Centre for Genomic & Experimental Medicine
Centre for Genomic & Experimental Medicine

Methylation differences in Alzheimer’s disease associated variants

Research from Dr Kathy Evans’ group (first author Dr Rosie Walker) identifies epigenetic differences between carriers of the APOE ε4 and APOE ε2 alleles, variants associated with an increased and decreased risk of Alzheimer’s disease, respectively. Jan 21.

Circular plot indicating the locations of APOE ε4 vs. ε2 carrier-associated DMP and DMR CpGs.
Circular plot indicating the locations of APOE ε4 vs. ε2 carrier-associated differentially methylated position (DMP) and differentially methylated region (DMR) CpGs. The first track shows a chromosome ideogram (hg19/GRCh37). The genomic locations of CpGs identified as being DMPs or in DMRs identified in APOE ε4 vs. ε2 carriers are indicated by blue lines on the second track and the methylation quantitative trait loci (meQTLs) associated with these CpGs are indicated by the red lines on the third track. The connections between CpGs and meQTLs indicate regulatory relationships (cis interactions in red; trans interactions in blue).

Variation in the DNA sequence of the Apolipoprotein E gene (APOE) is the strongest genetic risk factor for Alzheimer’s disease, the most common form of dementia.

Two APOE variants have been shown to be oppositely associated with risk of developing Alzheimer’s disease. One, known as APOE ε4, increases risk for Alzheimer’s disease up to 12-fold compared to the most frequently occurring genotype, ε3/ε3; whilst another, APOE ε2, decreases risk by up to 50% compared to the ε3/ε3 genotype.

The three APOE alleles (ε2/ε3/ε4) each encode a distinct isoform of the ApoE protein. The distinct isoforms display different behaviours in several functions that are affected in Alzheimer’s disease, including lipid metabolism, tau phosphorylation, and inflammation.  Identifying which of these altered functions represents the mechanistic link between genetic variation and disease risk remains an ongoing endeavour.

In the study, recently published in the journal Genome Medicine, Dr Evans’ team compared DNA methylation between carriers of the ε2 and the ε4 variants of the APOE gene. Differences in DNA methylation levels have previously been found in people with Alzheimer’s disease and are known to associate with risk factors including ageing and obesity.

Epigenome-wide methylation profiles ascertained using blood samples from over 3500 participants in the Generation Scotland: Scottish Family Health Study who do not have dementia allowed the team to identify differences that are associated with risk of developing the condition, rather than differences that occur in response to being ill. Identifying biological changes associated with risk is likely to help guide the development of treatments aimed at preventing the earliest stages of the disorder.

Carriers of the high- and the low-risk version of the APOE gene show differences in DNA methylation across several genes involved in lipid metabolism. In some cases, these appeared to be partially due to differences in levels of high density lipoprotein cholesterol circulating in the participants’ blood. In conclusion, the effects of widespread differences in DNA methylation, including links with lipid metabolism, should be taken into account when assessing the mechanism by which genetic variation in APOE confers risk for Alzheimer’s disease.


In future studies we will seek to explore whether these differences play a role in conferring risk for Alzheimer’s disease and whether they might, therefore, guide the development of either drug or lifestyle interventions to reduce risk for the condition.

Dr Rosie Walker, First Author


Publication in Genome Medicine https://doi.org/10.1186/s13073-020-00808-4

Dr Kathy Evans Research Group website