Higher Intron Retention Levels in Female Alzheimer's Brains May Be Linked to Disease Prevalence

Multimodal study of Alzheimer's disease (AD) dorsolateral prefrontal cortex (DLPFC) showed AD-related aberrant intron retention (IR) and proteomic changes not observed at the RNA level. However, the role of sex and how IR may impact the proteome are unclear. Analysis of DLPFC transcriptome showed a clear sex-biased pattern where female AD had 1645 elevated IR events compared to 80 in male AD DLPFC. Increased IR is correlated with lower mRNA levels, suggestive of nonsense-mediated mRNA decay. Two hundred thirty-three mRNAs with elevated IR in females were curated AD genes enriched for ubiquitin-like protein ligase and Tau protein binding. Increased IR genes in combined sex and female AD cohorts showed significant changes in their protein expression patterns with 11%-24% of them differential expressed proteins (DEP), alluding to the regulation of AD proteome by IR independent of RNA level. Upregulated DEPs in male AD were linked to RNA splicing that may prevent aberrant IR, whereas in female AD, they overlapped significantly more with the MAPK/metabolism module associated with cognitive decline. IR genes appeared to be significantly downregulated in specific female AD inhibitory and excitatory neurons compared to control. Differentially retained introns in female AD have elevated H3K27ac marks, strong CTCF binding at their flanking exons, and enriched for PABPC1 motif. Given that H3K27ac is repressive over gene bodies in aged brain and CTCF impedes transcription elongation, their binding patterns can delay co-transcriptional recruitment of spliceosome to cause IR, which may in turn contribute to different trajectories of AD pathology in women.