Robert A. Sweet, MD

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?

The definition of psychotic symptoms in AD has generally been limited to delusions and hallucinations. A wide variety of delusions have been reported in AD (Rubin et al., 1988; Tariot et al., 1995). Hallucinations in AD can occur in any sensory modality, but visual and auditory hallucinations are most common. Disorganized thought processes are not considered to represent a psychotic thought disorder, but rather are attributed to the cognitive impairments of AD.

Determining the presence of delusions in AD can be clinically challenging. Many putative delusions (e.g., theft, infidelity, abandonment) may actually be accurate interpretations of real events. Delusions must be distinguished from simple forgetting by further evaluation. Was the information ever encoded in memory? A patient with moderate or severe AD is unlikely to sustain memory of an event that occurs while in this stage. Additional characteristics, such as whether the individual refuses to accept reality-testing and whether the false idea is persistent over time, are useful in distinguishing delusions (Devanand et al., 1992). Although no absolute standard definition of persistence over time exists, the criteria used have ranged from more than two or three episodes in a week (Devanand et al., 1992; Sweet et al., 1998) to repeated episodes persistent for at least one month (Burns et al., 1990; Jeste and Finkel, 2000).

Determining the presence of hallucinations in patients with AD presents different challenges. Because of expressive language difficulties, it may not be clear whether an individual with AD is indeed hallucinating or experiencing illusions or agnosias. Nocturnal hallucinations can be especially challenging. Hallucinations that transiently occur upon falling asleep or awakening can be normal phenomena, but it may not be possible to make this distinction in a patient with AD. Finally, care must be taken to exclude the possibility that hallucinations (and delusions) are not solely limited to a period of acute delirium or a transient medication-induced state (Jeste and Finkel, 2000).

Despite the challenges inherent in correctly identifying psychotic symptoms in AD, most evidence indicates that this attribution can be made reliably. The inter-rater reliability for measuring the severity of individual psychotic symptoms in AD subjects is generally high (Cummings, 1997; Mack and Patterson, 1994). Inter-rater and test-retest reliability for the classification of a subject as having AD+P is similarly high (Sweet et al., in press).

There is fairly consistent evidence that psychotic symptoms rarely occur during the prodromal phase of AD, occur infrequently in the early stages of illness (Rubin and Kinscherf, 1989) and increase in frequency as the illness progresses to the moderate stage (Cohen-Mansfield et al., 1998; Devanand et al., 1997). The evidence is less consistent regarding late-stage illness. Post-mortem studies have reported AD+P rates of approximately 40% to 60%, indicating that not all subjects with AD progress to AD+P (Sweet et al., 2000). Similarly, AD+P has not consistently been associated with more severe or widespread neuropathologic changes at autopsy. Thus, AD+P does not appear to be an inevitable (and nonspecific) consequence of progression to later disease stages, but rather affects only a subset of AD patients.

Alzheimer's disease with psychosis has been defined by the presence of psychotic symptoms that persist for at least several weeks (Jeste and Finkel, 2000). This criterion guards against misclassification of brief psychotic symptoms that arise due to transient states. To be considered a trait, however, psychotic symptoms should persist longer than several weeks. A number of studies have examined the long-term persistence of AD+P, ranging in duration of follow-up from six months to five years (Devanand et al., 1997). Although results vary by study, all found either the presence of AD+P or the severity of psychotic symptoms to be at least moderately persistent over time, consistent with identification of a trait. Levy et al. (1996) found that the one-year recurrence rate of AD+P was 95%. This finding suggests that psychosis in AD is a trait and not a state-dependent phenomenon.

If psychosis represents a readily and reliably identifiable trait affecting about half of all subjects with AD, the hypothesis that there are unique genetic and neurobiologic determinants of AD+P can readily be tested. While there are many levels of evidence for genetic determination, first and foremost is whether the trait is heritable. We recently examined the familial aggregation of AD+P in a cohort of 371 AD probands and 461 of their siblings also diagnosed with AD (Sweet et al., 2002a). There was a significant association between the presence of psychotic symptoms in probands and in their siblings. The odds ratio (OR) for any occurrence of psychotic symptoms in siblings with AD was 2.4 (95% CI: 1.46-4.00; 

<0.001), an association that was strengthened when using a more restrictive definition of AD+P requiring multiple and/or persistent symptoms (OR 3.18; CI: 2.17-4.66; 

=0.0006). We followed up this finding with genome-wide multipoint linkage analysis in those families with two or more individuals with restrictively defined AD+P (Bacanu et al., 2002). Because the most important identified genetic risk factor for late-onset AD is the presence of one or more E4 alleles for the apolipoprotein E gene (APO E4), we restricted the analysis to the families in which at least two individuals also had one or more E4 alleles. We found evidence for significant linkage on chromosome 2p and suggestive linkages on chromosomes 6q and 21q.

An alternate approach to identifying a genetic basis for AD+P is to examine whether candidate genes, selected for possible contribution to psychotic symptoms based on knowledge of their function, are associated with AD+P. Polymorphic variation in the genes for the dopamine

) (Holmes et al., 2001; Sweet et al., 1998), the serotonin

) (Holmes et al., 1998), and long alleles of the serotonin transporter gene (5-HTT or SLC6A4) (Sweet et al., 2001b) have been found to confer moderate but significant increases in risk for AD+P. One of these genes, DRD3 has also been associated with a small but significant increase in the risk of schizophrenia in both case-control and family studies (Williams et al., 1998).

There is emerging neurobiologic evidence suggesting that AD+P is associated with excess neocortical pathology. Functional imaging studies in vivo have found that subjects with AD+P demonstrate excess impairment of frontal, temporal and parietal cerebral blood flow and glucose metabolism in comparison to AD subjects without psychosis (Starkstein et al., 1994; Sultzer et al., 1995). We recently examined post-mortem magnetic resonance spectroscopy in subjects with AD+P, finding significant reductions in neocortical N-acetyl-L-aspartate (NAA, a marker of neuronal integrity) concentrations, with superior temporal, dorsolateral prefrontal and inferior parietal cortex most affected (Sweet et al., 2002b). Subjects with AD+P also demonstrated significant elevations in concentrations of the phosphodiester membrane breakdown product glycerphosphoethanolamine compared to subjects without psychosis. It is noteworthy that similar observations have been emerging in the study of subjects with schizophrenia, in whom studies have also found reduced NAA concentrations and elevated concentrations of phosphodiesters (Keshavan et al., 2000). Similarly, post-mortem studies of subjects with schizophrenia have found evidence of reduced pyramidal cell volume (Pierri et al., 2001; Rajkowska et al., 1998; Sweet et al., 2001a) and reduced numbers of synaptic components in neocortical regions (Garey et al., 1998; Glantz and Lewis, 1997; Rosoklija et al., 2000). Thus, just as psychosis is associated with cognitive impairment in both schizophrenia and AD, there may be factors affecting neuronal and synaptic integrity and number that underlie psychosis in both disorders.

An emerging body of evidence indicates that AD+P identifies a clinically relevant subtype, characterized by an increased rate of cognitive deterioration, a liability toward aggressive behavior, greater caregiver burden and premature institutionalization. Efforts to identify the distinct genetic and neurobiologic determinants of AD+P are still in the early stages, although some promising leads are already emerging. For example, the association between AD+P and genetic variation in serotonin system receptors might not have been expected, but is consistent with emerging evidence that the selective serotonin reuptake inhibitors provide therapeutic benefit for agitated and psychotic symptoms in subjects with AD+P (Pollock et al., 2002). Whether study of AD+P will lead to additional insights into the biology of psychotic symptoms in AD, and in other psychotic disorders, remains to be determined.

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