Journal
NEUROBIOLOGY OF AGING
Volume 89, Issue -, Pages 83-88Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2020.01.001
Keywords
Alzheimer's disease; Brain; DNA methylation; Epigenetics; Psychosis; Schizophrenia
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Funding
- Alzheimer's Association US New Investigator Research Grant [NIRG-14-320878]
- Alzheimer's Society UK [AS-PG-14-038]
- Joint Programmed Neurodegenerative Disease Research (JPND) for the EPI-AD consortium
- NIH R01 grant [AG036039]
- Alzheimer's Research UK [ART-EG2010A-2]
- University of Exeter Medical School research ethics committee
- MRC [MR/N027973/1] Funding Source: UKRI
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Psychotic symptoms are a common and debilitating feature of Alzheimer's disease (AD) and are associated with a more rapid course of decline. Current evidence from postmortem 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 3 key brain regions implicated in the etiology of psychosis (prefrontal cortex, entorhinal cortex, and superior temporal gyrus) in postmortem 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 4 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. (C) 2020 Published by Elsevier Inc.
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