Dementia of the Alzheimer Type

Degenerative Causes of Dementia

Dementia of the Alzheimer Type

Historical Perspective

In 1906 Alois Alzheimer reported a case of presenile dementia in a 51-year-old woman who displayed progressive memory loss and disorientation.

Two years earlier, Alzheimer had written of miliary plaque formations that often appeared in the brains of patients with se-nile dementia. He and his coworkers subsequently described neurofibrillary changes and granulovacuolar degeneration in se-nile and presenile dementia (Bick, 1994). Almost 90 years later, Alzheimer’s disease is the most common form of dementia and remains a major focus of scientific investigation.

Epidemiology

Alzheimer’s disease is the most common cause of dementia, ac-counting for 55 to 65% of all cases. There were fewer than 3 mil-lion cases diagnosed in the USA in 1980, but the Census Bureau predicted that there will be more than 10 million American citi-zens with Alzheimer’s disease by the year 2050. Prevalence of the disease doubles with every 5 years between the ages of 65 and 85 years. Onset of symptoms occurs after the age of 40 years in 96% of cases.

Some authors separate Alzheimer’s disease into senile and presenile forms, but the two disorders represent the same patho-logical process. Significantly, however, early-onset (that is, onset before the age of 65) Alzheimer’s disease is associated with a more rapid course than later-onset disease.

Alzheimer’s disease affects women three times as often as men, for unknown reasons. Furthermore, at least one study suggests that dementia, including Alzheimer’s, is more com-mon in black than in white American women (Heyman et al., 1991). Comparison of population studies in diverse countries shows strikingly similar prevalence rates. Longitudinal studies have revealed the importance of family history as a risk factor; however, no consistent genetic pattern has been established. For Alzheimer’s alone, the probability of developing dementia if a first-degree relative (parent or sibling) is afflicted is four times greater than that of the general population, and if two or more first-degree relatives have the disease the risk is increased eightfold compared with a normal sample of US citizens. Among monozygotic twins 43% are concordant for the disorder, com-pared with only 8% of dizygotic twins.

In addition to age, gender and family history, the presence of Down syndrome, a history of head trauma and a low level of education have been proposed as risk factors. Most studies con-cur that individuals with trisomy 21 develop the features of AD by age 35 years; however, studies have looked at the possibil-ity that families with a member who has AD are more likely to produce offspring with Down syndrome and have had inconclu-sive results. Significant head injury, as either a single incident or a chronic occurrence as in sports injuries, increases the risk of developing Alzheimer’s by a factor of 2. An uneducated person older than 75 years is about twice as likely to develop dementia as one who has 8 years or more schooling, leading to the speculation that the cognitive processes involved in obtaining an education may be partially protective. Risk factors found in some but not all studies include myocardial ischemia in the elderly, having a child at 40 years or older, and exposure to aluminum (Katzman and Kawas, 1994).

Pathology

The etiology and pathogenesis of Alzheimer’s disease are un-known. Multiple agents and pathways are probably involved in this disorder. Many hypotheses have been proposed regard-ing the cause and progression of Alzheimer’s disease includ-ing genetic factors, slow or unconventional viruses, defective membrane metabolism, endogenous toxins, autoimmune disor-ders and neurotoxicity of such trace elements as aluminum and mercury.

The brains of patients with Alzheimer’s disease contain many senile plaques, neurofibrillary tangles and Hirano’s bodies (Figures 32.3 and 32.4). There is degeneration of nerve cells, but the significant atrophy seen on neurodiagnostic examination may be more the result of shrinkage of neurons and loss of dendritic spines than of actual neuronal loss (Wolf, 1980). The atrophy is most apparent in the associational cortex areas, and early decay on the primary motor and sensory areas are relatively spared (Figures 32.5 and 32.6). Significant degenerative changes in neurons are seen in the hippocampus, locus ceruleus and nucleus basalis of Mynert. With advancing disease, these changes, in effect, separate the hippocampus from the remainder of the brain. Initially, the parietal and temporal regions are most affected by plaques and tangles, accounting for the memory impairment and parietal lobe–associated syndromes (some apraxias, hemi-attention, anosognosia, Gerstmann’s syndrome) occasionally associated with Alzheimer’s disease. Neurofibrillary tangles do not correlate with the severity of

the dementia; however, the concentration of neuritic plaques is directly associated with the severity of the disease (Kaufman, 1990a).

Neurochemically, the brains of patients with Alzheimer’s disease exhibit significant cholinergic abnormalities (Kaufman, 1990b). There is a profound decrease in acetylcholine (ACh) in almost all patients, as well as decreased immunological activity of somatostatin- and corticotropin-releasing factors (Kaufman, 1990b). The enzyme required for ACh synthesis, choline acetyltransferase, is also greatly reduced. Other studies sug-gest involvement of noradrenergic and serotonergic systems in later-onset disease and diminished gamma-aminobutyric acid (GABA) (Kaufman, 1990b). Specifically, the noradrenergic de-ficiencies seen in younger patients may be connected to changes in the locus coeruleus, and abnormalities of serotonin to effects on the raphe nuclei (Korvath et al., 1989). The serotoninergic neurons of the raphe nuclei in patients with Alzheimer’s disease contain six to 39 times as many neurofibrillary tangles as those of age-appropriate control subjects, and noradrenergic neurons from the locus ceruleus of patients with Alzheimer’s disease show neuronal loss of 40 to 80%. Unfortunately, despite these observed neurochemical abnormalities, neurotransmitter-related treatment with cholinergic and GABAergic agents has proved largely unsuccessful.

Although the involvement of cholinergic transmission along the hippocampus and nucleus basalis is essential to the ability to learn new information, it seems that many of the symptoms of Alzheimer’s disease are not explainable solely on the basis of cholinergic abnormalities. Thus, investigators have examined a number of other potential etiological or con-tributory agents. Some researchers have investigated the role of beta-amyloid protein in Alzheimer’s disease, and some as-sert that this material, a significant component of all plaques, is a major contributor to the neurodegenerative changes in the disease as both an initiator and a promotor of the disease. Supporting this assertion are genetic studies of families with inheritable forms of presenile dementia, which show that dis-ease occurrence is linked to mutations involving beta-amyloid-related systems (Kidd, 1963). This hypothesis targets the pro-tein found in senile plaques; other investigators have focused on the neurofibrillary tangles and the identification of a major component of its helical filament, the tau protein. Specifically, these researchers analyzed the possibility that modification of tau protein, predominantly by phosphorylation, is an important feature of AD.

Aluminum, the third most common element in the uni-verse, is absorbed from the gastrointestinal tract, lungs, na-sal passage and skin. Crapper and Dalton (1972) reported in-creased aluminum in the brain of patients with Alzheimer’s disease, with about a quarter of such samples showing con-centrations three standard deviations above the control val-ues. Other studies of bulk brain aluminum in patients with Alzheimer’s disease have shown no such elevation. The cur-rent consensus appears to be that although aluminum and other elements such as iron and mercury might accelerate neuronal degeneration in AD, these elements are not primary etiologi-cal agents. The role of genetic factors in the development of AD has received increased attention as the role of the apoli-poprotein (APO) E4 allele as a major genetic susceptibility risk factor has been confirmed by numerous studies (Katzman, 1994). Corder and colleagues (1993) studied 234 members of 42 families with late-onset AD. Of 95 affected members, 80% had the E4 allele, compared with 26% in the general popula-tion (Corder et al., 1993). Furthermore, in these families, 91% of those homozygous for E4 had developed Alzheimer’s dis-ease by 80 years of age – evidence that the APO E E4 allele is causing these familial cases (Corder et al., 1993). In a study of 176 autopsy specimens of confirmed AD, Schmechel and coworkers in 1993 found that 65% of patients carried at least one APO E E4 gene. Examination of all such studies indicates that between 25 and 40% of AD cases can be attributable to this marker, making its presence one of the most common risk factors yet discovered for AD.

Finally, several studies suggest that changes in membrane function, metabolism and morphology are involved in the pathol-ogy of AD. Nonetheless, the basic molecular defect responsible for AD dementia has not been defined.

The neuropathology of Alzheimer’s disease should be compared with the normal neuropathic effects of aging. These include the following:

·   The leptomeninges become more fibrotic and are more adher-ent to the brain surface with increased opacity.

·   The ventricles show slight to moderate enlargement that in-creases with the passage of time.

·   The distance between the dura and the brain is increased.

·   Sulci widen and gyri become narrower.

·   The number of neurons decreases slightly.

·   The weight of the brain decreases in the fourth and fifth dec-ades, with significant decrease by the age of 80 years.

·   Neurofibrillary tangles and senile plaques occur in virtually every elderly individual by the 10th decade of life (Berg et al., 1994).

Laboratory and Radiological Findings

The role of laboratory determinations in the evaluation for AD is to exclude other causes of dementia, especially those that may prove reversible or arrestable. Before death, AD is largely a diag-nosis of exclusion. Throughout the course of this disorder, labo-ratory values are essentially normal. Some nonspecific changes may occur, but electroencephalography and lumbar puncture are not diagnostic. As the disease progresses, computed tomography (CT) and magnetic resonance imaging (MRI) may show atrophy in the cerebral cortex and hydrocephalus ex vacuo MRI may show nonspecific alteration of white matter (leukoariosis), and eventually the electroencephalogram (EEG) shows diffuse back-ground slowing.

Pneumoencephalography has demonstrated enlarged ven-tricles and widening of cortical sulci in Alzheimer’s disease, and positron emission tomography in the later stages shows de-creased cerebral oxygen and glucose metabolism in the frontal lobes. At present, in the work-up of a patient with a slowly pro-gressive dementia, a good family history, physical examination, and laboratory and radiographic tests to rule out other causes of dementia, are the most effective tools in the diagnosis of Alzhe-imer’s disease.

Clinical Features

The course and clinical features of AD parallel those discussed for dementia in general. Typically, the early course of AD is difficult to ascertain because the patient is usually an unreliable inform-ant, and the early signs may be so subtle as to go unnoticed even by the patient’s closest associates. These early features include impaired memory, difficulty with problem solving, preoccupa-tion with long past events, decreased spontaneity, and an inability to respond to the environment with the patient’s usual speed and accuracy. Patients may forget names, misplace household items, or forget what they were about to do. Often the individuals have insight into these memory deficits and occasionally convey their concerns to family members. Such responses as “You’re just get-ting older”, and “I do that sometimes myself” are common from these family members and as a result the patient becomes de-pressed, which can further affect cognitive functioning. Anomia, or difficulty with word finding, is common in this middle stage of Alzheimer’s disease. Eventually the patient develops schemes, word associations and excuses (“I never was very good in math”) to assist in retention and cover up deficits. The patient may also employ family members as a surrogate memory (Karp, 1984).

Because memory loss is usually most obvious for newly acquired material, the patient tries to avoid unfamiliar activities. Typically, the patient is seen by the physician when confusion, aggression, wandering, or some other socially undesirable be-havior ensues. At that time, disorders of perception and language may appear. The patient often turns to a spouse to answer ques-tions posed during the history taking. By this time the affected individual has lost insight into his or her dementia and abandons attempts to compensate for memory loss. Finally, in the late stage of Alzheimer’s disease, physical and cognitive effects are marked. Disorders of gait, extremity paresis and paralysis, seizures, peripheral neuropathy, extrapyramidal signs and urinary incon-tinence are seen, and the patient is often no longer ambulatory. The aimless wandering of the middle stage has been replaced by a mute, bedridden state and decorticate posture. Myoclonus occasionally occurs. Significantly, affective disturbances remain a distinct possibility throughout the course of the illness. AD progresses at a slow pace for 8 to 10 years to a state of complete helplessness.

Treatment

The two principles of management in AD are to treat what is treatable without aggravating existing symptoms and to sup-port caregivers, who are also victims of this disease. Despite the significant decrease in ACh and choline acetyltransferase in Alzheimer’s disease, treatments based on the cholinergic hypothesis have been unsuccessful (Kaufman, 1990a) Because vasopressin levels are slightly decreased in the hippocampus of patients with Alzheimer’s disease and somatostatin is adversely affected as well, attempts were made to replace these agents with little effect. In the belief that improving blood flow might be of benefit, such agents as the metabolic enhancer and vasodilator ergoloid mesylates (Hydergine) (an ergot alkaloid) were tried. Hydergine did seem to have some benefit; however, these effects may have been related to its mild antidepressant action. Onset of action of any beneficial effects of Hydergine was quite long. Corticotropin release is promoted by corticotropin-releasing fac-tor, which is decreased in patients with AD, but clinical trials with corticotropin were disappointing. Despite lackluster effects of physostigmine, a second cholinesterase inhibitor has shown promise. Tetrahydroaminoacridine (tacrine) produced significant cognitive improvement in 16 of 17 patients with AD in an early study (Summers et al., 1986). Subsequent studies have been less impressive, but significant improvement in a number of scales measuring cognitive performance illustrated the benefit of this agent for some patients. Side effects, particularly hepatic and cholinergic, were noted; however, in 1993 the US Food and Drug Administration (USFDA) approved of tacrine for the treatment of AD. Donepezil, an inhibitor of acetylcholinesterase, has also been utilized in an attempt to enhance cholinergic function by inhibiting its breakdown. This agent must be given early in the course of the dementia.

Whereas much attention has been focused on research aimed at understanding and altering the pathogenesis of AD, less work has been done regarding appropriate pharmacotherapy of the varied psychological manifestations of the disease. Depres-sion is often associated with AD. If antidepressant medication is to be used, low doses (about one-third to one-half of the usual ini-tial dose) are advised and only agents with minimal anticholin-ergic activity should be employed. Appropriate choices would be the selective serotonin reuptake inhibitors such as paroxetine, fluoxetine, sertraline and citalopram. Sertraline and citalopram are least likely to cause drug–drug interactions. Even these agents have the potential to increase confusion in Alzheimer’s patients. Agents such as trazodone and mirtazapine have occasionally been employed because of their sedating properties. If tricyclic antidepressants are used, the secondary amines (desipramine, nortriptyline) are recommended over the tertiary ones (am-itriptyline, doxepin). Careful attention to the possible side effects of these agents, particularly orthostatic hypotension, lowering of the seizure threshold, excessive fatigue, urinary retention, con-stipation, confusion and accelerated memory impairment, is sug-gested. Most clinicians now feel that tricyclic antidepressants are inappropriate for this patient population.

Anxiety and psychosis, particularly paranoid delusions, are common in AD. Benzodiazepines can be disinhibiting in such patients and may exacerbate confusion. They should be avoided if possible. If minor tranquilizers are required, agents with a shorter duration of action (e.g., lorazepam, oxazepam) are preferred. Antipsychotic medications with high anticholinergic potential (thioridazine, chlorpromazine) may also affect memory adversely. While these agents have been favored in the past be-cause of their tendency to produce sedation, newer agents such as olanzepine, risperdone, quetiapine and ziprasidone, have been reported to have lower incidences of neuroleptic-related side effects. Haloperidol has less anticholinergic activity but has a greater tendency toward extrapyramidal effects. These agents will be discussed in more detail in the consideration of manage-ment of delirious states. In summary, the psychopharmacological management of AD is designed to ameliorate cognitive deficits, if possible, control agitated, psychotic and dangerous behavior, and treat any underlying psychiatric disorder (e.g., major depressive disorder) that might be comorbid with dementia. The appropri-ate management of AD entails more than psychopharmacologi-cal intervention. Other elements of the treatment plan should be environmental manipulation and support for the family.

In the attempt to maintain patients with Alzheimer’s dis-ease in their homes for as long as possible, some adjustments of their environment are important. Written daily reminders can be helpful in the performance of daily activities. Prominent clocks, calendars and windows are important. An effort should be made to minimize changes in the patient’s daily activities and environment. Repeated demonstrations of how to lock doorand windows and operate appliances are helpful, and arranging for rapid dialing of essential telephone numbers can be useful. Maintaining adequate hydration, nutrition, exercise and clean-liness is essential. The family of the patient with Alzheimer’s disease is also a victim of the disease. Family members must watch the gradual deterioration of the patient and accept that a significant part of their own lives must be devoted to the care of the individual. Difficult decisions about institutionalization and termination of life support are distinct possibilities, and the pa-tients often turn their anger and paranoia toward the caregiver. Education is a valuable treatment tool for families. Information about the disease and peer support are available through Alzhe-imer’s associations, and many such agencies provide family members with a companion for the patient to allow the family some time away. (The National Alzheimer’s Education and Re-ferral Service can be accessed by calling 1-800-621-0379.) Many studies suggest that the primary reason for institutionalization of these patients is the tremendous burden of care they pose for their families. Aimless wandering seems to be a particularly dis-turbing behavior. Unfortunately, the unfamiliar surroundings of a nursing home often increase the patient’s level of confusion and anxiety. For these reasons, family members are at risk for depression, anxiety disorders, insomnia and a variety of other psychological manifestations. Should these occur, they should be promptly treated.