Alzheimer’s and the Brain

(Alzheimer’s Disease Education and Referral Center) The healthy human brain contains tens of billions of neurons, specialized cells that process and transmit information via electrical and chemical signals. Most neurons have three basic components: a cell body, multiple dendrites, and an axon. The cell body contains the nucleus, which houses the genetic blueprint that directs and regulates the cell’s activities. Dendrites are branch-like structures that radiate from the cell body and collect information from other neurons. The axon is a cable-like structure that extends from the other end of the cell body and transmits messages to other neurons.

The function and survival of neurons depend on several key biological processes:

  • Communication. When a neuron receives signals from other neurons, it generates an electrical charge that travels down the length of the neuron’s axon to a specialized structure called the synapse, where the axon comes into close contact with the dendrites of another neuron. At the synapse, chemicals called neurotransmitters are released and move across a microscopic gap to one of the dendrites of another neuron. There, each neurotransmitter molecule binds to a specific receptor molecule, like a key fitting into a lock, and triggers chemical or electrical signals within the dendrite that either stimulate or inhibit the next neuron’s activity. Each neuron’s axon can make connections with the dendrites of many other neurons, and each dendrite can receive connections from many axons. In fact, scientists estimate that in this brain cell communications network, one neuron may have as many as 7,000 synaptic connections with other neurons.
  • Metabolism. This term encompasses all chemical reactions that take place in a cell to support its survival and function. These reactions require chemical energy in the form of oxygen and glucose, which is supplied by blood circulating through the brain. The brain has one of the richest blood supplies of any organ and consumes up to 20 percent of the energy used by the human body—more than any other organ.
  • Repair, remodeling, and regeneration. Unlike many cells in the body, which are relatively short-lived, neurons have evolved to live a long time—more than 100 years in humans. As a result, neurons must constantly maintain and repair themselves. Neurons also continuously remodel their synaptic connections depending on how much stimulation they receive from other neurons. Neurons may strengthen or weaken synaptic connections, or even break down connections with one group of neurons and reestablish connections with a different group of neurons. In addition, a number of brain regions continue to generate new neurons, even in adults. Remodeling of synaptic connections and the generation of new neurons are thought to be important for learning, memory, and possibly brain repair.

Neurons are the cells responsible for transmitting messages between different parts of the brain, and from the brain to the muscles and organs of the body. However, the brain contains other cell types as well. In fact, glial cells are by far the most numerous cells in the brain, outnumbering neurons by at least 10 to 1. Glial cells (of which there are several varieties) surround neurons and play critical roles in supporting neuronal function. For example, glial cells help protect neurons from physical and chemical damage and are responsible for clearing foreign substances and cellular debris from the brain. To carry out these functions, glial cells often act in collaboration with blood vessel cells, which in the brain have specialized features not found in blood vessels elsewhere in the body. Together, glial and blood vessel cells regulate the delicate chemical balance within the brain to ensure optimal neuronal function.

healthy neuron
Healthy neuron

dying neuron
Dying neuron

How Does Alzheimer’s Disease Affect the Brain?

While the brain may shrink to some degree in healthy aging, it does not lose neurons in large numbers. In Alzheimer’s disease, however, damage is widespread as many neurons stop functioning, lose connections with other neurons, and die. Alzheimer’s disrupts processes vital to neurons and their networks, including communication, metabolism, and repair.

At first, the disease typically destroys neurons and their connections in parts of the brain involved in memory, including the entorhinal cortex and the hippocampus. It later affects areas in the cerebral cortex responsible for language, reasoning, and social behavior. Eventually, many other areas of the brain are damaged, and a person with Alzheimer’s becomes helpless and unresponsive to the outside world.

What Are the Main Characteristics of the Brain with Alzheimer’s Disease?

Many changes take place in the brain of a person with Alzheimer’s disease. Some of these changes can be observed in brain tissue under the microscope after death. The three abnormalities most evident in the brains of people who have died with the disorder are:

  • Amyloid plaques. Found in the spaces between neurons, plaques consist predominantly of abnormal deposits of a protein fragment called beta-amyloid. Beta-amyloid is formed from the breakdown of a larger protein called amyloid precursor protein. Beta-amyloid comes in several different molecular forms. One of these, beta-amyloid 42, has a strong tendency to clump together. When produced in excess, beta-amyloid 42 accumulates into plaques. Scientists used to think that amyloid plaques were the primary cause of the damage to neurons seen in Alzheimer’s. Now, however, many think that unclumped forms of beta-amyloid, seen earlier in the plaque formation process, may be the major culprits. Scientists have not yet determined if plaques are a cause or a byproduct of Alzheimer’s disease.
  • Neurofibrillary tangles. Found inside neurons, neurofibrillary tangles are abnormal clumps of a protein called tau. Healthy neurons are internally supported in part by structures called microtubules, which help guide nutrients and molecules from the cell body to the axon and dendrites. Researchers believe that tau normally binds to and stabilizes microtubules. In Alzheimer’s disease, however, tau undergoes abnormal chemical changes that cause it to detach from microtubules and stick to other tau molecules, forming threads that eventually clump together to form tangles. The tangles disrupt the microtubule network and create blocks in the neuron’s transport system. Abnormal tau may also cause blocks in synaptic signaling. As with beta-amyloid, some scientists think that other, smaller forms of abnormal tau may cause the most damage to neurons.
  • Loss of neuronal connections and cell death. In Alzheimer’s disease, the synaptic connections between certain groups of neurons stop functioning and begin to degenerate. This degeneration may be due to the abnormal deposits of beta-amyloid and tau. When neurons lose their connections, they cannot function properly and eventually die. As neuronal injury and death spread through the brain, connections between networks of neurons break down, and affected regions begin to shrink in a process called brain atrophy. By the final stage of Alzheimer’s, damage is widespread, and brain tissue has shrunk significantly.

This 4-minute captioned video shows the intricate mechanisms involved in the progression of Alzheimer’s disease in the brain:

Amyloid plaques, neurofibrillary tangles, synaptic loss, and cell death are the most striking features of the Alzheimer’s brain when it is viewed under the microscope after death. However, scientists are now realizing that many other cellular changes occur in the brain during the Alzheimer’s disease process. For example, glial cells show abnormalities, as certain populations of glial cells begin to swell up and divide to produce more glial cells.

The Alzheimer’s brain also shows signs of inflammation, a tissue response to cellular injury. In addition, brain blood vessel cells as well as brain neurons show signs of degeneration. Some of these other cellular changes likely occur in response to neuronal malfunction, and many of them could contribute to neuronal malfunction.

What Causes Alzheimer’s Disease?

In some rare cases, people develop Alzheimer’s in their late 30s, 40s, or 50s. This form of the disease, called early-onset dominantly inherited Alzheimer’s disease, always runs in families and is caused by a mutation in one of three genes that a person has inherited from a parent. An NIA-funded clinical study is underway to identify the sequence of brain changes in this form of early-onset Alzheimer’s, even before symptoms appear. (For more about the Dominantly Inherited Alzheimer’s Network study, see “Supporting Infrastructure and Initiatives.”)

More than 90 percent of Alzheimer’s cases occur in people age 60 and older. The development and progression of this late-onset form of the disease are very similar to what is seen in the early-onset form of the disorder. The causes of late-onset Alzheimer’s are not yet known, but they are believed to include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer’s differs from person to person—even between twins.

Much basic research in Alzheimer’s disease has focused on genes that cause the early-onset form of the disease and on how mutations in these genes disrupt cellular function and lead to the disorder. Scientists hope that what they learn about early-onset Alzheimer’s disease can be applied to the late-onset form of the disease.

Perhaps the greatest mystery is why Alzheimer’s disease largely strikes people of advanced age. The single best-known risk factor for Alzheimer’s is age, and studies show that the prevalence of the disease dramatically increases after age 70. Research on how the brain changes normally as people age will help explain Alzheimer’s prevalence in older adults. Other risk factors for Alzheimer’s may include cardiovascular disease, diabetes, depression, and certain lifestyle factors such as being physically inactive.

How Is Alzheimer’s Disease Diagnosed?

Clinicians use a number of tools to diagnose “possible Alzheimer’s dementia” (dementia that could be due to another condition) or “probable Alzheimer’s dementia” (no other cause of dementia can be found). Some people with memory problems may have mild cognitive impairment (MCI), a condition that may lead to Alzheimer’s disease.

People with MCI have more memory problems than normal for people their age, but their symptoms are not as severe as those seen in Alzheimer’s. Importantly, not all people with MCI go on to develop Alzheimer’s disease, and some may even recover from MCI and regain normal cognition. This recovery may happen if MCI is due to a medicine’s side effect or temporary depression, for example.

Tools for diagnosing probable Alzheimer’s disease include a medical history, a physical exam, and tests—preferably over time—that measure memory, language skills, and other abilities related to brain functioning. Information provided by family members or other caregivers about changes in a person’s day-to-day function and behavior also help in diagnosis.

Currently, the most definitive diagnosis of Alzheimer’s is made after death, by examining brain tissue for plaques and tangles. However, in specialized research facilities such as NIA’s network of Alzheimer’s Disease Centers, clinicians may also use brain scans and biomarkers found in blood and cerebrospinal fluid to help diagnose Alzheimer’s dementia in people, who may or may not be participating in a clinical trial.

Early, accurate diagnosis is crucial because it tells people whether they have Alzheimer’s disease or something else. Stroke, tumor, Parkinson’s disease, sleep disturbances, or side effects of medications are all known to affect cognitive function and memory, and some of these conditions are reversible. When Alzheimer’s is diagnosed, knowing early on can help families plan for the future, while the person with the disorder can still participate in making decisions.

Researchers are developing tests using biomarkers to detect the disease before memory loss or cognitive impairment is evident. One day these tests could be used in general medical practice.

How Is Alzheimer’s Disease Treated?

Only a few medications have been approved by the U.S. Food and Drug Administration to help control the cognitive loss that characterizes Alzheimer’s disease. Donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Razadyne®, formerly known as Reminyl®) are prescribed to treat mild to moderate Alzheimer’s symptoms. Donepezil also is approved to treat severe Alzheimer’s.

These drugs act by stopping or slowing the action of acetylcholinesterase, an enzyme that breaks down acetylcholine (a neurotransmitter that helps in memory formation). They maintain some people’s ability to carry out everyday activities and may slow down symptoms related to thinking, memory, or speaking skills. They also may help with certain behavioral symptoms. However, they do not stop or reverse the underlying disease process and help some people only for months to a couple of years.

Another type of medication, memantine (Namenda®), is prescribed to treat moderate to severe Alzheimer’s symptoms. This drug appears to work by blocking receptors for glutamate, another neurotransmitter involved in memory function. Studies in animals suggest that memantine may have disease-modifying effects, although this effect has not yet been demonstrated in humans.

In addition to these medications, physicians may use other drugs and nondrug approaches to treat behavioral and psychiatric problems associated with Alzheimer’s. These therapies address problems like agitation, verbal and physical aggression, wandering, depression, sleep disturbances, and delusions. (No drugs are specifically approved by the U.S. Food and Drug Administration to treat behavioral or psychiatric symptoms in dementia; such use is considered “off-label.”)

Researchers are exploring a number of lifestyle factors, from diet and exercise to stress and sleep problems, that may influence the risk of Alzheimer’s and age-related cognitive decline. Many studies have indicated links between cardiovascular health and brain health. Physical frailty, diabetes, depression, and cardiovascular disease have been linked to Alzheimer’s disease and/or other forms of age-related cognitive decline. Taking steps to reduce the risk of those conditions—through physical exercise, not smoking, limiting intake of high-fat and high-sugar foods, cholesterol and blood pressure control, and maintaining social and intellectual engagement as one ages—may also reduce one’s risk of Alzheimer’s.