Epigenome‐wide association study of Aβ42/Aβ40 in a sample of U.S. middle‐aged twins.

Background: DNA methylation may affect expression of genes that promote the accumulation of amyloid‐β (Aβ). Although prior studies suggest that DNA methylation correlates with Aβ in older adults (Levine et al. (2018). An epigenetic biomarker of aging for lifespan and healthspan. Aging, 10(4), 573.), Aβ begins to accumulate earlier than when clinical symptoms associated with Aβ are evident. The purpose of the current study is to present novel results on whether differentially methylated CpG sites (i.e., regions of DNA where methylation occurs) correlate with higher Aβ42/Aβ40 ratios across a sample of middle‐aged individuals. Method: Data from 193 individual twins from the Louisville Twin Study were used in the current analysis. Genomic DNA was extracted from venipuncture blood samples, and bisulfite‐converted DNA samples were assessed with the Illumina Infinium EpicArray BeadChip. Quality control and analyses were performed in R using the minfi package, and gene ontology analyses were performed using the MissMethyl package. Aβ42/Aβ40 was estimated using a capture sandwich immunoassay methodology that measures AD biomarkers in whole‐blood plasma. Differential DNA methylation was estimated using multivariable linear regression with an empirical Bayes estimator. Result: Estimation of differential DNA methylation was adequate (λ = 1.38), although some Type I inflation of p‐values was observed among CpG sites with higher p‐values. Although no CpG sites reached genome‐wide statistical significance, the top four CpG sites suggested differential methylation ranging between 2.8–4.8% per unit increase in the ratio of Aβ42/Aβ40. The top gene sets associated with differential methylation were response to glucocorticoids, response to corticosteroids, and response to Aβ. Conclusion: Despite no statistically significant CpG probes identified, likely due to the small sample size, the findings from the gene ontology analysis suggest that identification of epigenetic biomarkers may clarify the biological pathways through which the epigenome may regulate expression of Aβ proteins. As data collection is ongoing, we expect detected of genome‐wide significant probes with larger sample sizes. [ABSTRACT FROM AUTHOR]