Amyloid‐beta immunotherapy induces novel methylomic changes in Alzheimer’s disease brain

Abstract

AbstractBackgroundPost‐mortem neuropathological examinations following the first active immunotherapy strategy (AN‐1792, Elan Pharmaceuticals, 2000) for Alzheimer’s disease (AD) have evidenced amyloid‐β (Aβ) plaque clearance and increased microglial phagocytic activity in immunised individuals. This study characterises the epigenetic profiles of individuals who underwent Aβ immunotherapy with the aim of discovering novel therapeutic targets and biomarkers.MethodDNA was isolated from post‐mortem prefrontal cortex tissue of 16 immunised AD cases who received varying doses (ug) and number of doses during the trial period, including placebos. DNA methylation was quantified using methylation arrays and the raw intensity values processed and normalised for subsequent statistical analysis to identify differentially methylated positions (DMPs) across the genome associated with Aβ immunotherapy. Additional analyses included regions of enrichment analysis for identification of differentially methylated regions (DMRs) and weighted gene co‐expression network analysis to identify gene clusters with highly correlated methylation levels.ResultAfter correcting for known (age, sex, cell type composition) and unknown variables, a DMP located within Chromosome 19 Open Reading Frame 12 (C19Orf12) at the genome‐wide significance level (P < 9.00E−08) was associated with Aβ immunisation. 10 DMRs were further associated with immunisation, with three regions consisting of ≥ 3 CpG sites and having a Sidak‐corrected P < 0.05. These regions were located within the CRISP2 (chr6; 49681178:49681391 [8 probes], Sidak‐corrected P = 8.29E‐05), CTTNA1 (chr5; 138210906:138211184 [8 probes], Sidak‐corrected P = 5.96E‐06), and RNF39 (chr6; 30038859:30039025 [12 probes], Sidak‐Corrected P = 2.60E‐05) genes.ConclusionIndicating better inflammatory markers can help inform of effective preventative care strategies for elders. This study provides evidence for altered epigenetic processes in the pathophysiology of AD and identifies novel processes specific to Aβ immunotherapy. The next step for this project includes analysing RNA sequencing data, to determine if observed methylomic changes correlate with gene expression, and genotyping array data.