Rewired m6A methylation of promoter antisense RNAs in Alzheimer’s disease regulates global gene transcription in the 3D nucleome

N ⁶ -methyladenosine (m6A) is the most prevalent internal RNA modification that can impact mRNA expression post-transcriptionally. Recent progress indicates that m6A also acts on nuclear or chromatin-associated RNAs to impact transcriptional and epigenetic processes. However, the landscapes and functional roles of m6A in human brains and neurodegenerative diseases, including Alzheimer’s disease (AD), have been under-explored. Here, we examined RNA m6A methylome using total RNA-seq and meRIP-seq in middle frontal cortex tissues of post-mortem human brains from individuals with AD and age-matched counterparts. Our results revealed AD-associated alteration of m6A methylation on both mRNAs and various noncoding RNAs. Notably, a series of p romoter a ntisense RNAs (paRNAs) displayed cell-type-specific expression and changes in AD, including one produced adjacent to the MAPT locus that encodes the Tau protein. We found that MAPT-paRNA is enriched in neurons, and m6A positively controls its expression. In iPSC-derived human excitatory neurons, MAPT-paRNA promotes expression of hundreds of genes related to neuronal and synaptic functions, including a key AD resilience gene MEF2C , and plays a neuroprotective role against excitotoxicity. By examining RNA-DNA interactome in the three-dimensional (3D) nuclei of human brains, we demonstrated that brain paRNAs can interact with both cis - and trans -chromosomal target genes to impact their transcription. These data together reveal previously unexplored landscapes and functions of noncoding RNAs and m6A methylome in brain gene regulation, neuronal survival and AD pathogenesis.