Psychotic symptoms, namely hallucinations and delusions, are common in individuals with Alzheimer's disease (AD). This article will examine the proposal that Alzheimer's disease with psychosis (AD+P) has an underlying genetic and neurobiologic basis distinct from that of AD without psychosis.
Most estimates of the prevalence of psychosis in patients with AD range from 30% to 40% (Wragg and Jeste, 1989). Rates in community samples are similar (Lyketsos et al., 2000). The presence of psychotic symptoms can cause significant distress for the patient, as well as for family members and caregivers (Kaufer et al., 1998). Subjects with AD+P are also prone to aggressive behavior, further contributing to caregiver burden (Aarsland et al., 1996; Deutsch et al., 1991; Sweet et al., 2001b).
In addition to disruptive behavior, AD+P has been associated with more severe cognitive and functional deficits compared to patients who have AD without psychosis who are matched on other clinical characteristics (Jeste et al., 1992; Paulsen et al., 2000a; Stern et al., 1987). Alzheimer's disease with psychosis is also associated with more rapid cognitive and functional deterioration (Drevets and Rubin, 1989; Levy et al., 1996; Paulsen et al., 2000b). Finally, AD+P is a predictor of premature institutionalization (Lopez et al., 1999; Magni et al., 1996). The association between psychosis and excess cognitive impairment in AD is similar to that seen in idiopathic disorders (e.g., schizophrenia and major depression with psychotic features) and suggests the possibility of a common mechanism (Jeste et al., 1996; Sweet and Pollock, 1999).
Until recently, conventional neuroleptics were the first-line treatment for AD+P, despite having only moderate efficacy (Schneider et al., 1990) and substantial side effects in the elderly, including high rates of tardive dyskinesia even after brief treatment (Jeste et al., 1995) and increased rates of neuroleptic-induced parkinsonism (Sweet et al., 1996). These liabilities have led to the emergence of atypical antipsychotic medications as current first-line treatment. These agents offer an improved side-effect profile, although their efficacy is not substantially greater (De Deyn et al., 1999; Katz et al., 1999; Street et al., 2000). Despite treatment, many patients still fail to respond or continue to have persistent symptoms.
The development of innovative, specific and markedly more efficacious treatments for AD+P will likely require understanding of its specific biologic processes. Identification of these processes may also uncover mechanisms of cognitive impairment, with implications not only for AD but also for idiopathic psychoses. In addition, although the genetic architecture of AD remains mostly undetermined, it is likely that the effort to map liability genes for AD will be enhanced by use of readily defined, biologically homogeneous subgroups, one of which may be defined by AD+P (Sweet et al., in press).
Prior to embarking on a neurobiologic or genetic examination of AD+P, three important concerns need to be addressed: 1) Can psychotic symptoms in AD be readily and reliably identified? 2) Are psychotic symptoms merely a nonspecific consequence of disease progression? and 3) Are psychotic symptoms in AD a state or trait?
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