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. In this section, we  examine in greater detail what scientists are learning from their search for causes of AD, techniques to help in diagnosis, and new treatments. Results from this research will bring us closer to the day when we will be able to delay the onset, prevent, or cure the devastating disease.
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.

OTHER FACTORS AT WORK IN AD

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 and then gradually form into plaques. Armed with this knowledge, investigators are intensely interested in the toxic effects that beta-amyloid and plaques have on neurons. 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.

Another important area of research is how beta-amyloid may disrupt cellular communication well before plaques form. One recent study described how beta-amyloid collects to 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 is generating new excitement as an area of study. Scientists now speculate that tau may damage and kill neurons because it upsets the normal activity of the cell in addition to forming neurofibrillary tangles.
Other studies 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 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 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.

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.
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. 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.

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. 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.

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 study in mice found that diets high in DHA 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 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.

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 do.

• 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.

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. Clinical trials pursue all these goals.

Many clinical trials of AD interventions 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®). 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 only for months to a few years. Another AD medication memantine (Namenda®) 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.

As AD begins to affect memory and mental abilities, it also begins to change a person’s emotions and behaviors. 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.

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.

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.

Alzheimer’s disease disrupts critical metabolic processes that keep neurons healthy. These disruptions cause nerve cells in the brain to stop working, lose connections with other nerve cells, and finally die. The destruction and death of nerve cells causes the memory failure, personality changes, problems in carrying out daily activities, and other features of the disease. The brains of people with AD have an abundance of two abnormal structures—amyloid plaques and neurofibrillary tangles—that are made of misfolded proteins. This is especially true in certain regions of the brain that are important in memory. The third main feature of AD is the loss of connections between cells. This leads to diminished cell function and cell death.

AMYLOID PLAQUES
Amyloid plaques are found in the spaces between the brain’s nerve cells. They were first described by Dr. Alois Alzheimer in 1906. Plaques consist of largely insoluble deposits of an apparently toxic protein peptide, or fragment, called beta-amyloid. We now know that some people develop some plaques in their brain tissue as they age. However, the AD brain has many more plaques in particular brain regions. We still do not know whether amyloid plaques themselves cause AD or whether they are a by-product of the AD process.

NEUROFIBRILLARY TANGLES
The second hallmark of AD, also described by Dr. Alzheimer, is neurofibrillary tangles. Tangles are abnormal collections of twisted protein threads found inside nerve cells. The chief component of tangles is a protein called tau. Healthy neurons are internally supported in part by structures called microtubules, which help transport nutrients and other cellular components, such as neurotransmitter-containing vesicles, from the cell body down the axon. Tau, which usually has a certain number of phosphate molecules attached to it, binds to microtubules and appears to stabilize them. In AD, an abnormally large number of additional phosphate molecules attach to tau. As a result of this, tau disengages from the microtubules and begins to come together with other tau threads. These tau threads form structures called paired helical filaments, which can become enmeshed with one another, forming tangles within the cell. The microtubules can disintegrate in the process, collapsing the neuron’s internal transport network. This collapse damages the ability of neurons to communicate with each other.

LOSS OF CONNECTION BETWEEN CELLS AND CELL DEATH
The third major feature of AD is the gradual loss of connections between neurons. Neurons live to communicate with each other, and this vital function takes place at the synapse. Since the 1980s, new knowledge about plaques and tangles has provided important insights into their possible damage to synapses and on the development of AD. The AD process not only inhibits communication between neurons but can also damage neurons to the point that they cannot function properly and eventually die. As neurons die throughout the brain, affected regions begin to shrink in a process called brain atrophy. By the final stage of AD, damage is widespread, and brain tissue has shrunk significantly.

The brain is a remarkable organ. Seemingly without effort, it allows us to carry out every element of our daily lives. It manages many body functions, such as breathing, blood circulation, and digestion, without our knowledge or direction. It also directs all the functions we carry out consciously. We can speak, hear, see, move, remember, feel emotions, and make decisions because of the complicated mix of chemical and electrical processes that take place in our brains.

The brain is made of nerve cells and several other cell types. Nerve cells also are called neurons. The neurons of all animals function in basically the same way, even though animals can be very different from each other. Neurons survive and function with the help and support of glial cells, the other main type of cell in the brain. Glial cells hold neurons in place, provide them with nutrients, rid the brain of damaged cells and other cellular debris, and provide insulation to neurons in the brain and spinal cord. In fact, the brain has many more glial cells than neurons—some scientists estimate even 10 times as many.

Another essential feature of the brain is its enormous network of blood vessels. Even though the brain is only about 2 percent of the body’s weight, it receives 20 percent of the body’s blood supply. Billions of tiny blood vessels, or capillaries, carry oxygen, glucose (the brain’s principal source of energy), nutrients, and hormones to brain cells so they can do their work. Capillaries also carry away waste products.