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Methylation profiles in peripheral blood CD4+ lymphocytes versus brain: The relation to Alzheimer's disease pathology.

ABSTRACT: We investigated the change in DNA methylation in peripheral blood CD4+ lymphocytes over time, examined the relation between CD4+ lymphocytes and brain methylation, and compared their associations with AD pathology.Genome-wide methylation was measured three times in 41 older persons using Illumina Infinium HumanMethylation450 array. The two CD4+ lymphocytes measures were at study baseline and proximate to death. Brain tissue came from frozen dorsolateral prefrontal cortex.Global methylation features were conserved across tissue. At individual CpG sites, methylation level was concordant between the two CD4+ lymphocytes but more diffuse between CD4+ lymphocytes and brain. Previous associations of brain methylation with neuritic plaques at target methylation sites were not replicated in CD4+ lymphocytes.There is no strong evidence of change in CD4+ lymphocytes methylation among older persons over an average of 7.5 years. Methylation associations with AD pathology found in neocortex are not directly reflected in CD4+ lymphocytes.

SUBMITTER: Yu L

PROVIDER: S-EPMC5014706 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Methylation profiles in peripheral blood CD4+ lymphocytes versus brain: The relation to Alzheimer's disease pathology.

Yu Lei L Chibnik Lori B LB Yang Jingyun J McCabe Cristin C Xu Jishu J Schneider Julie A JA De Jager Philip L PL Bennett David A DA

Alzheimer's & dementia : the journal of the Alzheimer's Association 20160324 9

<h4>Introduction</h4>We investigated the change in DNA methylation in peripheral blood CD4+ lymphocytes over time, examined the relation between CD4+ lymphocytes and brain methylation, and compared their associations with AD pathology.<h4>Methods</h4>Genome-wide methylation was measured three times in 41 older persons using Illumina Infinium HumanMethylation450 array. The two CD4+ lymphocytes measures were at study baseline and proximate to death. Brain tissue came from frozen dorsolateral prefr ...[more]

PMID: 27016692

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Project description:BackgroundAlzheimer's disease results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized that the disease-associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs.ResultsComparison of 23 disease discordant Finnish twin pairs with reduced representation bisulfite sequencing revealed peripheral blood DNA methylation differences in 11 genomic regions with at least 15.0% median methylation difference and FDR adjusted p value ≤ 0.05. Several of the affected genes are primarily associated with neuronal functions and pathologies and do not display disease-associated differences in gene expression in blood. The DNA methylation mark in ADARB2 gene was found to be differentially methylated also in the anterior hippocampus, including entorhinal cortex, of non-twin cases and controls. Targeted bisulfite pyrosequencing of the DNA methylation mark in ADARB2 gene in 62 Finnish and Swedish twin pairs revealed that, in addition to the disease status, DNA methylation of this region is influenced by gender, age, zygosity, APOE genotype, and smoking. Further analysis of 120 Swedish twin pairs indicated that this specific DNA methylation mark is not predictive for Alzheimer's disease and becomes differentially methylated after disease onset.ConclusionsDNA methylation differences can be detected in the peripheral blood of twin pairs discordant for Alzheimer's disease. These DNA methylation signatures may have value as disease markers and provide insights into the molecular mechanisms of pathogenesis. We found no evidence that the DNA methylation marks would be associated with gene expression in blood. Further studies are needed to elucidate the potential importance of the associated genes in neuronal functions and to validate the prognostic or diagnostic value of the individual marks or marker panels.

Dataset Information

Methylation profiles in peripheral blood CD4+ lymphocytes versus brain: The relation to Alzheimer's disease pathology.

Publications

Methylation profiles in peripheral blood CD4+ lymphocytes versus brain: The relation to Alzheimer's disease pathology.

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