The landscape of m6A regulators in multiple brain regions of Alzheimer's Disease

Abstract Alzheimer's disease is a neurodegenerative disease researched for many years, yet no effective curing methods are found. N6-methyladenosine (m6A) RNA methylation, an essential epitranscriptome regulation mechanism, has been discovered to affect several diseases and essential biological functions, such as brain cell development and aging, which are closely related to neurodegenerative diseases like AD. But the relationship between AD and m6A needs further investigation. Our work evaluated the alterations of m6A regulators and influences on the disease in 4 brain regions: postcentral gyrus, superior frontal gyrus, hippocampus, and entorhinal cortex. We found the expression levels of m6A regulators FTO, ELAVL1, and YTHDF2 were altered in disease samples and relative to pathology development and cognitive scores. We assessed the activation state of pathways and biological processes by the GSVA method, and pathways including N glycan metabolism, amino acid metabolism, and protein metabolism pathways were found to be affected by the m6A regulators. We also found different m6A modification patterns among different brain regions, mainly due to alterations of m6A readers. At last, we further evaluated the importance of those AD-related regulators based on the WCGNA method and discovered their potential targets, and constructed diagnose models in three of all four regions using key regulators including FTO, YTHDC1, YTHDC2 etc. and their potential target genes. This work might offer a reference for the follow-up study between m6A and Alzheimer's disease.