Abstract
A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we have examined DNA methylation patterns in whole blood collected from 284 individuals in the AddNeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage.
Highlights
With an increasingly aging population the prevalence of dementia is expected to almost double in the coming 20 years, with Alzheimer’s disease (AD) being the greatest contributor
We first investigated whether any individual loci showed DNA methylation differences in either mild cognitive impairment (MCI) or AD relative to CTL using an analysis of variance (ANOVA) model after adjusting for the covariates of age, sex, cell proportions, and batch (Supplementary Table 1)
No differentially methylated positions (DMPs) reached the experiment-wide significance threshold that has been established for the 450K array (2.4 Â 10À7) (Saffari et al, 2018) with the smallest ANOVA p-value being 5.58 Â 10À6 for probe cg26146855, of which the closest transcription start site is located in the TFAMP1 gene
Summary
With an increasingly aging population the prevalence of dementia is expected to almost double in the coming 20 years, with Alzheimer’s disease (AD) being the greatest contributor. A number of genome-wide association studies (GWAS) have identified susceptibility loci associated with the more common, sporadic form of AD (Lambert et al, 2013) These do not account fully for disease risk, and the exact processes involved in the development and progression of this neurodegenerative disorder remain unknown. Four EWAS of AD blood have been published so far, which have identified a number of disease-associated loci These studies used a limited set of (nondemented) samples and/or did not include any individuals with mild cognitive impairment (MCI) (Kobayashi et al, 2016; Lardenoije et al, 2019; Lunnon et al, 2014; Madrid et al, 2018)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
