A brain DNA co-methylation network analysis of psychosis in Alzheimer's disease

IF 13 1区医学 Q1 CLINICAL NEUROLOGY Alzheimer's & Dementia Pub Date : 2025-02-12 DOI:10.1002/alz.14501

Morteza Kouhsar, Luke Weymouth, Adam R. Smith, Jennifer Imm, Claudia Bredemeyer, Yehani Wedatilake, Ali Torkamani, Sverre Bergh, Geir Selbæk, Jonathan Mill, Clive Ballard, Robert A. Sweet, Julia Kofler, Byron Creese, Ehsan Pishva, Katie Lunnon

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Abstract

INTRODUCTION

The presence of psychosis in Alzheimer's disease (AD) is suggested to be associated with distinct molecular and neuropathological profiles in the brain.

METHODS

We assessed brain DNA methylation in AD donors with psychosis (AD+P) and without psychosis (AD−P) using the EPIC array. Weighted gene correlation network analysis identified modules of co-methylated genes in a discovery cohort (PITT-ADRC: N = 113 AD+P, N = 40 AD−P), with validation in an independent cohort (BDR: N = 79 AD+P, N = 117 AD−P), with Gene Ontology and cell-type enrichment analysis. Genetic data were integrated to identify methylation quantitative trait loci (mQTLs), which were co-localized with GWAS for related traits.

RESULTS

We replicated one AD+P associated module, which was enriched for synaptic pathways and in excitatory and inhibitory neurons. mQTLs in this module co-localized with variants associated with schizophrenia and educational attainment.

DISCUSSION

This represents the largest epigenetic study of AD+P to date, identifying pleiotropic relationships between AD+P and related traits.

Highlights

DNA methylation was assessed in the prefrontal cortex in subjects with AD+P and AD−P.
WGCNA identified six modules of co-methylated loci associated with AD+P in a discovery cohort.
One of the modules was replicated in an independent cohort.
This module was enriched for synaptic genes and in excitatory and inhibitory neurons.
mQTLs mapping to genes in the module co-localized with GWAS loci for schizophrenia and educational attainment.

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.