DNA methylation of TOMM40-APOE-APOC2 in Alzheimer’s disease

Abstract

The apolipoprotein E (APOE) ε4 allele is the major genetic risk factor for Alzheimer's disease (AD). Multiple regulatory elements, spanning the extended TOMM40-APOE-APOC2 region, regulate gene expression at this locus. Regulatory element DNA methylation changes occur under different environmental conditions, such as disease. Our group and others have described an APOE CpG island as hypomethylated in AD, compared to cognitively normal controls. However, little is known about methylation of the larger TOMM40-APOE-APOC2 region. The hypothesis of this investigation was that regulatory element methylation levels of the larger TOMM40-APOE-APOC2 region are associated with AD. The aim was to determine whether DNA methylation of the TOMM40-APOE-APOC2 region differs in AD compared to cognitively normal controls in post-mortem brain and peripheral blood. DNA was extracted from human brain (n = 12) and peripheral blood (n = 67). A methylation array was used for this analysis. Percent methylation within the TOMM40-APOE-APOC2 region was evaluated for differences according to tissue type, disease state, AD-related biomarkers, and gene expression. Results from this exploratory analysis suggest that regulatory element methylation levels within the larger TOMM40-APOE-APOC2 gene region correlate with AD-related biomarkers and TOMM40 or APOE gene expression in AD.

DNA methylation in the APOE gene: its link with Alzheimer’s and cardiovascular health

“…After correcting for multiple testing, there was evidence for an association between APOE carrier-status and DNA methylation at five CpGs in the fully-adjusted models: cg14123992 (η 2 =0.003, p=3.9x10 -4 ), cg04406254 (η 2 =0.004 p=4.0x10 -6 ), cg06750524 (η 2 =0.022, p=8.6x10 - 16 ), cg16471933 (η 2 = 0.014, p=2.4x10 -16 ), and cg21879725 (η 2 =0.003, p=1.3x10 -4 ) (Figure 2, Supp. Table 2).…”

“…Twelve CpGs exhibited similar methylation levels to those previously described (Supp . Table 1; [15,16,22]), whereas one of them (cg20051876, which is unique to the Illumine EPIC array) had not been reported before. Based on the Illumina-annotated locations of the CpGs on the chromosome, their relative distances to each other, and their methylation levels, the CpGs were classified into three groups: hypermethylated (each site > 50% mean methylation) and lying in the promoter region (region 1: cg20051876, cg14123992, cg04406254), hypomethylated (each site < 50% mean methylation) and lying in the region encompassing the first two exons and introns (region 2: cg26190885, cg12049787, cg08955609, cg18768621, cg19514613, cg06750524), and hypermethylated and lying in the 4 th exon (region 3: cg16471933, cg05501958, cg18799241, cg21879725).…”

“…This might be due to a lack of appreciable changes in APOE methylation before the onset of symptoms of AD. Most previous studies that linked differential APOE methylation with AD were conducted on tissue from patients that had either been screened positive for cognitive dysfunction [15], or diagnosed with AD [14,16,17]; only one study [19] evaluated the relationship between DNA methylation and cognition in healthy participants. The epigenetic changes in APOE accompanying AD-related cognitive decline could result from the pathophysiology of the disorder or from adaptive responses of the organism as a result of AD, neither of which may be present at appreciable levels in the population studied here.…”

“…Indeed, it has been reported that patients with AD and healthy controls can be distinguished based on gene-expression patterns in blood [37]. However, the APOE gene is differently expressed between brain tissue and blood [16,17] and APOE CpGs exhibit relatively modest correlations between blood-and brain methylation [33,34,35]. Thus, blood-methylation may exhibit AD- 14 associated changes that are distinct from methylation changes in the brain or they might appear later in the course of the disorder.…”

“…gene is associated with dementia [14,15,16,17] with neuritic amyloid plaque burden [18], and with cognitive ability [19].…”