Alzheimers disease, a disorder of pivotal importance to older adults, strikes 8 to 15 percent of people over the age of 65 (Ritchie & Kildea, 1995). Alzheimers disease is one of the most feared mental disorders because of its gradual, yet relentless, attack on memory. Memory loss, however, is not the only impairment. Symptoms extend to other cognitive deficits in language, object recognition, and executive functioning.3 Behavioral symptomssuch as psychosis, agitation, depression, and wanderingare common and impose tremendous strain on caregivers. Diagnosis is challenging because of the lack of biological markers, insidious onset, and need to exclude other causes of dementia.
This section covers assessment and diagnosis, behavioral symptoms, course, prevalence and incidence, cost, etiology, and treatment. It features Alzheimers disease because it is the most prevalent form of dementia. However, many of the issues raised also pertain to other forms of dementia, such as multiinfarct dementia, dementia of Parkinsons disease, dementia of Huntingtons disease, dementia of Picks disease, frontal lobe dementia, and others.
Mild Cognitive Impairment
The diagnosis of Alzheimers disease depends on the identification of the characteristic clinical features and on the exclusion of other common causes of dementia. There are currently no biological markers for Alzheimers disease except for pathological verification by biopsy or at autopsy (or through rare autosomal dominant mutations). With the reliance on clinical criteria and the need for exclusion of other causes of dementia, the current approach to Alzheimers disease diagnosis is time- and labor-intensive, costly, and largely dependent on the expertise of the examiner. Although genetic risk factors, such as Apo-E status (see etiology section), give some indication of the relative risk for Alzheimers disease, they are as yet rarely useful on an individual basis.
The diagnosis of Alzheimers disease not only requires the presence of memory impairment but also another cognitive deficit, such as language disturbance or disturbance in executive functioning. The diagnosis also calls for impairments in social and occupational functioning that represent a significant functional decline (DSM-IV). The other causes of dementia that must be ruled out include cerebrovascular disease, Parkinsons disease, Huntingtons disease, subdural hematoma, normal-pressure hydrocephalus, brain tumor, systemic conditions (e.g., hypothyroidism, vitamin B12 or folic acid deficiency, niacin deficiency, hypercalcemia, neurosyphilis, HIV infection), and substance-induced conditions.
Some diagnostic schemes distinguish between possible, probable, and definite Alzheimers disease (McKhann et al., 1984). With these criteria, probable Alzheimers disease is confirmed to be Alzheimers disease at autopsy with 85 to 90 percent accuracy (Galasko et al., 1994). Definite Alzheimers disease can only be diagnosed pathologically through biopsy or at autopsy. The pathological hallmarks of Alzheimers disease are neurofibrillary tangles (intracellular aggregates of a cytoskeletal protein called tau found in degenerating or dead brain cells) and neuritic plaques (extracellular deposits largely made up of a protein called amyloid -peptide) (Cummings, 1998b). (See Figure 5-2.)
The diagnosis of dementia can be complicated by the possibility of other disorders that coexist with, or share features of, Alzheimers disease. For example, delirium is a common condition in older patients and can be confused with dementia in its acute stages. Other types of dementia, such as vascular dementia, share cognitive and behavioral symptoms with Alzheimers disease, and thus may be difficult to distinguish from Alzheimers disease. The cognitive symptoms of early Alzheimers disease and those associated with normal age-related decline also may be similar. Finally, cognitive deficits are prominent in both late-life depression and schizophrenia. While the severity of deficits is less in these disorders than that in later stages of dementia, distinctions may be difficult if the dementia is early in its course.
A further challenge in the identification of Alzheimers disease is the widespread societal view of senility as a natural developmental stage. Early symptoms of cognitive decline may be excused away or ignored by family members and the patient, making early detection and treatment difficult. The clinical diagnosis of Alzheimers disease relies on an accurate history of the patients symptoms and rate of decline. Such information is often impossible to obtain from the patient due to the prominence of memory dysfunction. Family members or other informants are usually helpful, but their ability to provide useful information sometimes is hampered by denial or lack of knowledge about signs and symptoms of the disorder.
With diagnosis so challenging, Alzheimers disease and other dementias are currently underrecognized, especially in primary care settings, where most older patients seek care. In a study in the United Kingdom, OConnor and colleagues found that general practitioners recognized only 58 percent of patients identified by research psychiatrists using a structured diagnostic interview (OConnor et al., 1988). Similarly, in a study conducted in the United States, Callahan and colleagues found that only 3.2 percent of patients with mild cognitive impairment were recognized by general practitioners as having intellectual compromise, and only 23.5 percent of those with moderate to severe dementia were identified as having a dementia syndrome (Callahan et al., 1995). The reasons for primary care provider difficulty with diagnosis are speculated to include lack of knowledge or skills, misdiagnosis of depression as dementia, lack of time, and lack of adequate referrals to specialty mental health care.
The urgency of addressing obstacles to recognition and accurate diagnosis is underscored by promising studies that point to the pronounced clinical advantages of early detection. Therapies that slow the progression of Alzheimers disease or improve existing symptoms are likely to be most effective if given early in the clinical course. Recognition of early Alzheimers disease, in addition to facilitating pharmacotherapy, has a variety of other benefits that improve the plight of patients and their families. Direct benefits to patients include improved diagnosis of other potentially reversible causes of dementia, such as hypothyroidism, and identification of sources of Alzheimers diseases excess disability such as depression and anxiety that can be targeted with nonpharmacological interventions. Family members benefit from early detection by having more time to adjust and plan for the future and by having the opportunity for greater patient input into decisions regarding advanced directives while the patient is still at a mild stage of the illness (Cummings & Jeste, 1999).
Diagnosis of Alzheimers disease would be greatly improved by the discovery of a biological marker that correlates strongly with neuropathological signs of Alzheimers disease, reflects the severity of pathological changes in Alzheimers disease, and precedes the appearance of clinical symptomatology. Ideally, such a marker also would be used to monitor the effectiveness of treatment on the clinical manifestations of Alzheimers disease, would show specificity for Alzheimers disease with few false positives (i.e., a diagnosis of Alzheimers disease in someone who does not have the disease), and would be convenient and inexpensive enough to justify wide use, including screening (Cummings & Jeste, 1999). Discovery of such a marker is clearly a research priority.
Figure 5-2. Neuritic plaques and many neurofibrillary tangles in the hippocampus of an Alzheimers disease patient.
Behavioral symptoms occur at some point during the disease with high frequencies: 30 to 50 percent of individuals with Alzheimers disease experience delusions, 10 to 25 percent have hallucinations, and 40 to 50 percent have symptoms of depression (Mega et al., 1996; Cummings et al., 1998b). Patients with psychotic disorders have greater cognitive impairment, more rapidly progressive dementia, and greater frontal and temporal dysfunction on functional brain imaging (Jeste et al., 1992; Sultzer et al., 1995). Patients with psychotic illness also exhibit more agitation, depression, wandering, anger, personality change, family or marital problems, and lack of self-care (Rockwell et al., 1994). Depression in patients with Alzheimers disease accelerates loss of functioning in everyday activities (Ritchie et al., 1998). Even modest reduction in behavioral symptoms can produce substantial improvements in functioning and quality of life.
Prevalence and Incidence
The graying of America is likely to result in an increase in the number of individuals with Alzheimers disease, yet shifts in the composition of the affected population also are anticipated. Increased education is correlated with a lower frequency of Alzheimers disease (Hill et al., 1993; Katzman, 1993; Stern et al., 1994), and future cohorts are expected to have attained greater levels of education. For example, the portion of those currently 75 years of age and olderthose most vulnerable to Alzheimers diseasewith at least a high school education is 58.7 percent. Of those currently age 60 to 64 who will enter the period of maximum vulnerability by the year 2010, 75.5 percent have at least a high school education. A higher educational level among the at-risk cohort may delay the onset of Alzheimers disease and thereby decrease the overall frequency of Alzheimers disease (by decreasing the number of individuals who live long enough to enter the period of maximum vulnerability). However, this trend may be counterbalanced or overtaken by greater longevity and longer survival of affected individuals. Specifically, improvements in general health and health care may lengthen the survival of dementia patients, increasing the number of severely affected patients and raising their level of medical comorbidity. Similarly, through dissemination of information to patients and clinicians, better detection, especially of early-stage patients, is expected. Increased use of putative protective agents, such as vitamin E, also may increase the number of patients in the middle phases of the illness (Cummings & Jeste, 1999).
Approximately 50 percent of individuals with a family history of Alzheimers disease, if followed into their 80s and 90s, develop the disorder (Mohs et al., 1987). Certain genotypes (the pattern of genetic inheritance in an individual) appear to confer risk for the more common late-onset form of Alzheimers disease. For example, the ApoE-e4 allele4 on chromosome 19, which increases the deposition of B amyloid, has been shown to increase risk for developing Alzheimers disease (Corder et al., 1993). Other possible candidate genes are under study (Kang et al., 1997).
Other biological risk factors for the development of Alzheimers disease include aging and cognitive capacities (Cummings et al., 1998b). The mechanisms by which these traits confer increased risk have not yet been fully determined; however, several neurobiologic changes related to normal aging of the brain may play a role in the increased risk for Alzheimers disease with increasing age. These include neuron and synaptic loss, decreased dendritic span, decreased size and density of neurons in the nucleus basalis of Meynert, and lower cortical acetylcholine levels (Cummings et al., 1998b). These findings, as well as extrapolations from the prevalence and incidence curves for Alzheimers disease, have led some to suggest that most individuals would eventually develop Alzheimers disease if the human life span was extended (for example, to age 120).
Several protective factors that delay the onset of Alzheimers disease have been identified. Genetic endowment with the ApoE-e2 allele decreases the risk for Alzheimers disease (Duara et al., 1996), although the mechanism of action is not yet fully understood. Higher educational level also is related to delayed onset of Alzheimers disease (Stern et al., 1994; Callahan et al., 1996a). The use of certain medications, such as nonsteroidal anti-inflammatory drugs (Andersen et al., 1995; McGeer et al., 1996) and estrogen replacement therapy (Paganini-Hill & Henderson, 1994), may delay onset of the disorder. Vitamin E and the drug selegiline (also known as deprenyl) appear to delay the occurrence of important milestones in the course of Alzheimers disease, including nursing home placement, severe functional impairments even as the disease progresses, and death (Sano et al., 1997).
The mechanism of action of these protective agents is not fully understood but is thought to counter the deleterious action of oxidative stress (via antioxidants such as vitamin E or estrogen) (Behl et al., 1995) or the action of inflammatory mediators associated with plaque formation (via anti-inflammatories) (Mrak et al., 1995).
Effective intervention for Alzheimers disease may involve interfering with the multiple steps within the putative Alzheimers disease pathogenetic cascade. Targets of intervention include reducing B amyloid generation from the amyloid precursor protein, decreasing B amyloid aggregation and formation of beta-pleated sheets, and interfering with amyloid-related neurotoxicity. In addition, therapies could involve interruption of neuronal cell death, inhibition of the inflammatory response occurring in neuritic plaques, use of growth factors and hormonal therapies, and replenishment of deficient neurotransmitters. Because complete blockade of steps within the B amyloid cascade may interfere with normal cerebral metabolic processes, efficacious interventions could involve partial interruptions (Cummings & Jeste, 1999).
Researchers in the molecular neuroscience of Alzheimers disease are exploring a number of important aspects of pathophysiology and etiology. As understanding of mechanisms of cell death and neuronal degeneration increases, new opportunities for the development of therapeutics are expected to emerge (National Institute on Aging, 1996).
Role of Acetylcholine
Pharmacological treatment of Alzheimers disease is a promising new focus for interventions. A delay in onset of Alzheimers disease for 5 years might reduce the prevalence of Alzheimers disease by as much as one-half (Breitner, 1991). In other words, to influence the prevalence of Alzheimers disease, it may be necessary only to delay the onset of the disease to the point where mortality from other sources supersedes the incidence of Alzheimers disease. Thus, a central goal in Alzheimers disease treatment research is the identification of agents that prevent the occurrence, defer the onset, slow the progression, or improve the symptoms of Alzheimers disease. Progress has been made in this research arena, with several agents showing beneficial effects in Alzheimers disease.
Treatment of Behavioral Symptoms
One area that has been studied is the treatment of depression in Alzheimers disease. Treatment with the antidepressants paroxetine and imipramine has been shown to be effective in depressed Alzheimers disease patients (Reifler et al., 1989; Katona et al., 1998). Treatment may not only be effective for relieving depressive symptoms but also for its potential to improve functional ability (Pearson et al., 1989; Ritchie et al., 1998).
Several challenges are encountered with the pharmacological treatment of Alzheimers disease. First, because of the cognitive deficits that are the hallmark of dementia, caregiver assistance is crucial for compliance with pharmacotherapy regimens. Second, although the current pharmacotherapies are likely to be most useful if administered early in the course of the disorder, early detection of Alzheimers disease is encumbered by the lack of a verified biological or biobehavioral marker. Third, little is currently known about the optimal duration of treatment with pharmacotherapies.
Psychosocial interventions are extremely important in Alzheimers disease. Although there has been some research on preserving cognition, most research has focused on treating patients behavioral symptoms and relieving caregiver burden. Support for caregivers is crucial because caregivers of older patients are at risk for depression, anxiety, and somatic problems (Light & Lebowitz, 1991). Psychosocial interventions targeted either at patients or family caregivers can improve outcomes for patients and caregivers alike.
Psychosocial techniques developed for use in patients with cognitive impairment may be helpful in Alzheimers disease. Strengthening ways to deal with cognitive losses may reduce functional limitations for patients with the early stages of Alzheimers disease, before multiple brain systems become compromised. For example, training in the use of memory aids, such as mnemonics, computerized recall devices, or copious use of notetaking, may assist patients with mild dementia. While initial research on the use of cognitive rehabilitation in dementia is promising, further studies are needed (Pliskin et al., 1996).
Of the behavioral symptoms experienced by patients with Alzheimers disease, depression and anxiety occur most frequently during the early stages of dementing disorders, whereas psychotic symptoms and aggressive behavior occur during later stages (Alexopoulos & Abrams, 1991; Devanand et al., 1997). Early evidence suggested that cognitive and behavioral therapies are beneficial in treating depressed older patients with dementia (Teri & Gallagher-Thompson, 1991; Teri & Uomoto, 1991). Cognitive therapy, seen as more promising for the early stages of dementia, strives to help patients cope with depression by reducing cognitive distortions and by fostering more adaptive perceptions. Behavioral therapy, seen as more promising for more moderately or severely affected adults with dementia, targets family caregivers directlyand patients indirectlyby helping caregivers identify, plan, and increase pleasant activities for the patient, such as taking a walk, designed to improve their mood (Teri & Gallagher-Thompson, 1991).
Further affirmation for behavioral therapy for depression of patients with Alzheimers disease recently was provided by a controlled clinical trial. The trial compared two types of behavioral therapy with a typical care condition and a waiting list control. One of the behavioral therapies targeted family caregivers to help them increase pleasant events for the patients, while the other gave caregivers more latitude in choosing which behavioral problem-solving strategies to deal with patients depression. Both behavioral therapies led to significant improvement in patients depressive symptoms. Moreover, the caregivers also showed significant improvement in their own depressive symptoms (Teri et al., 1997).
For alleviating caregiver and family distress, a broad array of psychosocial interventions was assessed in a meta-analysis of 18 studies (Knight et al., 1993). The interventions included psychoeducation, support, cognitive-behavioral techniques, self-help, and respite care. Individual and respite programs were found moderately effective at reducing caregiver burden and dysphoria, but group interventions were only marginally effective. Subsequent research buttressed the utility of adult day care in reducing caregivers stress and depression and in enhancing their well-being (Zarit et al., 1998). Beyond direct benefits to caregivers, support interventions also have benefited patients and have saved resources. For example, a psychosocial interventionindividual and family counseling plus support group participationaimed at caregiving spouses was shown to delay institutionalization of patients with dementia by almost a year in a randomized trial (Mittelman et al., 1993, 1996). Targeted behavioral techniques also improved the quality of caregivers sleep (McCurry et al., 1996), whereas psychoeducation and family support appeared to promote better patient management (Zarit et al., 1985).
The virtues of psychosocial interventions also extend to patients with Alzheimers disease in nursing homes. Until the late 1980s, nursing homes employed restraints and sedatives and other medications to control behavioral symptoms in patients with dementia. But the untoward consequences, in terms of injuries from physical restraints and increased patient disorientation, led to nursing home reform practices required by the Federal Nursing Home Reform Act of the Omnibus Budget Reconciliation Act of 1987 (Cohen & Cairl, 1996). In the past few years, a range of behavioral interventions for nursing home staff has been shown to be effective in improving behavioral symptoms of Alzheimers disease, such as incontinence (Burgio et al., 1990; Schnelle et al., 1995), dressing problems (Beck et al., 1997), and verbal agitation (Burgio et al., 1996; Cohen-Mansfield & Werner, 1997). A major problem is that interventions are not maintained or implemented correctly by nursing home staff (Schnelle et al., 1998). New approaches seek to teach and maintain behavior management skills of nursing home assistants through a formal staff management system (Barinaga, 1998; Stevens et al., 1998).
3 Executive functioning refers to the ability to plan, organize, sequence, and abstract.