Behavioral Aspects

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting 50 percent to 70 percent of dementia patients. Dementia involves impairments in daily functioning related to a progressive decline in two or more areas of mental ability. These mental and functional deficits are traceable to neuritic plaques and neurofibrillary tangles, which cause cell loss in the brain. As the disease progresses, it affects ever larger areas of the brain. Eventually, so many parts of the brain are involved that patients cannot move around normally and feed themselves. They then become susceptible to other potentially fatal diseases such as pneumonia. The disease can last from five to fifteen years. Many drugs are being developed to treat it, but there is no way of preventing the progression of the disease.

When the disease was first described by Alois Alzheimer in 1906, it seemed to affect only persons under the age of sixty-five. In the 1960s, researchers discovered during autopsies that patients whose severe cognitive decline had been attributed to diseases in the blood vessels of the brain (cerebrovascular disease or "hardening of the arteries") in fact exhibited the pathological hallmarks of AD (neurofibrillary tangles and neuritic plaques). The realization that AD affects persons of all ages is, therefore, a recent one. Because of the rarity of the disease among those under sixty—less than 2 percent—it used to be considered an uncommon disorder. Now it is understood that the likelihood of contracting AD increases with age. Among people sixty-five to eighty-five, its prevalence is 5 percent to l5 percent; 30 to 47 percent of those over eighty-five have AD. It is the fourth-leading cause of death among those sixty-five or older.

The earliest symptom of AD in most patients is severe difficulty in learning new information (i.e., anterograde memory impairment), especially increasing forgetfulness about day-to-day events. First, patients may forget a recent event from one week to the next, then from one day to the next, and finally from one minute to the next. AD impairs nearly all aspects of new learning. It is not, for example, limited to information that the patient is trying to learn (i.e., explicit or episodic memory), as is true in some amnesic disorders. Patients also have difficulty with implicit memory—learning information that impinges on consciousness in the absence of any effort at mastering it.

AD does not uniformly impair all implicit memory tasks. The same is true for the ability to learn new general skills (i.e., procedural knowledge). Patients have difficulty on some kinds of skill learning tasks but not others; for example, learning of motor skills is frequently spared. Early in the disease patients' memory for remote events is usually intact. As the disease progresses, however, remote memories also recede, but in reverse chronological order; the most recent memories evaporate first. Only the most severe impairment obliterates memories of earliest childhood.

The rapidity of anterograde memory impairment in AD is dramatic: It occurs after a delay of ten minutes or less after exposure to new information. The best way to reveal this rapid loss of information is to give a patient something new to learn—for example, a story—and to ask him/her to state how much is remembered immediately, and then after a delay. The delay should be less than ten minutes, because after ten minutes most types of patients, and even normal older persons, forget a substantial amount of information. For example, patients with other forms of dementia, such as Pick's disease or Huntington's disease, also have difficulty learning and retaining new information, but if delays last less than ten minutes, their retention is significantly better than that of AD patients. If delays are longer than ten minutes, then normal patients and those with other forms of dementia do not differ significantly from one another.

Two types of changes in the brain are primarily responsible for the severe anterograde memory impairment of AD. The first is damage to the brain regions in the medial temporal lobe that are essential for normal memory, specifically the entorhinal cortex and the hippocampus. Even in very mildly impaired patients, there is approximately a 30-percent neuronal loss in the entorhinal cortex, the primary input path to the hippocampus. There are also declines in the concentration of a number of neurotransmitters, the chemicals that are responsible for the transmission of nerve signals in the brain. One neurotransmitter, acetylcholine, which is important for normal human memory, declines by up to 70 percent in cases of severe impairment. The combination of these structural and chemical changes seems to be responsible for the unique severity of anterograde memory impairment in AD.

The cognitive impairments of AD are not confined to memory. These other difficulties interact with the memory impairment to increase its severity. Early on in the disease the other main area of impairment is the executive functions, which pertain to concept formation, directed attention, and the concurrent manipulation of information. Studies suggest that the early stages of AD present problems with the concurrent manipulation of information and a consequent difficulty with tasks that require simultaneous manipulation of several different components, even when the individual components of the tasks are deeply ingrained (e.g., preparing meals, paying bills, balancing a checkbook, and so on). That is why it sometimes seems as if the patients have difficulty with remote memory early in the disease. However, when the tasks are broken down into their constituent parts, patients can perform them.

Recent evidence suggests that problems with executive function are at least in part the result of pathology in the central portion of the cingulate gyrus. Studies in animals demonstrate that damage to the middle portion of the cingulate alters executive function. Another possible cause of executive-function impairment may be the loss of the corticocortical fibers, which connect different parts of the cortex to one another. The partial degeneration of this intracortical projection system in the early stages of AD could impair the performance that requires the rapid and simultaneous integration of multiple types of information.

The further progression of AD often severs the meaningful associations among words—hence a loss of semantic knowledge or semantic memory. Patients with AD begin to have difficulty with a number of linguistic tasks when they are mildly-to-moderately impaired. These difficulties affect the ability to produce the name of an object when shown the object itself or a picture of the object (confrontation naming). They also affect the ability to produce rapidly a series of words that belong to a particular category, such as vegetables or words starting with the letter s (verbal fluency).

Some researchers argue that AD involves a breakdown in the structure of semantic knowledge and that patients actually lose knowledge they once possessed. Others argue that semantic knowledge remains intact in mildly and moderately impaired patients but is more difficult to access; thus, when one asks them to intentionally search their semantic memory for information, they have difficulty, but if their semantic knowledge is evaluated indirectly, it appears to be preserved. It has been difficult to resolve this debate because research, although intensive, often yields contradictory findings.

AD is still difficult to diagnose during life. No test can definitively verify the onset of the disease short of examining brain tissue through a biopsy. Researchers have therefore developed a number of conventions to communicate the degree to which patients have been examined and the diagnostic criteria that the patients meet. Patients who have been carefully examined and who meet clinical research criteria but have not had a brain biopsy are said to have probable AD, or probable dementia of the Alzheimer type. Patients who have had dementia during life and in whom results of an examination of brain tissue meet pathological research criteria for the disease are said to have definite AD.

Because novel treatments are under investigation, there has been increasing interest in determining the earliest possible diagnosis of AD. The term mild cognitive impairment (MCI) has been developed to describe individuals with evidence of a functional difficulty in daily life that does not warrant a diagnosis of dementia. A large number of individuals with MCI (approximately 15 percent per year) are later diagnosed with AD. Drug trials are underway to see if treating patients with MCI reduces the likelihood that they will be diagnosed with AD.

AD is a common and serious disorder that is caused by damage to the structure and function of the brain. There are several hypotheses concerning the underlying cause of AD, but these remain unproved, and there are no effective treatments. The disease produces a gradual decline in cognitive function. The most common early symptom is a dramatic loss of new information after a brief delay, but AD can impair all aspects of mental ability.

See also:DEMENTIA; PHARMACOLOGICAL TREATMENTS OF MEMORY DEFICITS

Bibliography

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Petersen, R., Smith, G., Waring, S., Ivnik, R., Tangalos, E., and Kokmen, E. (1999). Mild cognitive impairment, clinical characterization and outcome. Archives of Neurology 56, 303-308.

Marilyn S.Albert