Integrated machine learning-based RNA sequencing and single-cell analysis reveal RNA methylation regulation patterns in the immune microenvironment of Alzheimer's disease.

Alzheimer’s disease (AD), which is the primary cause of dementia, is rapidly becoming one of the most costly and fatal neurological conditions (Scheltens et al., 2021). In the past few decades, there have been noteworthy developments in pharmacotherapy for AD, including the development of cholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor blockers, antidepressant drugs, and antipsychotic treatments (Briggs et al., 2016; Passeri et al., 2022). However, in practice, pharmacological treatments are not universally efficacious, which is mainly attributed to the heterogeneity of AD. Studies have shown that the heterogeneity of AD is usually manifested by distinct molecular characteristics (Kaszniak, 1988; Lambon Ralph et al., 2003; Canevelli et al., 2013). Research has established a significant connection between AD variability and the success rate of clinical treatments. Nevertheless, the molecular attributes contributing to this diversity in AD remain poorly defined. RNA methylation is pivotal in modulating several cellular processes, including RNA export from the nucleus, translation, transcript splicing, and processing of non-coding RNA sequences (Han et al., 2023; Wang et al., 2023). The most widely studied methylation modification patterns are N6-methyladenosine, 5-methylcytosine, and N1-methyladenosine (Shi et al., 2020). One study reported that N6-methyladenosine- and N1-methyladenosine-mediated gene expression levels are closely linked to AD progression (Han et al., 2020). Additionally, a recent study has revealed differences in the expression levels of 5-methylcytosine RNA methylation modifiers, specifically nucleolar protein 2 (NOP2)/Sun RNA methyltransferase 6 (NSUN6) and NOP2/Sun RNA methyltransferase 7 (NSUN7), between individuals with AD and healthy controls (PerezGrovas-Saltijeral et al., 2023). These discoveries suggest that RNA methylation is a possible target for AD treatment. Nevertheless, the role and detailed mechanisms of RNA in AD pathology are largely undefined, and thus require in-depth investigation. Long non-coding RNAs (lncRNAs) are transcripts that are over 200 nucleotides long and do not encode proteins. Acknowledged for their crucial involvement in biological processes such as cell division, differentiation, and energy metabolism, these RNA molecules are additionally linked to the onset of various diseases (Li et al., 2021; Nemeth et al., 2024). lncRNAs are associated with AD and are instrumental in modulating the expression of genes associated with the condition (Idda et al., 2018; Wu and Kuo, 2020; Chen et al., 2021; Lauretti et al., 2021). Consequently, lncRNAs may function as indicators for AD progression and are potentially feasible targets for therapeutic intervention. Currently, no evidence illustrates a connection between RNA methylation–associated lncRNAs and AD.