Blood N-glycomics reveals individuals at risk for cognitive decline and Alzheimer's disease.

BACKGROUND: Blood biomarkers with prognostic accuracy for Alzheimer's disease (AD) are crucial for selecting at-risk individuals for interventions. Altered protein N-glycosylation has been implicated in several pathogenic pathways in AD and could be an early AD biomarker. METHODS: We developed a mass spectrometry-based method to simultaneously quantify 62 blood N-glycan structures in individuals with biological or clinical AD and matched controls. We analysed N-glycan levels in a Swedish discovery cohort (n = 40) and validated our results in a Norwegian cohort (n = 60). Individuals were grouped according to N-glycan levels using unsupervised hierarchical clustering. Difference in disease progression between groups were modelled using linear mixed-effects models. FINDINGS: A subgroup of individuals exhibited low blood N-glycosylation (32.4% of Swedish cohort, 37.9% of Norwegian cohort). In the Swedish cohort, low N-glycosylation was associated with AD and cognitive decline. In the Norwegian cohort, low blood N-glycosylation showed no correlation with amyloid/tau, but importantly, strongly predicted future cognitive decline. In total, fourteen N-glycan structures were significantly less abundant in the low N-glycosylation group compared to the rest of the individuals in both cohorts. INTERPRETATION: Reduced blood N-glycan levels predict cognitive decline independent of amyloid or tau status. Blood N-glycome profiling could be used to identify individuals at risk for AD dementia. FUNDING: Stiftelsen för Gamla Tjänarinnor, Stockholm County Council-ALF, JPND, PMI-AD, Medical Diagnostics Karolinska, Helse-Nord, Gun och Bertil Stohnes stiftelse, Demensförbundet, Stiftelsen Dementia, Margaretha af Ugglas' foundation, Vinnova, the private initiative "Innovative ways to fight Alzheimer's disease-Leif Lundblad Family and others".