Anxiety and Age, but Not OCD Diagnosis, Predict Infection-Preventive Behaviours in Adolescents During COVID-19.

Alzheimer’s disease (AD) is a debilitating neuro-degenerative disorder characterized by progressive cognitive decline. As a multifactorial disease, AD involves complex pathogenic mechanisms. The primary pathological hallmarks of AD include the deposition of β-amyloid (Aβ) plaques, the accumulation of tau neurofibrillary tangles, and widespread neuronal loss []. These pathological alterations lead to synaptic dysfunction and the disruption of neurochemical processes essential for memory formation and cognitive function [, ]. Accumulating evidence suggests that dysregulation of DNA methylation contributes to AD pathogenesis []. DNA methylation refers to the covalent transfer of a methyl group from S-adenyl methionine (SAM) to the C5 position of a cytosine residue to form 5-methylcytosine (5-mC), which occurs predominantly on cytosines in CpG dinucleotides [, ]. DNA methylation modulates the expression of genes that are essential for cognitive functions [-]. Global and gene-specific DNA methylation changes have been widely reported in AD brains [-]. In the hippocampus, Chouliaras et al. reported that 5-mC and 5-hydroxymethylcytosine (5-hmC) immunoreactivity decreased by roughly 20% in AD patients compared to age-matched controls []. Similarly, Mastroeni et al. reported that the entorhinal cortex shows more than 2-fold reduction in 5-mC-positive neurons in AD, along with diminished 5-mC staining in microglia and astrocytes []. Using a high-throughput array method, Humphries et al. found that genomic CpGs in the temporal pole showed overall hypomethylation in late-onset AD patients compared to controls []. Phipps et al. found that nuclear 5-mC and 5-hmC levels are unchanged in pyramidal neurons and interneurons in the inferior temporal gyrus of late-stage AD patients, though extranuclear 5-mC decreases in pyramidal neurons []. Astrocytes in this region show reduced nuclear 5-mC and 5-hmC, correlating with amyloid plaque and neurofibrillary tangle burden []. Conversely, using the dot-blot method, Bradley-Whitman et al. found that 5-mC and 5-hmC levels in the hippocampus and parahippocampal gyrus were increased in both late-stage AD patients and cognitively normal people with AD histopathology compared to cognitively normal people without AD histopathology []. Lashley et al. observed no discernable difference in 5-mC and 5-hmC immunoreactivity in the entorhinal cortex between AD patients and controls []. In summary, while many studies reported decreased global DNA methylation in AD brains, others documented either increased or unchanged levels. These apparent discrepancies can be explained by locus-specific methylation changes across the genome, where distinct CpG sites may become either hypermethylated or hypomethylated [-]. Such locus specific variations could produce divergent global methylation patterns depending on the brain regions and cell types analyzed. Importantly, despite reported variabilities, the collective evidence strongly implicates DNA methylation dysregulation as a consistent feature of AD neuropathology. DNA methyltransferases (DNMTs) regulate DNA methylation, with DNMT1 maintaining methylation patterns during replication and in postmitotic cells [], while DNMT3a and DNMT3b catalyze methylation, exhibiting distinct genomic targeting preferences []. Active DNA demethylation is mediated by the Ten-eleven translocation (TET) enzymes, which oxidize 5-mC to initiate demethylation []. Methyl-binding domain (MBD) proteins interpret DNA methylation signals to modulate gene transcription []. The dynamic interplay between DNMTs, TETs, and MBDs in regulating methylation-demethylation cycles and gene expression remains an active area of investigation. As discussed above, dysregulated DNA methylation is implicated in the pathogenesis of AD. A DNMT3a single nucleotide polymorphism (SNP) that potentially leads to an alternative splice variant was shown to be associated with cognitive decline in mild cognitive impairment patients []. Two transcription regulating SNPs in the DNMT3b gene were found to be associated with AD []. Similarly, TET1 loss-of-function genetic variants are associated with early-onset AD [], and heterozygous knockout of TET1 in 5xFAD mice worsened fear-conditioning memory and Aβ deposition []. These findings collectively demonstrate that dysregulations in DNA methylation writers (DNMTs) and erasers (TETs) contribute to AD pathogenesis.