element of control allows scientists to be more certain about why they get the results they do. It also allows them to be more definitive in the words they use to describe their results. Of course, showing a cause-and-effect relationship in tissue samples or even in animal studies still does not mean that the relationship will be the same in humans. Clinical trials in humans are the gold standard for deciding whether a behavior or a specific therapeutic agent actually prevents or delays AD (see "Participating in a Clinical Trial" for more on this kind of research).


NEW TECHNIQUES HELP IN DIAGNOSING AD

A man in his mid-60s begins to notice that his memory isn’t as good as it used to be. More and more often, a word will be on the tip of his tongue but he just can’t remember it. He forgets appointments, makes mistakes when paying his bills, and finds that he’s often confused or anxious about the normal hustle and bustle of life around him. One evening, he suddenly finds himself walking in a neighborhood he doesn’t recognize. He has no idea how he got there or how to get home.

Not so long ago, this man’s condition would have been swept into a broad catch-all category called “senile dementia” or “senility.” Although we now know that AD and other causes of dementia are distinct diseases, in the early stages it is difficult to differentiate between the onset of AD and other types of age-related cognitive decline. We have improved our ability to diagnose AD correctly, and doctors experienced in AD can diagnose the disease with up to 90 percent accuracy. A definitive diagnosis of AD, however, is still only possible after death, during an autopsy, and we are still far from the ultimate goal—a reliable, valid, inexpensive, and early diagnostic marker that can be used in any doctor’s office.

Early diagnosis has several advantages. For example, many conditions cause symptoms that mimic those of AD. Finding out early that the observed changes in cognitive abilities are not AD but something else is almost always a relief and may be just the prod needed to seek appropriate medical treatment (see "Causes of Dementia" on page 50 for more information). For the small percentage of dementias that are treatable or even reversible, early diagnosis increases the chances of successful treatment. Increasing early diagnosis and improving treatment are among NIA’s most important goals.

Even when the cause of a loved one’s dementia turns out to be AD, it is best to find out sooner rather than later. One benefit of knowing is medical. The drugs now available to treat AD can help some people maintain their mental abilities for months to years, although they do not change the underlying course of the disease (see "Helping People with AD Maintain their Mental Functioning" for more about these drugs).

Other benefits are practical. The sooner the person with AD and the family have a firm diagnosis, the more time they have to make future living arrangements, handle financial matters, establish a durable power of attorney and advance directives, deal with other legal issues, create a support network, and even consider joining a clinical trial or other research study. Being able to participate for as long as possible in making personal decisions is important to many people with AD.

Early diagnosis also gives families time to recognize that life does not stop with a diagnosis of AD. The person is still able to participate in many of the daily activities he or she has always enjoyed, and families can encourage the person to continue with them for as long as possible. Finally, early diagnosis gives family caregivers the opportunity to learn how to recognize and cope with changes over time in their loved one as well as to develop strategies that support their own physical, emotional, and financial health.

Scientists also see advantages to early diagnosis. Developing tests that can reveal what is happening in the brain in the early stages of AD will help them understand more about the cause and development of the disease. It also will help scientists learn when and how to prescribe the use of drugs and other treatments so they can be most effective.



Current Tools for Diagnosing AD

With the tools now available, experienced physicians can be reasonably confident about making an accurate diagnosis of AD in a living person. Here is how they do it.

They take a detailed patient history, including:

* A description of how and when symptoms developed.
* A description of the person’s and his or her family’s overall medical condition and history.
* An assessment of the person’s emotional state and living environment.

They get information from family members or close friends:

* People close to the person can provide valuable insights into how behavior and personality have changed; many times, family and friends know something is wrong even before changes are evident on tests.

They conduct physical and neurological examinations and laboratory tests:

* Blood and other medical tests help determine neurological functioning and identify possible non-AD causes of dementia.

They conduct neuro-psychological testing:

* Question-and-answer tests or other tasks that measure memory, language skills, ability to do arithmetic, and other abilities related to brain functioning help show what kind of cognitive changes are occurring.
* They may do a computed tomography (CT) scan or a magnetic resonance imaging (MRI) test:
* CT and MRI scans can detect strokes or tumors or can reveal changes in the brain’s structure that indicate early AD.

Exams and tests may be repeated every so often to give physicians information about how the person’s memory and other symptoms are changing over time.

Based on findings from these exams and tests, experienced physicians can diagnose or rule out other causes of dementia, or determine whether the person has MCI, “possible AD” (the symptoms may be due to another cause), or “probable AD” (no other cause for the symptoms can be found).



Causes of Dementia

Dementia is the loss of cognitive functioning—thinking, remembering, and reasoning—to such an extent that it interferes with a person’s daily life and activities. It is not a disease itself, but a group of symptoms that often accompanies a disease or condition. Some dementias are caused by neurodegenerative diseases. Dementia also has other causes, some of which are treatable.

Neurodegenerative Diseases that Cause Dementia

* Alzheimer’s disease
* Vascular dementia
* Parkinson’s disease with dementia
* Frontotemporal lobar degeneration, including:
--- frontotemporal dementia
--- frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17)
--- Pick’s disease
--- supranuclear palsy
--- corticobasal degeneration

Other Causes of Dementia

* Medication side effects
* Depression
* Vitamin B12 deficiency
* Chronic alcoholism
* Certain tumors or infections of the brain
* Blood clots pressing on the brain
* Metabolic imbalances, including thyroid, kidney, or liver disorders


EXCITING NEW DEVELOPMENTS IN AD DIAGNOSIS

Scientists are now exploring ways to help physicians diagnose AD earlier and more accurately. For example, some studies are focusing on changes in mental functioning. These changes can be measured through memory and recall tests. Tests that measure a person’s abilities in areas such as abstract thinking, planning, and language can help pinpoint changes in these areas of cognitive function. Researchers are working to improve standardized tests that might be used to point to early AD or predict which individuals are at higher risk of developing AD in the future.

Other studies are examining the relationship between early damage to brain tissue and outward clinical signs. Still others are looking for changes in biomarkers in the blood or cerebro-spinal fluid that may indicate the progression of AD (see "Very Early Signs and Symptoms" for more on this work).

One of the most exciting areas of ongoing research in this area is neuroimaging. Over the past decade, scientists have developed several highly sophisticated imaging systems that have been used in many areas of medicine, including AD. PET scans, single photon emission computed tomography (SPECT), and MRI are all examples. These “windows” on the living brain may help scientists measure the earliest changes in brain function or structure in order to identify people who are at the very first stages of the disease—well before they develop clinically apparent signs and symptoms.

To help advance this area of research, NIA launched the multi-year AD Neuroimaging Initiative (ADNI) in 2004. This project is following about 200 cognitively healthy individuals and 400 people with MCI for 3 years and 200 people with early AD for 2 years. Over the course of this study, participants undergo multiple MRI and PET scans so that study staff can assess how the brain changes in the course of normal aging and MCI, and with the progression of AD. By using MRI and PET scans at regularly scheduled intervals, study investigators hope to learn when and where in the brain degeneration occurs as memory problems develop.

Another innovative aspect of ADNI is that scientists are correlating the participants’ imaging information with information from clinical, memory, and other cognitive function tests, and with information from blood, cerebrospinal fluid, and urine samples. Results from these samples may provide valuable biomarkers of disease progress, such as changing levels of beta-amyloid and tau, indicators of inflammation, measures of oxidative stress, and changing cognitive abilities.

An important ADNI achievement is the creation of a publicly accessible database of images, biomarker data, and clinical information available to qualified researchers worldwide. Biological samples also are available for approved biomarker projects. NIA hopes that this initiative will help create rigorous imaging and biomarker standards that will provide measures for the success of potential treatments. This would substantially increase the pace and decrease the cost of developing new treatments. The ADNI study is being replicated in similar studies by researchers in Europe, Japan, and Australia.

These types of neuroimaging scans are still primarily research tools, but one day they may be used more commonly to help physicians diagnose AD at very early stages. It is conceivable that these tools also may someday be used to monitor the progress of the disease and to assess responses to drug treatment.


New Technologies Help People Participate in AD Research at Home

Traditionally, AD scientists have collected data by asking people to come to a clinic once or twice a year over a period of years. They give the participants a physical exam and ask them to take a series of memory, language, and other cognitive function tests.

These studies collect much useful information, but they have their limitations. For one thing, participants are seen only once or twice during the year, so the data collected represent only a “snapshot” in time. The studies cannot effectively capture day-to-day fluctuations in behaviors and cognitive abilities. Another limitation is that participants are seen in a research setting, not in their natural community environment. For many, coming to the clinic can be inconvenient, difficult, or both.

Advances in technology, as shown in the two research projects described here, offer some hope for dealing with these challenges by bringing research to people right in their own homes.


Motion detectors tell an interesting story

Scientists who are trying to develop methods for diagnosing AD as early as possible continually grapple with two challenges in conducting their research. First, they need to find easy and accurate ways to collect data from older people, who often have physical, emotional, or cognitive problems. Second, they need to find ways to assess accurately the very early changes in physical or cognitive abilities that could indicate that AD is progressing.

Under an NIA grant, the Oregon Center for Aging and Technology (ORCATECH) at Oregon Health & Science University is exploring the use of unobtrusive, simple technology and intelligent systems to detect and monitor subtle changes in movement that may indicate age-related cognitive changes. This project is building on research that has suggested that motor-function changes may arise before memory changes become apparent (see "Very Early Signs and Symptoms" for more on this research).

All of the 300 study participants are 80 years or older or have a spouse of a similar age, and live independently in Portland-area retirement communities. Wireless, infrared motion sensors, like those used to automatically open grocery store doors, have been placed strategically throughout the participants’ homes to gather data about changes in their walking or dressing speed over time. Special software also has been installed on each participant’s home computer to measure motor skills and speed in typing or using a mouse. The sensors and computer software collect data about motion, not what the volunteer is actually doing. Privacy is largely not a concern therefore, because the volunteers are not directly observed and no video or photographs are taken.

The 3-year study began in early 2007, so results are not yet available. However, a small pilot study using the same type of sensors showed a clear difference in the walking speeds of people age 65 and older who had MCI, compared with cognitively healthy people of the same age, over time periods of nearly a year. These data suggest that a remote sensing system like this is a feasible technology and is potentially sensitive enough to distinguish accurately between affected and unaffected people.


Using technology to collect data at home

Researchers at nearly 30 sites nationwide are comparing various ways of collecting data, including the use of an in-home “kiosk” that combines a touch-screen computer monitor with a telephone handset, an interactive voice-response system, and traditional mail and telephone. All three methods gather the same data about several areas known to be important in early detection of cognitive decline: memory; language skills; attention and concentration; activities of daily living; quality of life; health care and resource use; and changes in “global” well-being as measured by self-rating of health, cognition, and mood. This study is looking at questions such as how likely people are to complete the questions using each method, which method is the most efficient, and how sensitive each method is.

Having a data collection system that is easy to use and that collects data accurately and completely may encourage wider participation in AD clinical trials. It also may reduce the expense and burden of conducting AD research. Early results from this study show that the older participants were skeptical at first about using the kiosk, but once they learned how to use it, they became enthusiastic and excited about participating.


THE SEARCH FOR NEW TREATMENTS

More and more, scientists are able to think about ways to treat, slow, or perhaps even prevent AD at a number of possible points during the years-long continuum of disease progression. This continuum begins with the very earliest disease stage, even before symptoms are evident, moves to the first signs of memory and cognitive problems, then continues through the mild and moderate stages, and ends with the very late stages and the person’s death.

As a result, researchers who focus on developing AD treatments think a lot about the importance of timing: When would it be best to intervene and what interventions are most appropriate at which time? These questions are similar to those asked with other conditions, such as heart disease. For example, a physician would prescribe different treatments for a patient who is seemingly healthy but who is at risk of having future heart disease than for a patient who is actually having a heart attack or whose heart disease is well established. The same decision process now can be applied to AD.

It has become clear that there probably is no single “magic bullet” that will, by itself, prevent or cure AD. Therefore, investigators are working to develop an array of options from which physicians can choose. For people who already have AD, the most immediate need is for treatments to control cognitive loss as well as problem behaviors, such as aggression, agitation, wandering, depression, sleep disturbances, hallucinations, and delusions. Safe medications that remain effective over time are needed to ease a broad range of symptoms and to improve a person’s cognitive function and ability to carry out activities of daily living. Scientists also are investigating treatments that combine medications with lifestyle strategies to lessen the risk of developing cognitive decline or AD. Eventually, scientists hope to develop treatments that attack the earliest manifestations and underlying causes of AD, thereby slowing, delaying, or preventing the disease from progressing and damaging cognitive function and quality of life. Scientists use clinical trials to pursue all these goals.

Today, NIA, other NIH institutes, and private industry are conducting many clinical trials of AD interventions (see "Participating in a Clinical Trial" for more about clinical trials). These studies focus on several key areas:

* Helping people with AD maintain their mental functioning
* Managing symptoms
* Slowing, delaying, or preventing AD


Helping people with AD maintain their mental functioning

In the mid-1970s, scientists discovered that levels of a neurotransmitter (a chemical that carries messages between neurons) called acetylcholine fell sharply in people with AD. This discovery was one of the first that linked AD with biochemical changes in the brain. Scientists found that acetylcholine is a critical player in the process of forming memories. It is used by neurons in the hippocampus and cerebral cortex, which are areas of the brain important to memory function. This discovery was an important initial breakthrough in the search for drugs to treat AD.

Four medications, tested in clinical trials, have been approved by the FDA for use in treating AD symptoms. Donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Razadyne®) are prescribed to treat mild to moderate AD symptoms. Donepezil was recently approved to treat severe AD as well. These drugs, known as cholinesterase inhibitors, act by stopping or slowing the action of acetylcholinesterase, an enzyme that breaks down acetylcholine. They help to maintain higher levels of acetylcholine in the brain. In some people, the drugs maintain abilities to carry out activities of daily living. They also may maintain some thinking, memory, or speaking skills, and can help with certain behavioral symptoms. However, they will not stop or reverse the underlying progression of AD and appear to help people only for months to a few years. The newest approved AD medication is memantine (Namenda®), which is prescribed to treat moderate to severe AD symptoms. This drug appears to work by regulating levels of glutamate, another neurotransmitter involved in memory function. Like the cholinesterase inhibitors, memantine will not stop or reverse AD.


Managing symptoms

“My father is often agitated. He paces up and down, wringing his hands and crying. I know he’s sad or anxious about something but he can’t tell me what’s bothering him. Asking him about it just makes him more upset.”

“Last week, I visited Mom in the nursing home. We had a great time. Then yesterday, I went to see her again. When I walked into her room, she didn’t know me. She thought I was her sister.”

“My husband used to be such an easy going, calm person. Now, he suddenly lashes out at me and uses awful language. Last week, he got angry when our daughter and her family came over and we sat down to eat. I never know when it’s going to happen. He’s changed so much—it scares me sometimes.”

“Gran hums all the time. She used to be a singer. Is she trying to relive her past?”

As AD begins to affect memory and mental abilities, it also begins to change a person’s emotions and behaviors. Between 70 and 90 percent of people with AD eventually develop one or more behavioral symptoms. These symptoms include sleeplessness, wandering and pacing, aggression, agitation, anger, depression, and hallucinations and delusions. Some of these symptoms may become worse in the evening (a phenomenon called “sundowning”) or during daily routines, especially bathing.

The damage of AD affects many different parts of the brain. This presents a problem because even small tasks require the brain to process signals that often involve more than one region of the brain. If this processing is disrupted because of AD, the person may not be able to do the task or may act in a strange or inappropriate way.

In light of our growing understanding about the effects of AD on the brain, behaviors like the ones highlighted above suddenly make sense or even provide a loving opportunity for caregivers:

For a man who can no longer distinguish between past and present, the anguish caused by the death of a parent may be as real today as it was many years before.

Sitting down to a family meal may produce intense anxiety when a person has no idea what to do with the knife and fork in front of him and all the conversation and activity feel overwhelming.

Memories of favorite songs from long ago resurface and provide a compelling link to a happy time in the past.

Behavioral symptoms, often emotional and upsetting, are one of the hardest aspects of the disease for families and other caregivers to deal with. They are also a visible sign of the terrible change that has taken place in the person with AD. Researchers are slowly learning more about why behavioral symptoms occur and are conducting clinical trials on new treatments—both drug and non-drug—to deal with difficult behaviors.


________
Coping with Behavioral Symptoms
For more information on how to deal with behavioral issues and symptoms, visit the caregiving section of NIA’s Alzheimer’s Disease Education and Referral (ADEAR) Center website at: www.nia.nih.gov/Alzheimers/Caregiving/HomeAndFamily.
________



Slowing, delaying, or preventing AD

AD research has developed to the point where scientists are looking beyond treating symptoms to addressing the underlying disease process. Slowing the progress of AD could do much to maintain the functioning of people with AD and reduce physical and emotional stress on caregivers. Delaying AD’s effects also could help to postpone or prevent placement in an assisted living facility or nursing home, and reduce the financial costs of the disease. Preventing AD altogether is, of course, the ultimate long-term goal.

NIA and pharmaceutical companies support treatment clinical trials that are aimed at slowing, delaying, or preventing AD. The advances in our knowledge about the mechanisms and risk factors associated with AD have expanded the types of interventions under study. These trials are examining a host of possible interventions, including cardiovascular treatments, hormones, type 2 diabetes treatments, antioxidants, omega-3 fatty acids, immunization, cognitive training, and exercise, among others.

For example, NIA funds pilot trials to learn whether treating one or another aspect of type 2 diabetes will affect cognitive health and AD progression. A pilot trial is a relatively small clinical trial that collects initial data on the safety, effectiveness, and best dosage of a potential treatment. This information helps investigators decide which treatments should be tested in larger, full-scale trials. One 4-month pilot trial has examined the effects on AD of administering a nasal-spray form of insulin. This trial is founded on evidence that AD is associated with reduced levels of insulin in cerebrospinal fluid and that treatment with insulin improves memory performance. The trial will provide useful data on the safety, feasibility, and potential effectiveness of this innovative treatment approach. Investigators may be able to use the results to plan future full-scale clinical trials.

Beyond pilot studies, investigators also are conducting full-scale AD clinical trials of various interventions. One of these trials, the Alzheimer’s Disease Cooperative Study (ADCS), is testing whether one omega-3 fatty acid (DHA), found in the oil of certain fish, can slow the progression of cognitive and functional decline in people with mild to moderate AD. During the 18-month clinical trial, investigators will measure the progress of the disease using standard tests for functional and cognitive change. Researchers also will evaluate whether taking DHA supplements has a positive effect on possible physical and biological markers of AD, such as brain atrophy and proteins in blood and spinal fluid. The ADCS is a federally established consortium conducting clinical trials on AD, with sites across the United States and Canada.

AD prevention trials are under-way as well. One such trial, Prevention of Alzheimer’s Disease with Vitamin E and Selenium (PREADVISE), is being conducted in conjunction with a National Cancer Institute-funded trial called the Selenium and Vitamin E Cancer Prevention Trial (SELECT). SELECT is evaluating whether taking selenium and/or vitamin E supplements can prevent prostate cancer in healthy men older than 60 years. PREADVISE is evaluating whether these supplements can help prevent memory loss and dementia by protecting brain cells from oxidative damage (see "The Aging Process" for more on oxidative damage). About 6,000 of the more than 30,000 men enrolled in SELECT are participating in PREADVISE.



PARTICIPATING IN A CLINICAL TRIAL

Rapid advances in our knowledge about AD have led to the development of many promising new drugs and treatment strategies. However, before these new strategies can be used in clinical practice, they must be shown to work in people. This means that clinical trials—and volunteer participants—are an essential part of AD research. Advances in prevention and treatment are possible thanks to volunteers who participate in clinical trials.

Clinical trials are the primary way that researchers find out if a promising treatment is safe. Clinical trials tell researchers which treatments are the most effective and for which people they may work best. Trials can take place in various settings, such as private research facilities, teaching hospitals, specialized AD research centers, and doctors’ offices. FDA approval is necessary before scientists can begin a clinical trial.

Participating in a clinical trial is a big step for anyone, including people with AD and their caregivers. That is why physicians and clinical trials staff spend time talking with participants about what it is like to be in a trial and the pros and cons of participating. It is also why they get a signed informed consent form before a person enrolls in a trial. Here are some facts that potential participants might want to know about clinical trials.


What kinds of trials are there?

Treatment trials with existing drugs or behavioral strategies assess whether an intervention already approved for other purposes may be useful in treating age-related cognitive decline or AD. For example, trials have tested whether drugs used to lower cholesterol help slow progression of AD