Summary Changes in protein N-glycosylation are a hallmark of Alzheimer’s disease (AD), but the molecular mechanisms for alterations in protein N-glycosylation are unknown. Mannosidases are key enzymes in protein N-glycosylation that participate in glycan processing in the Golgi. Only two pre-mRNAs involved in protein N-glycosylation form abundant circular RNAs (circRNAs): MAN2A1 and MAN1A2. CircMAN2A1 expression correlates with Alzheimer’s disease, whereas circMAN1A2 remains constant. We found that circMAN2A1 is translated after it undergoes adenosine to inosine RNA editing, catalyzed by ADAR1-p150 (adenosine deaminase acting on RNA). During AD progression, the overall RNA editing of circRNA increases, suggesting that circRNA-encoded proteins will be more and more translated. Due to their generation through backsplicing, circMAN2A1 encoded proteins lack the endoplasmic signal sequence and are cytosolic. Two of the three circMAN2A1 encoded proteins contain the catalytic active site and could be active. Transfection studies followed by lectin blots showed that circMAN2A1-encoded proteins change protein N-glycosylation. We hypothesize that the expression of circMAN2A1-encoded proteins correlates with AD progression and alters protein N-glycosylation. Similarly, the increase in circRNA editing will increase circMAN1A2-encoded protein expression. The hypothesis will be tested in two specific Aims, where in Aim#1, we characterize the expression of circMAN2A1 and circMAN1A2 in brain during AD development using immunohistochemistry, Western blot and RNAseq on tissue from AD subjects, test their suitability as biomarkers and determine their intracellular localization. In Aim#2, we will determine the influence of circMAN2A1 and circMAN1A2-encoded proteins on glycan formation, using in vitro assays and cell transfections followed by glycan analysis. The work is highly innovative, using the first antisera against circRNA-encoded proteins and investigates for the first time the role of an endogenous circRNA-encoded protein. It is significant, as it addresses protein N- glycosylation as a key pathological feature for AD, for which no molecular mechanisms are known so far.