Psychotic Symptoms in Alzheimer Disease

Molecular Psychiatry (2003) 8, 383–392 & 2003 Nature Publishing Group All rights reserved 1359-4184/03 $25.00 www.nature.com/mp REVIEW ARTICLE Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype RA Sweet1, VL Nimgaonkar1, B Devlin1 and DV Jeste2,3 1Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 2Departments of Psychiatry and Neurosciences, University of California, San Diego, USA; 3VA San Diego Healthcare System, USA

Though efforts to identify the genetic etiology of Alzheimer disease (AD) have made substantial progress, to date only some of the genes contributing to AD risk have been identified. Utilization of more etiologically homogeneous subphenotypes represents one strategy to facilitate the identification of novel risk genes in complex disorders. In this review, we evaluate the hypothesis that psychotic symptoms, such as delusions and hallucinations, define a suitable subphenotype in AD patients for gene-mapping efforts. Psychotic symptoms occur in 40–60% of patients with AD and are associated with more severe cognitive deficits and a more rapidly deteriorating course. The presence of psychotic symptoms in AD confers increased risk of similar symptoms to affected siblings. Candidate gene association analyses and initial linkage analysis have yielded significant results. We discuss possible genetic models of psychotic symptoms in AD, and suggest strategies for further investigation. Identification of such genetic factors may facilitate gene-mapping studies for both AD and idiopathic psychoses. Molecular Psychiatry (2003) 8, 383–392. doi:10.1038/sj.mp.4001262 Keywords: Alzheimer disease; psychosis; linkage

Overview The genes associated with a behavioral phenotype, however, are unknown. The task for the psychiatric The genetic basis of Alzheimer disease (AD) is geneticist, therefore, is to identify a behavioral unknown, although considerable strides have been phenotype that varies according to alleles at a made using gene-mapping efforts. Success has been restricted set of genes. As in all psychiatric nosology, most notable for the highly heritable early onset form, a behavioral phenotype must be readily and reliably which comprises a minority of the entire population identifiable in all patients of interest. If this behavior- of AD cases.1 While the impact of apolipoprotein E e4 al phenotype has clinical relevance (eg bipolar alleles (APOE4) is well established, the genetic illness) it provides a measure of face validity, and architecture of the more common late-onset AD adds significance to its use in the search for causative (LOAD) is unclear. Like other genetically complex genes. Tsuang et al.8 enumerated additional criteria disorders, such as diabetes mellitus, progressively for determining that a behavioral phenotype has a greater attention has been paid to utilizing defined substantial genetic basis, including state indepen- subgroups of AD (eg late age-of-onset, APOE4 pre- dence, biological specificity, familial aggregation, sence, autopsy confirmation) for mapping liability heritability, and cosegregation. genes.2,3 We have previously proposed that the This review will examine whether AD þ P repre- presence of psychotic symptoms, delusions and sents a reliably identifiable, clinically relevant beha- hallucinations, define a subgroup of AD4 that may vioral phenotype. Using the criteria above as a guide, be suitable for genetic investigation.5,6 To our knowl- we will summarize the available data informing the edge, however, the available evidence pertaining to extent to which AD þ P is a valid indicator of a whether AD with psychosis (AD þ psychosis behavioral phenotype for genetic study. We will (AD þ P)) identifies a phenotype suitable for genetic discuss possible models of AD þ P and examine the study has not been the subject of critical review. available evidence from existing genetic studies of Stedman’s Medical Dictionary defines phenotype AD þ P. Finally, we suggest strategies for future as ‘the observable characteristics, at the physical, investigation. morphologic, or biochemical level, of an individual, as determined by the genotype and environment’.7 Evidence for a distinct phenotype Correspondence: RA Sweet, MD, Western Psychiatric Institute Reliability of diagnosis of AD þ P and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, USA. E-mail: [email protected] The definition of psychotic symptoms in AD has Received 16 April 2002; revised 14 August 2002; accepted 20 generally been limited to the presence of delusions August 2002 and hallucinations. In the absence of delusions and Psychotic symptoms in Alzheimer disease RA Sweet et al 384 hallucinations, disorganized thought processes are oped for the identification of psychotic symptoms in attributed to the cognitive impairments of AD, and AD, and scoring of their severity.9,14–16 When inter- not taken to represent a ‘thought disorder’ indicating rater reliability for measuring the severity of indivi- a superimposed psychotic syndrome. A wide variety dual psychotic symptoms on these scales has been of delusions have been reported in AD, including assessed, it has generally been high.9,16,17 In contrast, delusions of persecution, delusions of infidelity, little data are available to inform whether a classifica- delusions of abandonment, or delusions that de- tion of an individual as having AD þ P can be ceased individuals (eg parents) are still living.9 In achieved reliably. Jeste and Finkel indicated that addition to these delusions, a set of misidentification their proposed diagnostic criteria for AD þ P could be delusions are frequent in AD patients: belief that one’s reliably applied,4 though no supporting data were home is not one’s home; belief that a family member is presented. One of us (RAS) recently examined the someone else, has been reduplicated or is an inter-rater and test–retest reliability of classifying AD imposter; belief in the presence of phantom boarders; subjects as AD þ P after a caregiver interview with the and, the belief that images on the television are Consortium to Establish a Registry for Alzheimer’s actually people present in the house.10 Hallucinations Disease (CERAD) Behavior Rating Scale.9 Inter-rater in AD can occur in any sensory modality, but visual reliability among 17 psychiatrists and psychiatric and auditory hallucinations are most common.9 social workers showed near-perfect agreement for the Determining that an individual with AD is in fact classification of AD þ P, with kappa’s ranging from 0.8 delusional can be clinically challenging. Many of the to 1.0. Test–retest reliability was assessed by con- above delusions (eg theft, infidelity, abandonment) ducting a telephone interview, within 1 week preced- can represent accurate interpretations of real events. ing or following a face-to-face evaluation by a second Care must be taken to exclude this possibility. Certain clinician. Test–retest kappa’s were in perfect agree- delusional ideas must be distinguished from simple ment, 1.0, for the presence of AD þ P (unpublished forgetting. Several accessory qualities of the idea need observations). to be assessed to make this differentiation. Was the information ever encoded in memory? A patient with Clinical significance of AD þ P moderate or severe AD is unlikely to sustain memory The clinical significance of identification of psychotic of an event that occurs while in this stage (eg that a symptoms in AD subjects cannot be overstated. First parent recently died). Some individuals will confa- and foremost, psychotic symptoms occur in a sub- bulate responses in the absence of memory for events. stantial proportion of AD patients. Estimates of In these cases, additional characteristics of the idea, psychosis prevalence in AD patients range from 10 such as whether the individual accepts reality testing to 73%, with most studies finding prevalences of 30 and the persistence of the idea over time, are useful in to 40%.18 A recent report identified a 3-year cumu- distinguishing delusions. Devanand et al11 proposed lative incidence of AD þ P of 51%.19 Post-mortem broad and narrow definitions of a delusion. A broad studies, which have the potential advantage of delusion was a false idea for which the individual recording a complete cumulative incidence of AD þ P, does not accept reality testing. The narrow definition have similarly reported rates of approximately 40– further required the idea to be persistent or recurrent 60%.20–22 However, all of the studies described above over time. This narrow definition has been more have conducted either cross-sectional assessment for generally adopted, though no clear consensus on the AD þ P, or longitudinal assessments with a limited duration required exists, with criteria ranging from duration of follow-up. Better estimates of the rate of more than two to three episodes in a week,5,11 to AD þ P could be obtained by thorough longitudinal repeated episodes persistent for at least 7 days,12,13 to assessments of subjects through their course of repeated episodes persistent for at least 1 month.4 illness. Determining the presence of hallucinations in AD When present, psychotic symptoms can cause patients presents different challenges. Since many AD significant distress for the patient experiencing them. subjects have expressive language difficulties, it may AD þ P is similarly associated with significant dis- not be clear whether they are indeed hallucinating or tress to family members providing care to these experiencing illusions. Nocturnal hallucinations pre- patients.23 There is also evidence for a significant sent another challenge. Hallucinations transiently association between AD þ P and the development of occurring upon falling asleep or awakening can be aggressive behaviors. Deutsch et al24 reported that normal phenomena, but it may not be possible to 40% of AD subjects with delusions, 42% of AD make this distinction in an AD patient. Finally, care subjects with misidentification delusions, and 42% of must be taken to exclude the possibility that halluci- AD subjects with hallucinations also experienced nations (and delusions) were not solely limited to a episodes of physical aggression. Aarsland et al25 period of acute delirium, or a transient, medication- found hallucinations to be associated with an in- induced state.4 creased risk of physical and verbal aggression. In the Despite the need for significant clinical judgment in largest of these cross-sectional studies, Sweet et al26 the identification of psychotic symptoms in AD, most found aggression to be significantly associated with evidence indicates that this attribution can be made AD þ P in 332 AD subjects. The odds ratio (95% reliably. A variety of rating scales have been devel- confidence interval) for aggression in AD þ P was 6.4

Molecular Psychiatry Psychotic symptoms in Alzheimer disease RA Sweet et al 385 (3.8,10.8). Two recent studies have also examined defined AD cohorts will contain a modest proportion whether current psychotic symptoms are predictive of of DLB subjects.43 Some studies have indicated that later aggressive behavior.27,28 Gilley et al27 found post-mortem verified DLB subjects may have a faster delusions to be strongly predictive of subsequent rate of cognitive decline than AD subjects.44,45 In physical aggression during 1 year of weekly follow-up contrast, other studies have not found post-mortem- of 270 probable AD subjects. In contrast, McShane et verified DLBs to be associated with faster cognitive al28 did not find a relationship between delusions and decline, or with psychosis.43,46 Even if DLB does later aggression, but did find that hallucinations account for some of the association between rate of predicted physical aggression during 4 years of cognitive decline and presence of psychotic symp- follow-up. Reflecting the contribution of AD þ Pto toms, it is unclear whether the proportion of DLB patient distress and its comorbidity with aggressive subjects included in studies of cognitive decline in behavior, psychotic symptoms in AD are a frequent AD þ P would be sufficient to account for the entire indication for pharmacotherapy,29 though AD þ P effect. Moreover, conclusions about the inter-relation- subjects typically require lower antipsychotic doses ships between AD, DLBs, presence of psychotic than elderly patients with idiopathic psychoses.4 symptoms, and rate of cognitive decline based on Perhaps less clinically dramatic than its association studies conducted to date must be considered with aggressive behaviors, most evidence indicates tentative. Understanding of the relationship between that AD þ P is a marker for more severe cognitive AD and DLBs is rapidly evolving. The use of new impairments. AD þ P has been associated with more more sensitive antialphasynuclein immunocytochem- severe cognitive and functional deficits in AD sub- ical staining has revealed that Lewy Body pathology jects matched on other clinical characteristics.30–34 may be more common than previously suspected in Studies conflict regarding whether AD þ P is asso- AD,47 rendering less certain the proper interpretation ciated with more rapid cognitive deterioration, of studies which identified post-mortem evidence of though most have found an association.19,35–38 It Lewy Bodies using immunocytochemical and histo- should be noted that most of these studies have not chemical methods which may only identify more controlled for the duration of AD prior to study entry. severe Lewy Body pathology. In McShane et al,39 however, the significant association between psychosis and rate of cognitive decline State independence of AD þ P remained when duration of AD was entered into the As applied to AD þ P, state independence would regression model. Similarly, Drevets and Rubin35 require psychotic symptoms to be persistent within found more rapid cognitive decline in AD þ P sub- individuals with AD over the course of illness. A jects, despite their having a mean duration of AD that number of studies have examined this question.37,48–51 did not differ from the nonpsychotic AD subjects. These studies ranged in duration of follow-up from 6 Importantly, Paulsen et al found evidence of more months to 5 years, and used different methods of rapid cognitive deterioration preceding the sympto- behavioral assessment and different data analytic matic onset of psychosis.19 Rate of decline in semantic approaches. Nevertheless, all found either the pre- fluency and in global cognition as measured by the sence of AD þ P, or the severity of psychotic symp- Mattis Dementia Rating Scale were both strongly toms, to be at least moderately persistent over time. predictive of psychosis onset within the subsequent Thus, Devanand et al48 found the 6-month probability year. Thus, more rapid cognitive deterioration in of persistence of delusions and hallucinations to be AD þ P is unlikely to be solely an artefact of 0.59 and 0.52, respectively. Levy et al37 found that the neuroleptic medication use.39 Reflecting the associa- 1-year recurrence rate of AD þ P was 95%. tion between psychosis and cognitive deterioration in subjects with AD, the presence of psychotic symp- Biologic specificity of AD þ P toms is also an independent predictor of more rapid The finding of a combined liability to psychotic functional decline.35,36 Finally, whether due to excess symptoms and excess cognitive impairment in AD cognitive and functional impairment, or due to raises the question of biologic specificity. That is, caregiver burden and aggressive behavior,40 AD þ P does AD þ P arise merely as an epiphenomenon of is a predictor of premature institutionalization.36,41 more severe stage of illness, or is there a distinct Whether the association between AD þ P and more pathology underlying both the generation of psycho- rapid cognitive and functional deterioration could be tic symptoms and the excess cognitive impairment? mediated by inadvertent over-representation of in- This question is informed by clinical, neuroimaging, dividuals with Dementia with Lewy Bodies (DLBs) in neuropathologic, and genetic studies. the more rapidly deteriorating AD þ P group is an There is fairly consistent evidence that psychotic important consideration. Well-formed visual halluci- symptoms are rare as a prodrome of AD, and nations are among the core diagnostic features of infrequent in the early stages of illness.52,53 AD þ P (DLBs), and delusions are an accessory diagnostic prevalence increases as the illness progresses from feature.42 Current antemortem diagnostic criteria for the mild-to-moderate stages of AD.35–37,48,50,53 DLBs may have low sensitivity and specificity for As patients progress to late stage illness, stable, discriminating between AD and DLBs in mild-to- higher, and lower AD þ P prevalences have been moderate illness, rendering it likely that clinically described.35–37,48,50,53 These data might suggest that

Molecular Psychiatry Psychotic symptoms in Alzheimer disease RA Sweet et al 386 AD þ P is a nonspecific concomitant of more severe AD þ P and increased neurofibrillary tangle area disease. However, several clinical findings argue density was found, but limited to select heteromodal against this interpretation. First, AD þ P is not an neocortical regions (middle frontal, superior tempor- invariant component of progression to later disease al, and inferior parietal). In contrast, in the medial stages. The cumulative incidence of AD þ P is only temporal lobe structures examined, no increase in 40–60% of all AD cases.19–22 Second, AD þ Pis neurofibrillary tangle area density was found. The associated with excess cognitive burden in AD associations were not altered after accounting for subjects matched on other clinical variables, includ- comorbid Lewy Body pathology. No association with ing dementia duration.31,33 Third, AD þ P is not only increased area density of senile plaques was found. associated with increased cognitive impairment, but The discrepancy between these results is not readily with a more rapid rate of cognitive deteriora- explained, though it remains possible that some cases tion.19,35,37,38 In the only study to examine cognitive of AD þ P do result from neurofibrillary pathology. decline prior to psychosis onset, the increased rate of Another consideration results from recent neuro- cognitive decline preceded psychosis onset.19 While pathologic data that suggests that Lewy body pathol- the association between AD þ P and more rapid ogy may be far more frequent than previously realized cognitive deterioration could suggest that it is the rate in neuropathologically confirmed AD.47 The presence of cognitive decline which identifies the true pheno- of well-formed visual hallucinations and delusions type of interest, evidence from other disorders, for are among the criteria for the clinical diagnosis of example, schizophrenia and major depression, that DLBs. In subjects with a neuropathologic diagnosis of psychosis is inextricably linked to cognitive impair- AD, however, post-mortem evidence of concurrent ment,54 supports the interpretation that AD þ P cortical Lewy body pathology has only inconsistently and excess cognitive burden arise from the same been associated with AD þ P. 58 Whether the presence underlying mechanism.55 of psychotic symptoms in AD may be related to The clinical observation that AD þ P was associated regional severity of superimposed Lewy Body43,46 with more severe cognitive pathology also led pathology has not been examined. investigators to examine whether AD þ P was corre- If there is little evidence to indicate that AD þ P lated with evidence of more severe AD neuropathol- arises as an epiphenomenon of more advanced AD, is ogy in specific brain regions. Several early studies there evidence of a specific biologic process that reported varying results: increased area density of might contribute to the genesis of psychotic symp- senile plaques in prosubiculum,56 increased area toms and more severe cognitive impairment? Emer- density of neuritic plaques averaged across neocor- ging evidence suggests that AD þ P is associated with tical and medial temporal brain regions,57 or no neocortical dysfunction in excess of that seen in AD change in area density of senile plaques.22 Similarly without psychosis. Functional imaging studies in vivo with regard to neurofibrillary tangles, either increased have found AD þ P subjects to demonstrate excess area density in middle frontal cortex,56 no change in impairment of frontal, temporal, and parietal cerebral area density in frontal and parietal cortex but blood flow and glucose metabolism in comparison to increased area density in parahippocampal cortex,22 AD subjects without psychosis.59,60 We recently and no change in area density averaged across examined post-mortem magnetic resonance spectro- neocortical and medial temporal regions have been scopy in AD þ P subjects, finding significant reduc- reported.57 These earlier studies were limited as a tions in neocortical N-acetyl-L-aspartate (NAA, a group, as they did not control for the presence of marker of neuronal integrity) concentrations, with Lewy Body pathology and also because they did not superior temporal gyrus, dorsolateral prefrontal cor- correct for multiple comparisons and/or account for tex, and inferior parietal cortex most affected.61 the within-subject correlation of severity of neuro- AD þ P subjects also demonstrated significant pathology across brain regions (see Sweet et al20 for a elevations in concentrations of the phosphodiester discussion of these issues). membrane breakdown product, glycerophospho- Two studies recently redressed these latter limita- ethanolamine, in comparison to AD subjects without tions. Sweet et al20 examined semiquantitative area psychosis. It is noteworthy that similar observations density of neuritic plaques and neurofibrillary tangles have been emerging in the study of idiopathic in six brain regions: middle frontal cortex, hippo- psychosis in subjects with schizophrenia. In vivo 31P campus, inferior parietal cortex (IPC), superior tem- and 1H MRS studies in subjects with schizophrenia poral cortex, occipital cortex, and transentorhinal have found reduced NAA concentrations and ele- cortex in 24 AD þ P subjects and 25 AD subjects vated concentrations of phosphodiesters (glyceropho- without psychosis. The groups were matched on sphoethanolamine and glycerophosphocholine).62 clinical characteristics and on the presence of Lewy These in vivo findings may reflect the reductions in Body pathology. There were no significant associa- neocortical pyramidal cell volume63–65 and synaptic tions between neuritic plaque and neurofibrillary markers66–69 seen in post-mortem studies of subjects tangle severity and AD þ P, and no significant associa- with schizophrenia. These congruent findings raise tions with any individual psychotic symptom. Farber the hypothesis that factors effecting neocortical et al21 examined 69 AD þ P and 40 AD subjects neuronal and synaptic integrity and number, and without psychosis. A significant association between their genetic determinants may contribute to psycho-

Molecular Psychiatry Psychotic symptoms in Alzheimer disease RA Sweet et al 387 sis in both disorders, though the obvious differences small sample sizes and an absence of structured in the neuropathology of AD and schizophrenia diagnostic interviews of multiple family members. suggest that the specific pathologic mechanisms Conversely, it is not known if there is an increased may not overlap. rate of AD þ P in families of subjects with schizophrenia or other idiopathic psychoses. There is strong Familial aggregation and heritability of AD þ P evidence, however, that even among subjects with A multigenerational early onset familial non-AD schizophrenia who have evidence of dementia, AD dementia with prominent schizophreniform psychopathology is rare.74 sis has been described.70 We are not aware of similar reports in AD. However, there is emerging evidence Possible genetic models of AD + P that AD þ P is more prevalent among the affected siblings of AD þ P probands than among the affected Several possible pathways by which genetic factors siblings of AD subjects without psychosis. Tunstall et may lead to AD þ P are presented in Figure 1. We have al71 examined 99 sibling pairs concordant for AD and previously proposed the presence of disease modify- found a concordance rate of 0.21 for AD þ P. This rate ing genes that lead to AD þ P in individuals who of concordance was moderately higher than that develop AD due to other genetic and environmental predicted by the observed prevalence of 0.41 of influences, as illustrated in Pathway A1.5 This path- AD þ P in their cohort, though no statistical tests of way is consistent with certain findings discussed significance were reported. Sweet et al recently examined the familial risk of AD þ P in a larger cohort of 371 AD probands and 461 of their siblings also diagnosed with AD, recruited and characterized as part of the National Institutes of Mental Health AD Genetics Initiative.6 There was a significant association between proband psychosis status and the occurrence of AD þ P in siblings. After fitting a GEE- based logit model with dementia stage entered as a covariate, the estimated Odds Ratio (OR) for AD þ Pin siblings of AD þ P probands was 2.41 (95% CI: 1.46 – 4.00; P o 0.001) in comparison to the siblings of nonpsychotic AD probands. Using a more restrictive definition of AD þ P strengthened the observed association (OR 3.18; CI: 2.17 – 4.66; P o 0.0001). The association was unaltered when sibling age, and sibling age-of-onset of AD, or presence of extrapyramidal symptoms were entered as covariates in the analysis. Increased risk of a similar magnitude was also seen when analyses were limited to siblings diagnosed only with definite or probable AD. It is not known if the morbid risk for AD þ P is also increased among the other relatives of AD þ P probands. Nor have twin studies of AD þ P been reported, and thus the degree of contribution to the observed familial aggregation of AD þ P from genetic and from environmental sources cannot yet be estimated.

Cosegregation of AD þ P and idiopathic psychoses If genetic factors underlying idiopathic psychoses (eg schizophrenia) increase susceptibility for AD þ P, an Figure 1 Pathways to AD and AD þ P. In Pathway A1, increased morbid risk for idiopathic psychoses could alleles at modifier genes lead to AD þ P after onset of AD, be expected among relatives of AD þ P probands. which is due to distinct genetic and environmental Clinical experience and limited data suggest that a influences. Some of these disease-modifying alleles could family history of major psychiatric illness is not more also modify the course of other neurodegenerative (Pathway frequent in AD þ P than in AD subjects without A2) or neurodevelopmental (Pathway A3) illnesses, con- psychosis. Gilley et al72 found no increase in family tributing to psychosis risk in these conditions. In Pathway B, alleles at genes that increase the liability to onset of AD history of psychiatric illness in 67 AD subjects with would also increase the risk for AD þ P. In Pathway C, hallucinations in comparison to 137 AD subjects 73 alleles contributing major risk for idiopathic psychoses such without hallucinations. Similarly, Kotrla et al found as schizophrenia would be seen to also contribute to AD þ P no increase in family history of schizophrenia in 36 risk. See text (section Possible genetic models of AD þ P) for AD þ P subjects in comparison to 21 nonpsychotic AD additional details regarding existing data supporting or subjects. These studies were limited, however, by contradicting the proposed pathways.

Molecular Psychiatry Psychotic symptoms in Alzheimer disease RA Sweet et al 388 above: AD þ P is rare as a prodrome of AD, and occurs families. Interestingly, some support for both the 2p with increasing frequency as individuals traverse the and the 6q region can be garnered from the schizo- early and middle disease stages. Some of these disease phrenia literature.81–84 While this concurrence of modifying genes may modify the course of other findings in schizophrenia and LOAD þ P provides neurodegenerative (Pathway A2) or neurodevelopmen- some support for the presence of common psychosis tal (Pathway A3) illnesses, contributing to psychosis genes (Pathways A and C), cautious interpretation is risk in these conditions.5 In Pathway B, genes that still required. Despite the common psychosis pheno- increase the liability to onset of AD would increase risk type, there are substantial clinical and neurobiologi- for AD þ P. In Pathway C, genes contributing major risk cal differences between the two disorders, and the for idiopathic psychoses such as schizophrenia would chromosomal region in which linkage has been be seen to also contribute to AD þ Prisk. detected in these two conditions is broad. Initial studies conducted in unrelated AD þ P and In Pathway B, genes that increase the liability to AD without psychosis subjects have found associa- onset of AD would increase risk for AD þ P. For tions of candidate genes consistent with this model. example, a familial frontotemporal dementia in which

Polymorphic variation in the genes for the dopamine1 affected individuals often present with a schizophre- 5,75 70 and dopamine3 receptors (DRD1 and DRD3), the niform psychosis has been reported. We are una- serotonin2A and serotonin2C receptors (HTR2A and ware, however, of reports of similar pedigrees for HTR2C),76 and long alleles of the serotonin transpor- AD þ P. A number of investigations have examined ter gene (HTT or SLC6A4),26 have been found to whether APOE4 might contribute to the AD þ P confer moderate, but significant, increases in risk for phenotype. While one large and two smaller studies AD þ P. One of these, DRD3, has also been associated have found an association of APOE and AD þ P, 85–87 with a small but significant increase in the risk of most reports have found no association of APOE4 schizophrenia in both case–control and family stu- with AD þ P. 33,88–93 Furthermore, though the major dies.77 These findings are most consistent with a effect of APOE4 on AD phenotype is to reduce age-of- disease-modifying gene (Pathway A), though Pathway onset of AD,94 APOE4 genotype is not associated with C cannot be excluded. reduced time to onset of AD þ P. 95 Nor was association Recently, using publicly available genome scan data of increased risk for AD þ P with the putative AD risk from the NIMH AD Genetics Initiative,3,78 we con- gene, alpha-1-antichymotrypsin (ACT) detected.95 ducted the first linkage analysis of AD þ Pin Similarly, there is no evidence that any of the risk individuals with LOAD.79 Genome-wide multipoint genes found to be associated with AD þ P in case– linkage analysis was performed in families with two control studies (see above) also contribute to AD risk. or more individuals with LOAD þ P. In our principal Though some,96,97 but not all,98 studies have found an analysis, we focused on Pathway A1. Since the most association of AD with short alleles of a 44 bp important identified genetic risk factor for LOAD is insertion/deletion polymorphism in the 50 promoter the presence of one or more e4 alleles for the region of HTT, it was the presence of long alleles that apolipoprotein E gene (APOE4), we restricted analy- was associated with increased AD þ P risk.26 sis to the 42 families in which at least two individuals In Pathway C, genes contributing major risk for also had one or more e4 alleles (LOAD þ P þ e4 idiopathic psychoses such as schizophrenia would be families). In our secondary analysis, we examined seen to also contribute to AD þ P risk. In this scenario, all 65 LOAD þ P families (Pathway A and/or Pathway an increased morbid risk for schizophrenia would be B). To evaluate the results of the linkage analysis, we anticipated in the families of AD þ P probands, and an performed extensive simulations, which yielded elevated risk for AD þ P would also be anticipated in a critical values for genome-wide significant and subgroup of subjects with schizophrenia or in their suggestive linkage of 3.18 and 1.70, respectively. family members. Though data are limited, families of Linkage analysis of LOAD þ P þ e4 families revealed AD þ P probands do not appear to have an increased one significant and two suggestive linkages: MLS ¼ frequency of syndromal psychosis.72 We are not aware 3.52 on 2p, near D2S1356; MLS ¼ 2.01 on 6q, near of data informing whether families of schizophrenia marker D6S1021; and MLS ¼ 1.94 on 21q, at probands have an increased morbid risk of AD þ P, D21S1440. Linkage analysis of LOAD þ P families though there is compelling evidence that AD is rare in yielded one suggestive linkage, MLS ¼ 2.51, at the subjects with schizophrenia.73,74 same 6q location as the linkage signal from the Thus, most data presently available are consistent LOAD þ P þ e4 families. with Pathway A. Definitive discrimination between The suggestive linkage on Chromosome 6q for the these genetic models of AD þ P, however, is not LOAD þ P þ e4 sample, and in the total LOAD þ P possible at this time, leaving open the possibility that sample, was more distal from the best linkage signal multiple pathways are operative. produced by prior linkage analysis of AD cohorts.3,80 The significant linkage signal on Chromosome 2p, Limitations and future investigative strategies produced by analysis of LOAD þ P þ e4 families, has Though the above review provides substantial evi- no equivalent finding in the AD literature aside from dence in support of the hypothesis that psychotic the original Kehoe study, which reported an MLS symptoms define a suitable subphenotype in AD peak of 1.01 at the same location for e4 positive patients for gene-mapping efforts, several limitations

Molecular Psychiatry Psychotic symptoms in Alzheimer disease RA Sweet et al 389 persist. We have focused on psychotic symptoms as previously demonstrated that the presence of aggres- the clinical marker for this phenotype. Most indivi- sive behavior, which occurs in approximately half of duals diagnosed with AD, however, will experience AD þ P subjects, defines a subphenotype more several behavioral disturbances. Exclusive focus on strongly associated with long alleles for the serotonin psychotic symptoms as the defining element may transporter (HTT) promoter polymorphism than exclude other important accessory symptoms. Simi- AD þ P alone.26 Similarly, misidentification delu- larly, a psychosis phenotype may best be defined by sions, paranoid delusions, auditory and visual hallu- the interaction between the presence of the defining cinations may identify subgroups within AD þ P with symptoms and the timing of their emergence during distinct neurobiologic and genetic determinants.76 the illness course, that is AD þ P onset in early illness Evaluating the independence and longitudinal stabi- maydefineadifferentphenotypethanADþ Ponsetin lity of these symptom clusters in AD þ P should late illness. Finally, psychosis may be merely an improve the ability to detect biologically relevant epiphenomena or marker of the true underlying associations, including clinical–pathologic correla- endophenotype, which may itself be more directly tions with regional severity of neuropathologic mar- defined by a specific pattern or rate of change of kers. Identified subphenotypes might also be cognitive deficits, or by an additional neuropathologic quantitative traits, with the advantages for linkage process such as the presence of Lewy Bodies. These and association analysis described above. limitations suggest several areas of future study to Finally, firmly establishing the genetic basis of further refine the AD þ P phenotype that may augment AD þ P would be furthered by additional familial both neurobiologic and genetic studies of AD þ P. studies addressing the heritability and cosegregation It is unknown if the biologic substrate leading to of AD þ P. This may require de novo characterization AD þ P does so in a quantitative manner, or if there is of families, with attention both to adequately detailed a threshold which, when exceeded, leads to AD þ P. cataloging of the psychotic symptoms present in Prior genetic studies of AD þ P have treated AD þ Pas subjects with AD and to a detailed assessment of a dichotomous variable, in essence adopting the latter minor psychotic symptoms in unaffected family model. However, if AD þ P can be modeled as a members. Such a sample would be appropriate for quantitative trait, additional genetic analysis methods application of linkage analysis in an effort to identify can be brought to bear on the examination of AD þ P. contributory genes. Studies of AD þ P in monozygotic For example, methods for linkage analyses of affected vs dizygotic twins would also be valuable. sibling pairs utilizing covariates have recently been developed.99–101 Covarying for psychosis may lead to Summary new or refined findings in linkage analysis of AD proper. A quantitative psychosis trait would also Psychotic symptoms are reliably identified in AD allow for the possibility of QTL modeling of genome patients. The presence of AD þ P appears to identify a scan data for novel psychosis loci, though issues of clinically significant syndrome with more rapid sample size may constrain the value of this ap- cognitive and functional deterioration, and a greater proach.102,103 Finally, with the development of high- liability to aggressive behavior. Multiple studies throughput genotyping methods, and the availability indicate at least moderate state independence of of analytic approaches such as genomic control that AD þ P. Thus, while AD þ P typically does not become can enhance the utility of association analysis,104 the apparent in an individual until the middle stages of use of a quantitative trait may increase the power to AD, it tends to be persistent. The available evidence detect the association of AD þ P with candidate gene suggests that AD þ P reflects a biologically specific loci. These efforts will require clinical studies that process, and is not merely an epiphenomenon of AD. categorize the frequency and persistence of specific If there is an association of AD þ P with the severity psychotic symptoms in individuals with AD. Several of neuropathologic lesions of AD, it appears to be different approaches to quantifying psychotic symp- modest. There is emerging evidence of familial toms might be used: number of psychotic symptoms aggregation of AD þ P. Significant findings from endorsed, frequency of occurrence of individual candidate gene association studies and initial linkage psychotic symptoms, time to onset of psychotic analyses are encouraging. Future efforts will benefit symptoms, persistence of psychotic symptoms over from the collection of new cohorts of families, with time, presence of other behavioral symptoms and detailed behavioral characterizations. If the specific combinations of these aspects. Other aspects of the genetic factors contributing to AD þ P can be identi- psychotic symptoms such as treatment responsive- fied, they may provide leads to the understanding of ness may also be informative. Even if modeling a mechanisms of psychosis and cognitive impairment. quantitative psychosis trait is unsuccessful, such studies should inform the appropriate threshold (or Acknowledgements cutpoint) to use in classifying someone as AD þ P. Improved characterization of the AD þ P phenotype This work was supported in part by Research Grant would also result from evaluation of possible sub- AG05133 from the National Institute of Aging, by types. AD þ P may be a composite of several biologi- NIMH grants MH-43693, MH-49671, MH-59101, and cally, and genetically, relevant phenotypes. We have by the Department of Veterans Affairs. The authors

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