The apolipoprotein E ϵ4 allele is not associated with psychiatric symptoms or extrapyramidal signs in probable Alzheimer's disease

López, Oscar L.; Kamboh, M. Ilyas; Becker, J.; Kaufer, Daniel I.; DeKosky, Steven T.

doi:10.1212/wnl.49.3.794

Cited by 62 publications

(49 citation statements)

References 16 publications

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“…However, the most frequent positive association has been between e4 and psychotic symptoms. Fifteen studies (including the present one) have examined psychotic symptoms, and six (including the present one) have reported that e4 increased the risk for psychosis (Ramachandran et al, 1996;Ballard et al, 1997;Harwood et al, 1999;Weiner et al, 1999;Scarmeas et al, 2002), whereas nine have found no effect of e4 (Lehtovirta et al, 1996a;Cacabelos et al, 1997;Lopez et al, 1997;Lyketsos et al, 1997;Hirono et al, 1998Hirono et al, , 1999Levy et al, 1999;Gabryelewicz et al, 2002;Sweet et al, 2002). Among the six positive studies only two others (Weiner et al, 1999;Scarmeas et al, 2002) have considered delusions and hallucinations separately.…”

Section: Comparison To Other Apoe E4 Ad Psychosis Studiesmentioning

confidence: 67%

“…Previous studies have used a variety of methods to identify psychotic symptoms in their subjects, including general clinical examination (Lehtovirta et al, 1996a;Lyketsos et al, 1997;Hirono et al, 1999), rating scales (Ballard et al, 1997;Cacabelos et al, 1997;Hirono et al, 1998;Levy et al, 1999;Weiner et al, 1999;Gabryelewicz et al, 2002;Scarmeas et al, 2002), or a combination (Ramachandran et al, 1996;Lopez et al, 1997;Sweet et al, 2002). Those studies that have employed research rating scales have used a wide range of scales (see Table 4), making it difficult to reconcile discrepant reports.…”

Section: Comparison To Other Apoe E4 Ad Psychosis Studiesmentioning

confidence: 99%

“…Given the well-documented increase in psychotic symptoms with AD severity (Lopez et al, 1997;Hirono et al, 1998;Harwood et al, 1999;Gabryelewicz et al, 2002), variations in subject disease stage may represent an important difference among studies. Harwood et al (1999), observed that the elevated risk for psychosis was present specifically at the severe stage (MMSEo12) of cognitive impairment among AD patients carrying the e4 allele.…”

Section: Comparison To Other Apoe E4 Ad Psychosis Studiesmentioning

confidence: 99%

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Apolipoprotein E ɛ4 Allele Increases Risk for Psychotic Symptoms in Alzheimer's Disease

Zdanys

Kleiman

MacAvoy

et al. 2006

Neuropsychopharmacol

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The apolipoprotein E (ApoE) e4 allele is a well-documented genetic risk factor for sporadic Alzheimer's disease (AD). Its association with psychopathology among AD patients has been the subject of discrepant reports. We aimed to determine whether ApoE e4 + and e4-AD patients exhibit a different risk profile for psychotic symptoms and other behavioral disturbances. The Neuropsychiatric Inventory (NPI) was administered to determine the frequency and severity of psychotic and other behavioral symptoms in a sample of n ¼ 266 AD patients who had been genotyped for ApoE. Multiple logistic regression models were used to calculate the association between the ApoE e4 allele and the presence of psychotic symptoms (delusions or hallucinations). Exploratory analyses were also conducted to determine the impact of disease severity on e4 effects and to examine the association between e4 and other behavioral symptoms. ApoE e4 was significantly associated with psychotic symptoms (odds ratio (OR) ¼ 1.87, 95% CI ¼ 1.07-3.29, P ¼ 0.029), adjusting for age, sex, education, and MMSE score. More stringent definitions of clinically significant psychosis yielded similar results. Exploratory analyses suggested that this effect accrued specifically from patients with severe-stage AD and primarily from an association between e4 and delusions. The e4 allele did not appear to influence the development of most other behavioral symptoms in our sample. In conclusion, AD patients who carry the ApoE e4 allele are at greater risk than noncarriers for developing psychotic symptoms, particularly as the severity of their dementia progresses.

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Section: Comparison To Other Apoe E4 Ad Psychosis Studiesmentioning

confidence: 67%

Section: Comparison To Other Apoe E4 Ad Psychosis Studiesmentioning

confidence: 99%

Section: Comparison To Other Apoe E4 Ad Psychosis Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Apolipoprotein E ɛ4 Allele Increases Risk for Psychotic Symptoms in Alzheimer's Disease

Zdanys

Kleiman

MacAvoy

et al. 2006

Neuropsychopharmacol

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“…A number of studies have found that AD þ P subjects, in comparison to AD subjects without psychosis, demonstrate more severe cognitive and functional deficits, [61][62][63][64] and more rapid cognitive decline. 10,[12][13][14]65 Thus, in AD, psychosis presence is a marker for a cognitive risk phenotype.…”

Section: Discussionmentioning

confidence: 99%

Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease

Devlin

et al. 2005

Mol Psychiatry

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Psychotic symptoms in subjects with Alzheimer disease (AD with psychosis, AD þ P) define a phenotype characterized by greater cognitive burden than in AD without psychosis. We have proposed that genes of small effect may contribute to the risk for expression of psychosis in multiple disorders, including AD. Recently, sex-differential association of a three-locus haplotype, including a G-A transition at codon 108/158 of catechol-O-methyltransferase (COMT) resulting in a Val-Met substitution, has been reported to confer an increased risk for schizophrenia. The main objective of the study was to determine if COMT genetic variation is associated with risk of psychosis in AD, and included a case-control study of 373 individuals diagnosed with AD with, or without, psychosis. All subjects were characterized for alleles at the three loci associated with schizophrenia, RS737865, COMT G-A 108/158 (RS4680), and RS165599, and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Both single locus and haplotype tests of association were conducted. Logit models were used to examine independent and interacting effects of alleles at the associated loci. All analyses were stratified by sex. In female subjects, RS4680 demonstrated a modest association with AD þ P; RS737865 demonstrated a trend towards an association. There was a highly significant association of AD þ P with the four-locus haplotype, which resulted from additive effects of alleles at RS4680 and ERE6 (or RS737865, as this locus was in almost absolute linkage disequilibrium (LD) with ERE6). In male subjects, no single locus test was significant, but there remained a strong association between AD þ P and the four-locus haplotype. This association appeared to result from interaction of the ERE6/ RS737865, RS4680, and RS165599 loci. Genetic variation in COMT is associated with AD þ P, and thus appears to contribute to psychosis risk across disorders. Sex-differential associations of COMT with psychosis may result from variation at, or in LD with, ERE6. Examination of variation at ERE6 in subjects with schizophrenia, and further examination of the independent and additive effects of variations in COMT on gene expression, is warranted.

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“…AD þ P has been associated with more severe cognitive and functional deficits in AD subjects matched on other clinical characteristics. [30][31][32][33][34] Studies conflict regarding whether AD þ P is associated with more rapid cognitive deterioration, though most have found an association. 19,[35][36][37][38] It should be noted that most of these studies have not controlled for the duration of AD prior to study entry.…”

Section: Evidence For a Distinct Phenotypementioning

confidence: 99%

Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype

et al. 2003

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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. OverviewThe genetic basis of Alzheimer disease (AD) is unknown, although considerable strides have been made using gene-mapping efforts. Success has been most notable for the highly heritable early onset form, which comprises a minority of the entire population of AD cases. 1 While the impact of apolipoprotein E e4 alleles (APOE4) is well established, the genetic architecture of the more common late-onset AD (LOAD) is unclear. Like other genetically complex disorders, such as diabetes mellitus, progressively greater attention has been paid to utilizing defined subgroups of AD (eg late age-of-onset, APOE4 presence, autopsy confirmation) for mapping liability genes. 2,3 We have previously proposed that the presence of psychotic symptoms, delusions and hallucinations, define a subgroup of AD 4 that may be suitable for genetic investigation. 5,6 To our knowledge, however, the available evidence pertaining to whether AD with psychosis (AD þ psychosis (AD þ P)) identifies a phenotype suitable for genetic study has not been the subject of critical review.Stedman's Medical Dictionary defines phenotype as 'the observable characteristics, at the physical, morphologic, or biochemical level, of an individual, as determined by the genotype and environment '. 7 The genes associated with a behavioral phenotype, however, are unknown. The task for the psychiatric geneticist, therefore, is to identify a behavioral phenotype that varies according to alleles at a restricted set of genes. As in all psychiatric nosology, a behavioral phenotype must be readily and reliably identifiable in all patients of interest. If this behavioral phenotype has clinical relevance (eg bipolar illness) it provides a measure of face validity, and adds significance to its use in the search for causative genes. Tsuang et al. 8 enumerated additional criteria for determining that a behavioral phenotype has a substantial genetic basis, including state independence, biolog...

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The apolipoprotein E ϵ4 allele is not associated with psychiatric symptoms or extrapyramidal signs in probable Alzheimer's disease

Cited by 62 publications

References 16 publications

Apolipoprotein E ɛ4 Allele Increases Risk for Psychotic Symptoms in Alzheimer's Disease

Apolipoprotein E ɛ4 Allele Increases Risk for Psychotic Symptoms in Alzheimer's Disease

Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease

Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype

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