Global glycoproteomic analysis reveals specific glycation and glycosylation events associated with cognitive decline in older adults with type 2 diabetes

Abstract INTRODUCTION: Molecular mechanisms underlying the well-known association between Type 2 diabetes (T2D) and late-life cognitive impairment are unknown. Alterations in glyco post-translational modifications (PTM) of serum proteins reflect altered cellular physiology and are associated with T2D and impaired cognition. This novel large-scale mass spectrometry based glycoproteomics study aimed to identify therapeutic PTM targets that may link T2D with poor cognition. METHODS: We performed LC-MS/MS–based novel glycoproteomic profiling of sera samples from 23 cognitively normal older adults with T2D. At baseline all people had normal cognition, but during 36-months, 8 participants developed cognitive impairment while 15 maintained normal cognition RESULTS: We identified and quantified a total of 1,866 unique glycoproteoforms (i.e., peptides with a post-transcription sugar modification) that matched 201 annotated proteins. Group differences were observed for 72 glycoproteoforms at baseline. At the time of cognitive testing three years later, there were group differences for 137 glycoproteoforms. Group differences were observed for 14 glycoproteoforms both at baseline and at 3-year follow-up. DISCUSSION: Glycoproteoforms may contribute to cognitive impairment in T2D, may identify adults with T2D at risk for cognitive impairment and are high value therapeutic targets for new therapies to mitigate the negative cognitive effects of T2D in old age.