Human Brain and Blood N-Glycome Profiling in Alzheimer's Disease and Alzheimer's Disease-Related Dementias

Abstract

Glycosylation, the process of adding glycans (i.e., sugars) to proteins, is the most abundant post-translational modification. N-glycosylation is the most common form of glycosylation, and the N-glycan moieties play key roles in regulating protein functions and many other biological processes. Thus, identification and quantification of N-glycome (complete repertoire of all N-glycans in a sample) may provide new sources of biomarkers and shed light on health and disease. To date, little is known about the role of altered N-glycome in Alzheimer's Disease and Alzheimer's Disease-related Dementias (AD/ADRD). The current study included 45 older adults who had no cognitive impairment (NCI) at baseline, followed and examined annually, and underwent brain autopsy after death. During about 12-year follow-up, 15 developed mild cognitive impairment (MCI), 15 developed AD, and 15 remained NCI. Relative abundances of N-glycans in serum at 2 time points (baseline and proximate to death, ∼12.3 years apart) and postmortem brain tissue (dorsolateral prefrontal cortex) were quantified using MALDI-TOF-MS. Regression models were used to test the associations of N-glycans with AD/ADRD phenotypes. We detected 71 serum and 141 brain N-glycans, of which 46 were in common. Most serum N-glycans had mean fold changes less than one between baseline and proximate to death. The cross-tissue N-glycan correlations were weak. Baseline serum N-glycans were more strongly associated with AD/ADRD compared to change in serum N-glycans over time and brain N-glycans. The N-glycan associations were observed in both AD and non-AD neuropathologies. To our knowledge, this is the first comprehensive glycomic analysis in both blood and brain in relation to AD pathology. Our results suggest that altered N-glycans may serve as mechanistic biomarkers for early diagnosis and progression of AD/ADRD.

Keywords: AD/ADRD; N-glycans; cognition; glycosylation; neuropathologies.

FIGURE 1

Illustrates the correlations of individual sera N-glycans at baseline and separately proximate to death. (A) Is the histograms of pairwise correlations for sera N-glycans at baseline (blue) and proximate to death (red). (B,C) Are the heatmaps that further visualize the correlation patterns of sera N-glycan at baseline and proximate to death.

FIGURE 2

Illustrates the level difference of sera N-glycans between baseline and proximate to death. Individual N-glycans are shown as m/z ratios on the x-axis. Horizontal dotted lines represent ± onefold change. Sera N-glycans that passed these thresholds are highlighted in red.

FIGURE 3

Illustrates the associations of baseline sera N-glycans (A) and level difference of sera N-glycan (B) with AD/ADRD. Individual N-glycans are shown as m/z ratios on the x-axis. Clinical and neuropathologic AD/ADRD outcomes are shown on the y-axis. Associations with nominal statistical significance are highlighted (in red if the direction of association is positive and in blue if the direction of association is negative).

FIGURE 4

Illustrates the associations of cortical N-glycans with β-amyloid load (A) and PHFtau tangles density (B). Individual N-glycans are shown as m/z ratios on the x-axis. Statistical significance, represented by –log10 of the p-value, is shown on the y-axis. The horizontal dotted line represent the nominal significance level of α = 0.05. Red indicates a positive direction of association and light blue indicates a negative direction of association.