Psychosis-associated DNA methylomic variation in Alzheimer’s disease cortex

Abstract

Psychotic symptoms are a common and debilitating feature of Alzheimer’s disease, associated with a more rapid course of decline. Current evidence from post-mortem and neuroimaging studies implicates frontal, temporal and parietal lobes, with reported disruptions in monoaminergic pathways. However, the molecular mechanisms underlying this remain unclear. In the present study, we investigated methylomic variation associated with AD psychosis in three key brain regions implicated in the etiology of psychosis (prefrontal cortex, entorhinal cortex and superior temporal gyrus) in post-mortem brain samples from 29 AD donors with psychosis and 18 matched AD donors without psychosis. We identified psychosis-associated methylomic changes in a number of loci, with these genes being enriched in known schizophrenia-associated genetic and epigenetic variants. One of these known loci resided in the AS3MT gene – previously implicated in schizophrenia in a large GWAS meta-analysis. We used bisulfite-pyrosequencing to confirm hypomethylation across four neighboring CpG sites in the ASM3T gene. Finally, our regional analysis nominated multiple CpG sites in TBX15 and WT1, which are genes that have been previously implicated in AD. Thus one potential implication from our study is whether psychosis-associated variation drives reported associations in AD case-control studies.