**7. Gender differences**

**6.1. Histone modifications**

230 Update on Dementia

**6.2. DNA methylation/demethylation**

disease severity and clinical progression [122].

production [105].

(PP2A) [102, 103, 124].

neurons and aging AD brains [105].

**6.3. miRNAs regulation in AD**

A few recent studies reported histone modifications in AD [105, 109, 110]. For example, histone acetylation such as H4 acetylation was decreased in APP/PS1 transgenic mice, which might be involved in cognitive deficits [109, 111, 112]. Another study reported increased H3 and H4 acetylation in the 3xTg-AD mouse model compared to wild-type mice [113]. Levels of phosphorylated histone proteins such as HDAC6 and H3S10 were found to be increased in AD brain regions and neurons [114, 115]. Finally, levels of methylation, acetylation, and phosphorylation of histone H3 were showed to be elevated in AD individual cortex [116].

Genes containing CpG islands are methylated in their promoter regions. Differences in methylation have been reported in APP, BACE, PS1, and APOE genes [105, 107]. For example, one study showed that methylation in APP promoter region was decreased in the brains of old AD patients compared to young [117]. Evidence suggests that hypo-methylated promoter region of APP gene was correlated with an increased Aβ production [118], which resulted in an increase of the genome-wide hypo-methylation, leading to upregulation of neuro-inflam‐ mation and apoptosis genes, subsequently applying a positive feedback control on Aβ

The changes in DNA methylation at PSEN1 and APOE promoter regions are variable based on results from different studies. PSEN1 promoter may be up- or downregulated by DNA methylation in AD [119, 120]. PSEN1 promoter hypo-methylation increased PSEN1 expression which resulted in an elevated Aβ production [121]. The APOE gene presents a duality in its structure; while its 5′-promoter CpG site is hypo-methylated, the 3′-CpG island is hypermethylated. Wang et al. suggested that aberrant epigenetic modifications in these CpG sites may contribute to LOAD [105, 118]. High levels of CLU (APOJ) gene, due to high methylation of CpG regions in the promoter of CLU, were observed in AD and might be associated with

Tau promoter region was also found to be affected by methylation changes during AD [117]. For example, Aβ25–35 induced demethylation and increased tau phosphorylation and NFTs formation [123], which may be resulted from hypo-methylation of protein phosphatase 2A

Recently, Sánchez-Mut et al. studied CpG 5′-region gene methylation patterns in different brain regions of AD mouse models and found hyper-methylation of three new target genes which could be involved in AD: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3), and spectrin β4 (SPTBN4) [125]. Finally, genes involved in cell cycle and apoptosis were found to be modulated by DNA methylation and upregulated in AD

MicroRNAs (miRNAs) are noncoding regulatory RNAs that are known to modulate ∼60% of genome via post-transcriptional gene silencing. The alterations in epigenetic modulations by Sex difference has a strong impact on AD risk. More than 60% of AD individuals are composed of postmenopausal women [76, 77]. Two decades ago, a study showed that APOE4 risk for AD was higher in women. Women expressing just one allele of APOE4 presented the same risk to develop AD as men with two APOE4 alleles [142]. This observation has been confirmed by other studies [142–145]. APOE4 women with a single allele had a fourfold increase in risks of having AD, similarly as men with two copies of APOE4 allele [143]. APOE4 homozygous women exhibited the greatest risk of developing AD and the shortest age of onset when compared to APOE2 or 3 carriers [142, 143, 145]. The gender effects on rate of cognitive decline were also reported in APOE4 female carriers compared to men. For example, APOE4 hetero‐ zygous women displayed a faster decline in cognitive deterioration than elderly heterozygous men [142]. Compared to men, APOE4 female carriers presented with a reduced neuronal network connectivity in the anterior cingulate cortex which is structurally connected to medial temporal lobe, showing reduced glucose metabolism [146]. Payami et al. showed that APOE4 female mild cognitive impairment (MCI) patients displayed higher levels of CSF tau/Aβ ratios and tau than male MCI carriers [143]. APOE4 female carriers suffering from mild AD were more prone to have high burden of Aβ plaques and NFT than AD male carriers [147].

Finally, estrogen receptor (ER) has been shown to regulate the risk of AD [80, 148]. Two ERs are involved in this regulation: ERα and β. While ERβ was found to downregulate APOE gene and protein expression, ERα acted on upregulation of APOE expression. Genetic polymor‐ phisms in both ER (rs4986938) and (rs2234693) have been associated with high risks of AD [148].
