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Published in final edited form as: Am J Med Genet B Neuropsychiatr Genet. 2016 Jan 12;174(1):27–35. doi: 10.1002/ajmg.b.32413

Genetics of Psychosis of Alzheimer Disease

Chintan Shah 1, Mary Ann A DeMichele-Sweet 1, Robert A Sweet 2,3,*
PMCID: PMC5154859  NIHMSID: NIHMS833984  PMID: 26756273

Abstract

Psychotic symptoms, comprised of delusions and hallucinations, occur in about half of individuals with Alzheimer disease (AD with psychosis, AD+P). These individuals have greater agitation, aggression, depression, functional impairment, and mortality than individuals without psychosis (AD−P). Although the exact etiopathogenesis of AD+P is unclear, the rapidly developing field of genomics continues to expand our understanding of this disease. Several independent studies have demonstrated familial aggregation and heritability of AD+P. Linkage studies have been suggestive of loci on several chromosomes associated with AD+P. Association studies examining apolipoprotein E gene, the best established genetic risk factor for late-onset AD, did not find any significant association of this gene with AD+P. Other candidate gene studies focusing on monoamine neurotransmitter systems have yielded equivocal results. A genome-wide association study and studies examining copy number variations recently have detected suggestive associations, but have been underpowered. Approaches to increase sizes of AD+P samples for genome wide association studies are discussed.

Keywords: Alzheimer disease, psychosis, genome-wide association, heritability

INTRODUCTION

Alzheimer disease (AD) is a neurodegenerative illness that currently affects 5.3 million Americans with numbers projected to grow to over 10 million by mid-century. The genetics of AD is subdivided into early-onset AD (EOAD) and late-onset AD (LOAD). EOAD typically has an onset prior to age 60 years and accounts for less than 5% of all cases [Campion et al., 1999; Bertram and Tanzi, 2005]. It usually follows an autosomal dominant inheritance pattern where mutations in a single gene can cause the disease. Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) have been reported in development of EOAD [Goate et al., 1991; Levy-Lahad et al., 1995; Sherrington et al., 1995]. Over the past decade, duplication of APP has also been described as a cause of EOAD [Rovelet-Lecrux et al., 2006]. LOAD has an onset after age 60 years and is the more prevalent form of AD. The genetics of LOAD is more complex involving multiple genes with only modest familial aggregation. Apolipoprotein E (APOE) is the most well-established gene associated with LOAD where individuals with e4 allele (APOE e4) have a substantially higher risk of developing AD [Corder et al., 1993; Strittmatter et al., 1993]. Genome-wide associations studies (GWAS) have identified over 20 additional genetic loci for LOAD [Chouraki and Seshadri, 2014].

About 50% of individuals with AD will develop psychotic symptoms, (AD with psychosis, AD+P) [Murray et al., 2014]. These symptoms include hallucinations and delusions. Common delusions include those of persecution, infidelity, abandonment or deceased relatives being alive [Tariot et al., 1995]. Delusions must be distinguished from simple forgetfulness, often by their persistence or recurrence over time. Even though there is no fixed definition of persistence, 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 present for at least a month [Burns et al., 1990; Jeste and Finkel, 2000]. Hallucinations in AD can occur in any sensory modality, but visual and auditory hallucinations are most typical [Tariot et al., 1995]. One must be careful to distinguish visual hallucinations from illusions, or from normal hypnogogic and hypnopompic phenomena, and exclude any possible delirium that may be causing transient perceptual disturbances or delusional ideas [Jeste and Finkel, 2000]. Because some patients with AD may have infrequent distortions of thought or perception which may represent a true psychotic syndrome, or a phenocopy due to some of the above confounding circumstances, some investigators have classified such cases as AD + intermediate psychosis for association studies (e.g., [Zheng et al., 2014]). Another important consideration is the classification of individuals with AD as not psychotic for association testing. Psychotic symptoms typically emerge between the early and moderate stages of cognitive impairment in AD [Sweet et al., 2010]. Thus, to enhance the power of association testing, individuals should have reached at least this stage of impairment before being classified as AD without psychosis (AD without psychosis, AD−P).

The occurrence of psychotic symptoms in AD+P identifies a subgroup of AD patients with a more severe phenotype. This includes greater cognitive impairment and more rapid cognitive decline when compared to AD−P patients [Ropacki and Jeste, 2005]. Moreover, AD+P is associated with higher rates of co-occurring agitation [Gilley et al., 1991], aggression [Gilley et al., 1997; Sweet et al., 2001], depression [Lyketsos et al., 2001; Sweet et al., 2010], caregiver burden [Kaufer et al., 1998], functional impairment [Scarmeas et al., 2005], and mortality [Wilson et al., 2006] than AD−P. Pharmacological interventions with typical and atypical antipsychotic medications have limited effectiveness and come with sizable risks [Schneider et al., 2006; Huybrechts et al., 2012]. These medications are FDA approved for schizophrenia and their use in treatment of psychosis of AD is off-label.

Given the disease burden of AD+P and lack of efficacious treatments, it is imperative to pursue avenues that may lead us to the etiopathogenesis of this debilitating phenotype of AD. There have been numerous studies over the past several years looking at clinical correlates, brain imaging, and neuropathology related to AD+P. This review aims to summarize our current knowledge about the genetic basis of psychosis in AD. We provide a review of studies examining the heritability and familial aggregation, linkage, candidate gene associations, genome wide association, and copy number variation studies, followed by a summary providing a critique of the existing findings.

Heritability and Familial Aggregation

Heritability is the extent to which individual genetic differences contribute to individual phenotypic differences. Familial aggregation refers to the occurrence of a given trait in two or more members of a family that cannot be readily accounted for by chance.

The first published study to look at familial aggregation of AD+P by Tunstall et al. [2000] found evidence for familiality of psychosis in AD to be equivocal. Sweet et al. [2002] found compelling evidence that AD+P is familial. In a cohort of 371 subjects with AD and 461 siblings also diagnosed with AD, collected as part of the National institute of mental health (NIMH) AD Genetics Initiative, it was found that AD+P demonstrated familial aggregation. The odds ratio for AD+P siblings of AD+P probands was 2.4 (1.46–4.0). When the definition of psychosis was narrowed (requiring multiple psychotic symptoms to be present over time) the odds ratio (OR) of psychosis rose to 3.2 in siblings. Since then, the familiality of AD-related psychosis has been shown in two other studies of independent family cohorts [Hollingworth et al., 2007; Sweet et al., 2010].

Hollingworth et al. [2007] replicated and extended the 2002 study by Sweet et al. studying a subset of the NIMH AD Genetics Initiative families and a new set of families from the United Kingdom (UK). In total there were data from 374 families in which at least two members met criteria for AD and had complete data regarding psychotic symptoms. They found a significant association between proband psychosis status and the occurrence of AD+P in siblings in the UK (OR =4.17, P =0.002) and US (OR =3.2, P <0.001) samples [Hollingworth et al., 2007].

In a later study by Sweet et al. [2010], they were able to verify previous familial aggregation studies when they looked at families with multiple members with LOAD. They identified 143 families in which at least two people were diagnosed with a dementia and characterized for the presence or absence of psychosis. There was a highly significant association of psychotic symptoms in the pro-band with the presence of psychosis in the family member (χ2 =15.8, df =4, P =0.003). Once again, the association was strongest in comparing individuals with multiple/recurrent symptoms to those with no symptoms [OR (95%CI) 3.80 (1.54–9.40); χ2 =9.0, df =1, P =0.003].

Evidence of familial aggregation of psychosis in AD suggests that this phenotype is under genetic control. Work done by Bacanu et al. [2005] first estimated heritability of psychosis in AD to be 61% in the NIMH AD Genetics Initiative families. More recently, Barral et al. [2015] examined an independent group of 607 families from the National institute of aging (NIA)-LOAD cohort and also found heritability of LOAD+P to be 61%.

Linkage Studies

Having established heritability of AD+P, some questions that need exploration are: what loci may be linked to AD-related psychosis and what are the implicated genes? To answer such queries, in the first published linkage study, Bacanu et al. [2002] evaluated 65 families where two or more members had AD+P. They found evidence of linkage on chr 2p, 6 and 21. However, a later study [Hollingworth et al., 2007], showed that linkages on chr 6q16.3 and 21q22.13 appeared to be due to inclusion of APOE genotype as a covariate. The same group found a significant linkage on chr 7q21.11 (LOD =2.84) and 15q25 region (LOD =3.16) [Hollingworth et al., 2007].

Neuregulin-1 (NRG1), a gene on chromosome 8, has been linked with psychosis in schizophrenia [Stefansson et al., 2002; Harrison and Law, 2006]. Go et al. [2005] examined 437 families and found linkage for NRG1 with AD+P. They then analyzed four SNPs within NRG1 for linkage and association with AD+P in a predominantly Anglo-European sample. Three of these SNPs were associated with risk for schizophrenia (SNP8NRG221533, SNP8NRG243177, SNP8NRG2419) [χ2 =0.333, 0.286, 0.818 and P =0.564, 0.593, 0.366, respectively] and the fourth was an exonic SNP (rs3924999). However, rs3924999 was the only one to show significant association with AD+P in single SNP analyses (P =0.008). rs3924999 results in a missense mutation that changes arginine to glutamine, although the impact of this change is not known.

Avramopoulos et al. [2005] found a region on chromosome 14 is linked to the absence of hallucinations in AD+P. They examined 148 families with at least two siblings with age at onset of 50 years. They identified linkage to a locus on chr 14q24.3 (LOD =3.91) 4.3 Mb from PSEN1 locus related to the absence of hallucinations. Sequencing of PSEN1 in the families with greatest linkage did not detect any coding or splice site variations and they concluded that presence of PSEN1 in the region might be coincidental. In addition, they found some suggestive linkage to the presence of delusions on chromosome 2p (LOD =1.98) thereby supporting the findings of Bacanu et al. [2002].

Barral et al. [2015] evaluated 263 families from the NIA-LOAD cohort. These families, in which multiple family members had AD, were separated into those in which at least one family member had AD and psychosis (LOAD+P, n =215) and those in which no family member had psychosis (LOAD–P, n =48). They carried out linkage analysis to the AD phenotype within each set. They found significant evidence for linkages on chromosome 19q13.12 in the LOAD+P families and identified SNP rs2945988 to have a strong suggestive association with psychosis (P =8.7 ×10−7). Using additional Caribbean hispanic and non-hispanic Caucasian cohorts they conducted a meta-analysis of 246 SNPs in the 19q13.12 region. The strongest signal in all Caribbean hispanic datasets was found for SNP rs10410711 (Pmeta = 5 ×10−5), an intronic variant in ZNF566 gene (zinc-finger binding proteins are involved in transcription and, of interest, variants in a zinc-finger protein gene, ZNF804A has been shown to increase susceptibility to psychosis, schizophrenia, and bipolar disorder [Steinberg et al., 2011]. When non-hispanic Caucasian cohorts were included, a 19q13.12 variant, rs10421862, located 24 kb upstream of rs10410711 appeared strongly associated with LOAD+P (Pmeta = 1.0 ×10−5). Interestingly, the earlier linkage study done by Hollingworth et al. [2007] also reported suggestive linkage (LOD =1.86) to chromosome 19, about 5 Mb upstream of the 19q13.12 region Barral et al. reported. Furthermore, genomic variation in 19q13.12 has been associated as a risk factor for other psychiatric disorders such as schizophrenia [Xu et al., 2008]. In a large schizophrenia Genome-wide association study a SNP was identified just 13 Mb upstream of 19q13.12 region identified in the study by Barral et al. [2015] [Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014].

Genetic Association Studies

One way to determine in what way genetic factors might lead to psychosis in Alzheimer’s disease is via studying specific genetic variations in AD+P samples and comparing them to AD−P samples in association studies. These studies initially focused on variants in APOE and in candidate genes in the monoamine neurotransmitter systems.

APOE

APOE is the best established genetic risk factor for LOAD. Therefore, many researchers have evaluated whether APOE e4 increases risk of AD+P.

DeMichele-Sweet and Sweet [2010] reviewed 22 studies examining the association of the APOE e4 allele with AD+P. The reports in this review, and one additional more recent study [Christie et al., 2012] had a conflicting pattern of results in which APOE e4 genotype increased, decreased, or had no effect on psychosis risk. These conflicting findings may have resulted from the considerable variability in the subject populations, sample sizes (most of which were small, median sample size =173), definitions of AD+P, and analytic approaches. Hence, DeMichele-Sweet et al. [2011a] examined the association of AD+P with APOE in the Uniform data set from the National Alzheimer’s coordinating center, comprising 2,317 predominantly (84.5%) Anglo-European sample of individuals with AD of which 802 (34.6%) had psychosis. They found no association of the APOE e4 alleles with AD+P (OR =0.999, P =0.996).

Alternatively, conflicting findings regarding the association of APOE with AD+P may have resulted if other genetic variation in partial linkage disequilibrium with the two SNP APOE e4 locus is causally related to AD+P. Recent investigations sequencing the APOE region on chromosome 19 identified a variable length poly-T repeat sequence in intron six of TOMM40 [Roses et al., 2010]. Individuals with APOE e3/e4 genotype and long poly-T repeats (defined as >27) had a much lower age of onset of LOAD than individuals with APOE e3/e4 genotype and short repeats [Roses et al., 2010]. Therefore, Chu et al. [2011] evaluated the impact of APOE genotype and TOMM40 poly-T repeats on AD+P risk. They developed a novel statistical method for allele length calls for the poly-T polymorphism and found it had a trimodal distribution, which differed significantly by APOE e4genotype (χ2 =659, df =10, P <0.001). Neither APOE e4genotype, TOMM40 repeat length, nor their joint effect associated with AD+P. Finally, in the GWAS study by Hollingworth et al. [2012], described below, including 1,299 cases with AD+P and 735 with AD−P, no APOE/ TOMM40 SNPs were significant in the comparison of AD+P versus AD−P (all P >0.2). However, this latter negative finding may be limited as it should be noted that APOE rs7412 and rs429358 are not genotyped on the arrays and that their linkage disequlibrium with the proxy markers is low.

Other genes

Numerous genetic association studies have focused on polymorphisms in serotonin and dopamine receptors and the catechol-O-methyltransferase (COMT) enzyme. The evidence from such studies to date is inconclusive (reviewed extensively in DeMichele-Sweet and Sweet, 2010). Results of these as well as polymorphisms in the D-Amino acid oxidase activator (DAOA), amyloid precursor protein (APP), sortilin-related receptor (SORL1), β-site amyloid precursor protein cleaving enzyme (BACE1), and microtubule-associated protein tau (MAPT) are summarized in Table I.

TABLE I.

Studies With Significant Associations of AD+P to Serotonin and Dopamine Receptors, COMT, DAOA, APP, SORL1, BACE1, and MAPT

Gene Number of studies reported # of AD subjects included across all studies Outcomes
HTR2A 8 1,645 5-HT2A C102 allele associated with risk of psychosis [Holmes et al., 1998; Nacmias et al., 2001; Rocchi et al., 2003; Assal et al., 2004]
Genotype significant for delusions and CC genotype protective for delusions [Lam et al., 2004]
Three studies did not find genotype or allele frequency significant for psychosis [Craig et al., 2007; Wilkosz et al., 2007; Pritchard et al., 2008a]
HTR2C 3 701 5-HT2C Ser23 allele frequency significant for visual hallucinations [Holmes et al., 1998]
Two other studies found allele frequency to be not significant for psychosis [Assal et al., 2004; Pritchard et al., 2008a]
One study found genotype to be not significant for psychosis [Pritchard et al., 2008a]
SLC6A4 6 1,315 L allele and LL genotype significant for psychosis [Sweet et al., 2001]
LL genotype significant for protecting against delusions [Borroni et al., 2006]
Ten-repeat allele significant for psychosis [Pritchard et al., 2007]
Two other studies did not find genotype significant for psychosis [Ha et al., 2005; Ueki et al., 2007] and one study did not find allele frequency significant for psychosis [Rocchi et al., 2003]
DRD1 2 356 B2/B2 genotype significant for psychosis [Sweet et al., 1998]
B1/B2 genotype significant for hallucinations [Holmes et al., 2001]
DRD2 1 267 Cys311 allele frequency not significant for psychosis [Sweet et al., 1998]
DRD3 3 789 Ser/Ser and Gly/Gly genotype significant for psychosis [Sweet et al., 1998]
Gly/Gly genotype significant for protecting against delusions [Holmes et al., 2001]
One study found allele frequency and genotype not significant for psychosis [Craig et al., 2004]
DRD4 1 225 Allele frequency not significant for psychosis [Sweet et al., 1998]
SLC6A3 1 395 Genotype not significant for psychosis [Pritchard et al., 2008b]
COMT 2a 693a rs4680 G allele frequency significant for psychosis [Sweet et al., 2005; Borroni et al., 2006, 2007]
DAOA 1 185 Nominally significant association (P <0.05) with one SNP (rs2153674) [DiMaria et al., 2009]
APP 1 867 No association of SNPs tagging the majority of genetic variation within each of the target genes with AD+P [DeMichele-Sweet et al., 2011b]
SORL1
BACE1
MAPT
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HTR2A, serotonin 2A receptor; HTR2C, serotonin 2C receptor; SLC6A4, serotonin transporter; DRD1, dopamine-1 receptor; DRD2, dopamine-2 receptor; DRD3, dopamine-3 receptor; DRD4, dopamine-4 receptor; SLC6A3, dopamine transporter; COMT, catechol-O-methyltransferase; DAOA, D-amino acid oxidase activator; MAPT, microtubule-associated protein tau; APP, amyloid beta (A4) precursor protein; BACE1, beta-site APP-cleaving enzyme 1; SORL1, sortilin-related receptor, L(DLR Class) A repeats containing.

a

Borroni et al. [2006] study had 232 subjects and the same study was continued with new results published in 2007 which included 88 new subjects with AD.

Genome-Wide Association Studies

GWAS, like genetic association studies, compare the frequency of alleles of a given variant in case and control populations. The difference is the number and selection of tested variants, which instead of being chosen based on a priori hypothesis of a few candidate genes and variants, covers the entire genome. By covering the whole genome one can detect in an unbiased fashion variants that may contribute to a disease. This makes GWAS a favorable method for the discovery of common genes associated with complex diseases, such as LOAD. A limitation of GWAS is that large sample sizes are required, in part due to the loss of statistical power from the conduct of multiple tests [Chouraki and Seshadri, 2014].

The first genome-wide association study of AD+P was done by Hollingworth et al. [2012]. This meta-analysis combined three AD GWAS datasets: GERAD1 [Harold et al., 2009], the NIA-LOAD Family study [Sweet et al., 2010; Wijsman et al., 2011] and the University of Pittsburgh Alzheimer Disease Research Center [DeMichele-Sweet et al., 2011b]. All AD cases met criteria for either possible, probable or definite AD [McKhann et al., 1984; Mirra et al., 1991]. All elderly controls were screened for dementia using structured clinical assessments or were determined to be free from neurodegenerative disease at neuropathological examination. Following quality control (QC) there were 1,299 cases with AD+P, 735 with AD−P, and 5,659 controls. The AD+P versus AD−P analysis included 1,882,172 SNPs, AD+P versus control analyses 1,847,262 SNPs.

When comparing AD+P to AD−P cases, the SNP with the strongest evidence for association with psychosis was rs753129 which is located in an intergenic region of chromosome 4 (OR =0.66; P =2.85 ×10−7). SNP rs6834555 was found to be the most statistically significant SNP when comparing AD+P cases to controls (although it should be noted that no SNP reached the threshold of genome wide significance in this report). This SNP is upstream of the solute carrier family two member 9 (SLC2A9) gene (OR =1.39, P =3.0 ×10−7). However, when comparing AD+P to AD−P cases, the association of AD+P with this SNP was no longer present [Hollingworth et al., 2012]. An intronic SNP, rs4038131, in the visinin-like 1 (VSNL1) gene approached statistical significance in both AD+P versus control (OR =0.65, P =5.9 ×10−7) and AD+P versus AD−P groups (OR =0.72, P =1.84 ×10−2) Hollingworth et al. [2012]. VSNL1 codes for the protein, VILIP-1, neuronal calcium sensor [Amici et al., 2009]. VILIP-1 has been shown to be a cerebrospinal fluid biomarker of Alzheimer disease [Lee et al., 2008; Tarawneh et al., 2011].

Additionally, this GWAS by Hollingworth et al. [2012] included an investigation on 11 SNPs that have shown genome-wide significance in GWAS of bipolar disorder and schizophrenia. Independently, none of the SNPs had a significant genome-wide association with AD+P, but as a group there was a trend towards association (Pcombined = 0.109) [Hollingworth et al., 2012].

Copy Number Variants

Rare structural variation such as copy number variants (CNVs) are a growing area of interest in risk for neuropsychiatric disorders. CNVs are genomic regions that have added (duplications) or deleted (deletions) genetic material. They may overlap one or more genes, thereby affecting their function. Recent studies have shown that autism and schizophrenia share several rare CNVs [Carroll and Owen, 2009; Heinzen et al., 2010]. Genome-wide scans for CNVs have been conducted recently to identify genetic factors associated with AD [Heinzen et al., 2010; Shaw et al., 2011; Ghani et al., 2012; Rovelet-Lecrux et al., 2012; Swaminathan et al., 2012; Chapman et al., 2013; Guffanti et al., 2013; Szigeti et al., 2013, 2014]. More recently, some studies have evaluated CNVs in AD+P.

Zheng et al. [2014] evaluated whether seven CNVs that have demonstrated recurrence in autism and schizophrenia were present in AD+P. Of these, a large duplication on chromosome 16p11.2 was found to be present in two of 440 AD+P subjects (frequency of 0.46%) but in none of 136 AD−P subjects, none of 593 subjects with AD +intermediate psychosis, and none of 855 non-AD controls (P =0.047). This finding suggests that the 16p11.2 duplication may act to increase risk for neuropsychiatric illness across developmental epochs, being associated with autism, then schizophrenia, and finally AD+P [Weiss et al., 2008; McCarthy et al., 2009]. The CNV region involved contains about 25 genes, several of which have been found to be involved in the pathogenesis of AD (SPN, CORO1A, QPRT, MAZ, MAPK3). The CNV duplication seen in this study almost fully overlaps with the previously reported 16p11.2 CNV region in schizophrenia and autism. The frequency of this CNV duplication in AD+P (0.46%) is comparable to that reported in the sample of a large schizophrenia study where 21 of 4551 (0.46%) cases had the duplication [McCarthy et al., 2009]. However, given that only two participants with AD+P had the 16p11.2 duplication, replication with larger cohorts is needed to enhance confidence in the association of this locus with AD+P.

To more systematically identify the association of CNVs with AD+P, Zheng et al. [2015] conducted the first genome-wide CNV study of AD+P. They looked at 496 AD+P cases, 639 subjects with AD +intermediate psychosis and 156 AD−P subjects. CNV load analysis found no significant difference in total and average CNV length and CNV number in the AD+P or AD intermediate P groups compared with the AD−P group. Their analysis revealed a marginally significant lower number of duplication events in AD+P cases compared with AD−P controls (P =0.059). An interesting discovery was the presence of a duplication in the APC2 gene on chromosome 19p13.3, which was protective against AD+P (OR =0.42; P =7.2 ×10−10). The frequency of this duplication was 9.8% in AD+P compared with 24.3% in AD−P. This study also found four other duplications and two deletions that did not achieve genome-wide significance summarized in Table II.

TABLE II.

CNVs Identified by Zheng et al. [2014, 2015]

Chromosome CNV type CNV position Gene Frequency in AD+P/AD int P/AD−P (%); P-value
9 Duplication 130 459 243–130 492 493 SET 6.1/16/17.6; 1.95 ×10−6
14 104 694 657–104 708 792 JAG2 4.8/17.7/14; 5.01 ×10−7
16 87 124 205–87 132 458 ZFPM1 7/21.4/18.4; 2.13 ×10−7
16 29 554 843–30 105 652 25 Different genes 0.45/0/0; 0.047
17 20 651–31 497 No known gene 7.5/21.8/14.7; 4.25 ×10−6
19 1 411 473–1 424 152 APC2 9.8/29/24.3; 7.20 ×10−10
4 Deletion 162 098 516–162 104 179 No known gene 26.1/19.6/12.5; 8.27 ×10−5
9 17 259 437–17 388 404 CNTLN 1.6/0/0; 8.87 ×10−4
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CONCLUSION

In this review, we have attempted to summarize the current knowledge of AD+P genetics covering older familial aggregation and association studies to newer GWAS and CNV studies.

Familial aggregation and heritability studies have been crucial for establishing that psychosis risk within AD is likely to be influenced by genetic variation. Several independent replications have established the familial aggregation of AD+P, while two independent studies estimated the heritability of psychosis in AD at 61%. This indicates a substantial genetic component, approaching both heritability estimates for AD itself and for the major primary psychotic disorder, schizophrenia.

Despite the evidence of the heritability of psychosis in AD, genetic studies to date have not been definitive. Most early studies of the genetics of AD+P used linkage analysis or tested candidate genes, approaches that have largely been abandoned in favor of genome-wide association in studies of polygenic disorders, as is presumed to be the case for AD+P. However, some possible exceptions should be noted. It remains possible that some of the familial risk for AD+P could reflect rare mutations of large effect within select families, and thus could be detectable using linkage approaches, although preferably within pedigrees much larger than most studied to date. Similarly, a possible exception to the above conclusion as it relates to candidate gene studies has been the study of APOE in AD+P. There is substantial support to conclude that APOE is not associated with risk for AD+P.

Recently, a few studies have used genome wide approaches to evaluate SNPs and CNVs for association with AD+P. A limitation to these studies has been their relatively small sample sizes, and thus limited statistical power, to date. For example, although the single GWAS study of AD+P provided a number of suggestive associations of common variants, no single variant reached the genome-wide significance threshold. While some CNV studies have been promising, for example finding a genome-wide significant association of AD+P with a protective effect of a duplication of the APC2 gene, many studied CNVs have low frequencies. As a result, even a small shift in CNV rates between cases and controls can eliminate putative associations, and so larger samples with independent replications are needed before concluding that detected associations are true positives.

Thus clearly larger samples of AD+P and AD−P subjects are needed for definitive genome-wide association methods. This is not a trivial task, and requires careful attention to longitudinal behavioral characterizations and phenotyping. Individuals with AD must be followed into the period of moderate impairments at which the greatest risk of psychosis occurs. Otherwise, characterizing individuals as AD−P before reaching this threshold will substantially reduce the ability to detect associations as many such “non-psychotic” subjects would have demonstrated psychosis had they been followed longer. Similarly, a large number of subjects with an intermediate phenotype, some of whom are phenocopies, but some of whom are true AD+P cases, are present in most samples. Longer follow-up will similarly benefit clarifying these intermediate phenotypes. However, at a practical level, many such cases will be present in any potential study sample. It would therefore be desirable to increase sample sizes and statistical power by developing methods that would provide appropriate weighting of these individuals (based on similar individuals for whom complete longitudinal data is available) for inclusion in association studies.

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