Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype

Abstract

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...

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

“…1,6 The observation of an association of COMT haplotype with AD þ P is consistent with the hypothesis that COMT is one such gene, as is a recent report of an association of COMT haplotype with risk for Bipolar disorder. 66 Independent confirmation of the association of AD þ P with COMT haplotype, including confirmation in familybased designs, is needed.…”

“…1 AD þ P occurs in approximately 30-60% of individuals with AD. 1 The AD þ P phenotype is familial, 2 with an estimated heritability of 61-70%.…”

“…1 AD þ P occurs in approximately 30-60% of individuals with AD. 1 The AD þ P phenotype is familial, 2 with an estimated heritability of 61-70%. 3 AD þ P demonstrates linkage to specific chromosomal regions, 4,5 is associated with variation in biologically plausible candidate genes, [5][6][7][8] and is characterized by distinct post-mortem neurochemical changes.…”

“…[10][11][12][13][14] Guided by the recognition that some of the reported genetic associations, regions of linkage, post-mortem neurochemical changes, and clinical features of AD þ P overlap with those identified in schizophrenia, we have proposed a genetic model in which disease-modifying genes of small individual effect might contribute to the liability to psychosis across disorders. 1 Recently, the association between schizophrenia and the catechol-O-methyltransferase gene (COMT) has been explored extensively. COMT is located on chromosome 22q11.2, proximate or within the site of microdeletions found in patients with Velocardiofacial syndrome, a disorder in which up to 30% of sufferers have schizophrenia.…”

Clinical Profile of Alzheimer’s Disease Non-Responder Patient

“…The physiopathological and psychological mechanisms involved in the development of neuropsychiatric symptoms are still poorly understood. Thus, several neuro-anatomical correlative studies have been made, and association between discrete regional pathologies and psychiatric symptoms emerged (Mega et al, 2000;Sweet et al, 2003;Rosen et al, 2005;Sultzer et al, 2003;Shanks and Venneri, 2004;Migneco et al, 2001). Most of recent literature tried to correlate neuro-psychiatric symptoms to morphological features, particularly in early stages of AD.…”