Genetic risk for schizophrenia and psychosis in Alzheimer disease

Abstract

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

Figure 1. Diagram of the study design and workflow

Abbreviations used: ACE: Fundació ACE Barcelona Alzheimer Treatment and Research Center; ADRC: University of Pittsburgh Alzheimer Disease Research Center; NIA LOAD: National Institute on Aging’s Late Onset Alzheimer’s Disease Family Study; NIMH: National Institute of Mental Health Genetics Initiative AD Cohort; UK: Genetic and Environmental Risk in AD Consortium 1; ADC: consortium of National Institute on Aging Alzheimer Disease Centers; CHS: Cardiovascular Health Study; AD-P: Alzheimer disease without psychosis; AD+P: Alzheimer disease with psychosis; SCZ: schizophrenia; GWAS: Genome-wide association study

Figure 2. Discovery (a) and replication (b) analysis of AD+P risk SNPs

A. 67 SNPs reached p < 5e-4 in Stage 2 samples (dashed line). B. Stage 3 examined 60 of the 67 SNPS, three of which (top blue circles, Table 3) approached significance in meta-analysis (P = 1.61×10⁻⁶). In blue, SNPs showing same risk allele in Stages 2 and 3; red, Stage 2 versus 3 results differ in sign (risk allele); size of circle reflects meta-analysis −log₁₀(P).

Fig. 3. Relationship between schizophrenia risk score and risk of psychosis in AD

Displayed are the risk scores for each subject, the score for schizophrenia uses the allele found to confer risk in , whereas the AD+P aligned score uses the same SNPs but assigns risk according to the AD+P association results. Red and blue circles indicate AD+P and AD-P subjects, respectively.