An Epigenome‐wide association study of psychosis in Alzheimer’s disease dorsolateral prefrontal cortex

Abstract

AbstractBackgroundPsychosis is a debilitating syndrome occurring in 40‐60% of people with Alzheimer’s disease (AD) and corresponds with a more severe disease course. Evidence suggests that psychosis in AD (AD+P) is associated with a distinct profile of neurobiological changes, but little is known about the molecular processes driving aetiology. In this study, we performed an epigenome‐wide association study (EWAS) to investigate DNA methylation associated with AD+P in the dorsolateral prefrontal cortex of post‐mortem brain samples.MethodBrain samples were obtained from the University of Pittsburgh Alzheimer’s disease Research Centre (PITT‐ADRC). AD pathology was assessed and classified using CERAD neurotic plaque density score, Braak neurofibrillary tangle stages and NIA‐RI criteria. We used the presence or absence of delusions and hallucinations, Mini‐Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) to categorise our samples into AD with Psychosis (AD+P) and AD without Psychosis (AD‐P) groups. DNA was extracted, bisulfite‐treated and profiled on the Illumina Methylation EPIC Array and genotyping was carried out on the Illumina Global Screening Array (GSA).ResultAfter data quality control, 153 samples (40 AD‐P, 113 AD+P) remained for further analysis. The normalized beta values and the effect estimate values were used to extract Differentially Methylated positions (DMP) and differentially methylated regions (DMRs), respectively. To identify methylation quantitative trait loci (mQTLs) in both cis and trans, SNP‐CpG pairs with a p‐value threshold of <1e‐5 were calculated. We performed a colocalization analysis for the most significant DMPs and mQTLs, using publicly available summary statistics of relevant genome‐wide association studies (GWAS).ConclusionThe development of effective therapies for AD+P is an urgent priority and requires a better understanding of the molecular mechanisms underlying this syndrome. To address this, we have collated a well‐powered study cohort to interrogate the epigenetic basis of AD+P in the brain and have identified several loci of interest that require further study.