Named for the German physician who first identified it in 1906, Alzheimer’s disease is the most common form of dementia, accounting for 60 to 80 percent of cases. It is a progressive disorder of the brain and is characterized by a gradual deterioration of mental faculties caused by a loss of nerve cells and the connections between them.
The disease is often accompanied by changes in behavior and personality. Its course is relentless and relatively predictable, but the rate of mental decline varies from person to person. People who are age 65 and older survive an average of four to eight years after the initial Alzheimer’s diagnosis, but some individuals can live for 20 years or more after diagnosis.
In Alzheimer’s disease, nerve cells (neurons) stop functioning, lose connections with each other and ultimately die. The death of many neurons in key parts of the brain causes those areas to atrophy (shrink) and results in abnormalities in memory, thinking and behavior.
Early in the disease, destruction of neurons is particularly prominent in the parts of the brain that control memory, especially the hippocampus. This explains why memory impairment is often the first sign of Alzheimer’s disease. As nerve cells in the hippocampus break down, memory of recent events begins to fail, and the ability to do familiar tasks begins to decline as well.
The other part of the brain that sustains major damage is the cerebral cortex, particularly the areas responsible for language, reasoning, perception and judgment (the temporal, frontal and parietal lobes). As a result, unwarranted emotional outbursts (referred to as catastrophic reactions), disturbing behaviors (such as wandering) and episodes of extreme agitation occur and become more frequent as the disease progresses.
As additional areas of the brain are affected, the person with Alzheimer’s disease becomes bedridden, incontinent, requires total care, and eventually is minimally responsive to the outside world.
Plaques and tangles
Amyloid plaques and neurofibrillary tangles are the microscopic structural hallmarks of Alzheimer’s disease. Plaques and tangles must be present to make a definitive diagnosis of Alzheimer’s, but currently these abnormal brain deposits can be seen only at autopsy. However, recently approved imaging techniques are bringing real-time diagnosis of Alzheimer’s disease closer to reality.
It remains unclear whether amyloid plaques and neurofibrillary tangles are the cause of Alzheimer’s or simply a byproduct of the disease, but researchers now have a better understanding of how plaques and tangles are formed. This improved understanding has spawned new attempts to block the underlying process that lead to their buildup.
If plaques and tangles are, in fact, the cause of Alzheimer’s disease, the success of these new approaches may ultimately provide the foundation for effective prevention strategies and treatments.
• Plaques. Amyloid plaques are a mixture of abnormal proteins and nerve cell fragments that develop in the tissue between nerve cells. Early in the disease they are most prevalent in areas of the brain involved in memory. Their main component is beta-amyloid, a protein fragment that breaks off from a larger molecule called the amyloid precursor protein.
Amyloid precursor protein is part of the cell membrane that encases every nerve cell. When nerve cells die, this large molecule must be broken down and removed from the brain. Enzymes called secretases split the protein in pieces, forming smaller beta-amyloid fragments.
Beta-secretase, one of the enzymes that slices the amyloid precursor protein, cuts the protein into a piece that is insoluble, that is, not easily dissolved. The result is that the beta-amyloid fragment is deposited in the brain. Investigators hope that blocking beta-secretase activity might prevent production of this undesirable form of beta-amyloid, and experiments are currently under way to test this hypothesis.
The beta-amyoid segment is toxic to brain cells and appears to kill them, but whether this is the initial cause of Alzheimer’s disease remain a mystery. Researchers can now detect levels of beta-amyloid in the brain through imaging test scans and spinal fluid tests.
Studies show that markers of beta-amyloid in many “normal” older people are associated with brain changes consistent with mild cognitive impairment and Alzheimer’s dementia, and this may identify people who are not yet showing symptoms of Alzheimer’s. Many researchers believe these individuals are in the preclinical state of Alzheimer’s—that is, brain cells are already dying but not enough cell death has occurred to cause symptoms.
• Tangles. Neurofibrillary tangles are the other structural abnormality associated with Alzheimer’s disease. Composed mostly of a protein called tau, these twisted, hair-like threads are what remain after a neuron’s internal support structure (known as microtubules) collapses.
In healthy neurons, microtubules function like train tracks to carry nutrients from one destination to another. Tau normally serves as the supporting “railroad ties.” In Alzheimer’s, however, the protein becomes hopelessly twisted and disrupts the function of the microtubules. This defect interferes with communication within nerve cells and eventually leads to their death.
Researchers are not sure why tau goes awry, but an enzyme called Pin1 may play an important role in keeping tau intact. In test tube experiments, when Pin1 binds to an altered tau, the protein begins to function properly and microtubule assembly is restored.
Researchers have found substantially lower-than-normal levels of Pin1 in autopsied brains of people with Alzheimer’s. The significance of these findings remains uncertain, but the presence of an enzyme such as Pin1 may help maintain or restore the proper functioning of tau, thereby preventing the formation of tangles. This possibility raises the hope that therapies aimed at preserving the function of tau might one day prevent Alzheimer’s.
Another characteristic of Alzheimer’s disease is a reduction in the levels of certain neurotransmitters that are necessary for healthy brain function. The so-called cholinergic neurons in the brain produce acetylcholine, a neurotransmitter crucial to memory and learning.
These neurons are plentiful in the hippocampus and the cerebral cortex—the two regions of the brain most ravaged by Alzheimer’s. (As is true for plaques and tangles, it is not known whether loss of neurons in these parts of the brain is a cause or an effect of Alzheimer’s.)
As the disease progresses, acetylcholine levels drop dramatically, and dementia becomes more pronounced. Levels of other neurotransmitters involved in many brain functions—serotonin, norepinephrine, somatostatin and GABA—also drop in nearly half of people with Alzheimer’s. These imbalances may lead to insomnia, depression, aggression and mood or personality changes.