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 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.
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 presenilin 1 and 2 also cause an increased amount of the damaging beta-amyloid to be made in the brain.
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 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.
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.
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, 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.
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.
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.
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.
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.
The Brain’s Vascular SystemThis 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.
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.
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.
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.
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.
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:
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/Go4Life.
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.
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 do.
The reasons for these findings are not entirely clear, but a number of explanations are possible. Among them:
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).
Fecha de publicación: Septiembre 2008
Última actualización: Enero 22, 2015