This is the hallmark of Alzheimer's disease. Initially, only short-term memory is impaired, and the person merely seems forgetful. But because short-term memory is essential for absorbing new information, the impairment soon interferes with the ability to interact socially and perform one's work. Long-term memory may be retained longer, often in great detail, but it becomes fragmented as the disease progresses. Toward the final stage, people with Alzheimer's may be unable to recall their own names.
The cerebral cortex
The third level of the brain is the cerebral cortex, commonly called the "gray matter." The cerebral hemispheres contain two specialized regions, one dedicated to voluntary movement and one to processing sensory information. But most of the gray matter is the association cortex, which becomes progressively larger as animals move up the evolutionary ladder. The association cortex is the region of conscious thought: It is where you store memory and language skills, process information, and carry out creative thinking.
Inside the brain In Alzheimer's disease, brain cells die and neuronal connections wither in all parts of the brain, but especially in the hippocampus and the amygdala — important parts of the limbic system that coordinate memory storage and recall — and the cerebral cortex, the seat of higher-level thinking, memory, and language. |
A micro view of the brain
Up close, the brain is a web of interconnecting cells called neurons. How these cells communicate and what happens when these cells die form the basis of our understanding of brain disease.
How brain cells communicate
The neuron is the brain's basic unit for processing information. The human brain contains an incredible number of neurons — about 100 billion, give or take 10 billion. The neuron is a unique cell in activity and appearance. It generates both electrical and chemical signals, making it able to communicate quickly with distant neurons. Instead of the compact shape typical of other cells in the body, the neuron is like an oak tree with giant branches stretched out. Each neuron has a body containing a nucleus, one long fiber called an axon, and many shorter branching fibers called dendrites.
The neuron is both a receiver and a transmitter. When a neuron receives a signal, it generates an electrical impulse. This impulse travels through the neuron and down the axon to its end (the axon terminal). The signal is then passed on to other neurons. Viewed under a microscope, neurons look like a dense forest of trees whose branches are so closely intertwined that they appear to touch. But when the details are highlighted with a silver stain, it is clear that each cell is separated from its neighbors by tiny gaps called synapses. Because the electrical signal cannot bridge this space, some other mechanism is required for a neuron to communicate with its neighbors. This is where the neuron's chemical signal comes in.
Stored in the axon terminal are chemical messengers called neurotransmitters. The electrical impulse opens tiny pores in the axon terminal, allowing a supply of neurotransmitters to flood into the synapse. The chemical then attaches to receptors on a neighboring neuron. What happens next depends on whether the neurotransmitter has an exciting or inhibiting effect on the neuron.
How nerve cells communicate -
Electrical signal travels down axon of neuron. -
Chemical neurotransmitter is released. -
Neurotransmitter binds to receptor site. -
Signal continues into new neuron. -
Reuptake occurs; neurotransmitter is transported back into the cell that released it.
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An excitatory neurotransmitter passes the message on by creating an electrical impulse in the cell that receives it, and the process of electrical-to-chemical signaling is repeated. But if an impulse were to be transmitted to every neuron in the brain, the result would be chaos; much like a power surge can cause a short circuit, neurons firing all at once would cause a prolonged epileptic seizure. To safeguard against this happening, inhibitory neurotransmitters suppress communication to neighboring neurons.
Of the more than 20 chemical messengers discovered thus far, a few are fairly well understood. Several of them are involved in memory, including acetylcholine, serotonin, and dopamine. Many of these neurotransmitters have additional functions; for example, serotonin helps regulate sleep and sensory perception, while dopamine helps regulate movement.
As biological processes go, the speed of thought is rapid (although slow compared with a computer). Electrical impulses in some neurons reach speeds of nearly 200 mph, and transmission from cell to cell takes about a thousandth of a second. In addition, one nerve cell may have more than 1,000 synapses and, with a single impulse, can transmit simultaneously to all its neighbors.
Plaques and tangles The brains of Alzheimer's patients contain neurofibrillary tangles inside neurons and clumps of fibers called neuritic plaques outside of neurons. A set of enzymes, called secretases, in the neurons cause plaques to form. The secretases snip pieces from a large amyloid precursor protein (APP), leaving behind fragments of amyloid proteins that snarl and clump with the debris of dying neurons (pieces of dendrites). In contrast to the neuritic plaques, neurofibrillary tangles form within neurons and are composed of aggregates of a different protein known as tau. |
Beta-amyloid is a peptide composed of approximately 40 amino acids. Research has shed light on the chemical process responsible for the formation and deposit of this sticky, starchlike protein in the brains of Alzheimer's patients. This understanding has prompted pharmaceutical companies to start manufacturing drugs to block the formation of amyloid deposits (see "Amyloid production blockers").
These tangles and plaques, first described by Alois Alzheimer in 1907, have been the main focus of research for decades, and for good reason: The worse the mental deterioration, the more amyloid and tangles are found in brain tissue. The prevailing view among neurologists used to be that these deposits caused the mental changes in Alzheimer's disease.
However, tangles and plaques are not unique to this condition. Some are found in other dementing disorders, and a few are scattered about in the brains of healthy middle-aged and elderly people. Some neuroscientists have wondered if these occasional deposits might explain the mild forgetfulness associated with normal aging, but studies have cast doubt on this theory.
Studies now indicate that dementia in Alzheimer's patients is caused by the shrinkage and death of neurons and synaptic loss, not by tangles and plaques themselves. However, according to the leading hypothesis, amyloid deposits play an early role by setting in motion a cascade of biochemical events that causes the cells to shrink and die.
With advances in technology enabling them to count neurons, neuroscientists were able to make this discovery by examining brain tissue from 10 people with normal brain function who died after age 60. All the samples contained about the same number of neurons in an area of the association cortex richly supplied with nerves from the sensory region. For the first time, scientists had a standard for defining how many neurons were "normal" in the human brain. Furthermore, this finding indicated that neuron loss was not a product of normal aging.
Next, the researchers compared the normal samples with brain tissue from 10 people with Alzheimer's and discovered, on average, a 41% reduction in the number of neurons. And the longer dementia had been present, the fewer neurons were found. There was also a correlation with neurofibrillary tangles: People with the greatest neuron loss had more tangles, about 95% of which were inside the remaining neurons. However, loss of neurons was dramatically greater than the number of tangles.
The researchers offered "housekeeping" as a possible explanation for this discrepancy: Molecules that clear away dead cells in the body eventually removed the tangles. When they counted neuritic plaques, the researchers found no relationship with either neuron loss or disease duration, reinforcing the view that neuronal dysfunction and death cause dementia. Although tangles and plaques are still considered the diagnostic hallmarks of Alzheimer's disease, synaptic loss and neuron death correlate best with dementia.
Experts also believe that decreased levels of the neurotransmitter acetylcholine, a chemical that bridges synapses between neurons that affect memory, also contribute to the memory loss of Alzheimer's disease. In the cortex and hippocampus, where this neurotransmitter is needed for memory and learning, the acetylcholine-producing neurons (called cholinergic neurons) are normally plentiful. But of the several types of neurons that can degenerate in Alzheimer's disease, the cholinergic neurons are especially hard hit. As acetylcholine production falls in the cortex and hippocampus, dementia becomes progressively worse. By the time someone with Alzheimer's disease dies, the cortex may have lost 90% of its acetylcholine.
Other neurotransmitter abnormalities may also be present. Reduced levels of serotonin and noradrenaline have been found in some people with Alzheimer's disease. Imbalances among these and other neurotransmitters could explain why some patients experience sensory disturbances, depression, sleep problems, aggressive behavior, and mood swings.
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