Table 1.

Overview of studies illustrating epigenetic signatures of apolipoprotein E gene (APOE) in aging and Alzheimer’s disease (AD).

APOE Exons, Promoter, and CGI
Study	Study Design	Sample Size	Age or Mean Age at Death (Years)	Principal Findings
Foraker et al., 2015 [40]	Cross-sectional	AD: 15 Controls: 10	AD: 82.7 ± 9.3 Controls: 84.9 ± 8.9	In the cerebellum there was the highest levels of methylation (marginal mean = 93%), with lower levels in the hippocampus (marginal mean = 85%), and the lowest levels in the frontal lobe (marginal mean = 77%) of AD brain compared to controls. There was a complex interaction among the presence of the APOE ε4 allele, AD status, and DNA methylation levels in the APOE CpG islands. AD-specific methylation differences were mainly attributed to the ε3/ε4 heterozygous subjects
Lambert et al., 1997 [60]	Cross-sectional	Frontal lobe ε3ε4, ε2ε4, ε2ε3 AD cases: 14 Controls: 12	AD: 74.1 ± 11.8 (five male and nine female) controls: 83.0 ± 10.6	In heterozygotes AD, APOE ε4 mRNA expression is increased in patients with AD compared with healthy controls: genetic variability in the neural expression at the APOE locus contributes to AD risk. APOE ε3ε4 heterozygote subjects (high ε4 expressors and/or low ε3 expressors) were more likely to develop AD than subjects with high ε3 expressors and/or low ε4 expressors
Lee et al., 2020 [69]	Cross-sectional	Frontal lobe AD: 44 Controls: 21 Cerebellum AD: 51 Controls: 25	Frontal lobe AD: 86.8 ± 6.9 Controls: 87.9 ± 8.6 Cerebellum AD: 74.6 ± 9.3 Controls: 73.5 ± 10.9	APOE has a single CpG island overlapping with its 3′-exon. APOE circular RNA and full-length mRNA each constitute one third of the total APOE RNA, with truncated mRNAs likely constituting some of the missing fraction. All APOE RNA species had significantly higher expression in AD frontal lobe than in controls, suggesting a possible modified mechanism of gene action for APOE in AD involving also an epigenetically regulated transcriptional program driven by DNA methylation in the APOE CpG island
Yu et al., 2013 [73]	Cross-sectional	Frontal lobe AD: 9 Controls: 6	AD: 86.8 ± 6.9 Controls: 87.9 ± 8.6	APOE 3′-exon CpG island exhibited transcriptional enhancer/silencer activity, modulating expression of genes at the APOE locus in a cell type-, DNA methylation- and ε2/ε3/ε4 allele-specific manner. These results suggested a novel functional role for a 3′-exon CpG island involving the protein isoforms and also an epigenetically regulated transcriptional program
Ma et al., 2015 [76]	Cross-sectional	475 men and 518 women	18–87	The 13 APOE CpG sites were categorized into three groups: Group 1 exhibited hypermethylation (>50%, in the promoter region), Group 2 showed hypomethylation (<50%, in the first two exons and introns), and Group 3 exhibited hypermethylation (>50%, in the exon 4). APOE methylation was significantly associated to age and plasma total cholesterol. APOE methylation patterns differed across APOE ε variants and the promoter variant rs405509, which further had a significant interaction with age
Wang et al., 2008 [77]	Cross-sectional	Prefrontal cortex AD: 24 Matched controls: 10 Blood samples AD: 6 Matched controls: 6	AD: 80.9 ± 9.3 matched controls: 80.0 ± 9.8 Blood samples AD: 81 ± 4.5 matched controls: 80.0 ± 5.2	In the AD brain samples, a notably age-specific epigenetic drift was identified, suggesting a role of epigenetic effects in the AD development. APOE gene is of bimodal structure, with a hypomethylated CpG-poor promoter and a fully methylated 39-CpG-island, containing the sequences for the ε4-haplotype

CpG: 5′-C-phosphate-G-3′; CpG: cytosine-phosphate-guanine.