The APOE Gene is Differentially Methylated in Alzheimer’s Disease

Article type: Research Article

Authors: Foraker, Jessica^{a; c; *} | Millard, Steven P.^b | Leong, Lesley^a | Thomson, Zachary^a | Chen, Sunny^a | Keene, C. Dirk^d | Bekris, Lynn M.^e | Yu, Chang-En^{a; c}

Affiliations: [a] Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA | [b] Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA | [c] Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, USA | [d] Neuropathology Division, Department of Pathology, University of Washington, Seattle, WA, USA | [e] Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland Ohio, USA

Correspondence: [*] Correspondence to: Jessica Foraker, Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, 1660S Columbian Way, Box #358280, Seattle, WA 98108, USA. Tel.: +1 206 277 6200; jforaker@u.washington.edu

Abstract: The ɛ4 allele of the human apolipoprotein E gene (APOE) is a well-proven genetic risk factor for the late onset form of Alzheimer’s disease (AD). However, the biological mechanisms through which the ɛ4 allele contributes to disease pathophysiology are incompletely understood. The three common alleles of APOE, ɛ2, ɛ3 and ɛ4, are defined by two single nucleotide polymorphisms (SNPs) that reside in the coding region of exon 4, which overlaps with a well-defined CpG island (CGI). Both SNPs change not only the protein codon but also the quantity of CpG dinucleotides, primary sites for DNA methylation. Thus, we hypothesize that the presence of an ɛ4 allele changes the DNA methylation landscape of the APOE CGI and that such epigenetic alteration contributes to AD susceptibility. To explore the relationship between APOE genotype, AD risk, and DNA methylation of the APOE CGI, we applied bisulfite pyrosequencing and evaluated methylation profiles of postmortem brain from 15 AD and 10 control subjects. We observed a tissue-specific decrease in DNA methylation with AD and identified two AD-specific differentially methylated regions (DMRs), which were also associated with APOE genotype. We further demonstrated that one DMR was completely un-methylated in a sub-population of genomes, possibly due to a subset of brain cells carrying deviated APOE methylation profiles. These data suggest that the APOE CGI is differentially methylated in AD brain in a tissue- and APOE-genotype-specific manner. Such epigenetic alteration might contribute to neural cell dysfunction in AD brain.

Keywords: Alzheimer’s disease, apolipoprotein E, CGI, CpG island, DMR, DNA methylation, epigenetics, pyrosequencing

DOI: 10.3233/JAD-143060

Journal: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 745-755, 2015